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Chem 206
http://www.courses.fas.harvard.edu/~chem206/ http://evans.harvard.edu/problems/
The molecule illustrated below can react through either Path A or Path B to form salt 1 or salt 2. In both instances the carbonyl oxygen functions as the nucleophile in an intramolecular alkylation. What is the preferred reaction path for the transformation in question? O O Br N H O Br
Path B Path A 1
Br
N O H Br O
N O H Br
Br
This is a "thought" question posed to me by Prof. Duilo Arigoni at the ETH in Zuerich some years ago
El(+)
O P O B
+ (RO)3PEl
(1)
O P OMe O C
Rank the phosphites from the least to the most nucleophilic and provide a concise explanation for your predicted reactivity order.
D. A. Evans
Chem 206
Universal Effects Governing Chemical Reactions There are three: Steric Effects
Nonbonding interactions (Van der Waals repulsion) between substituents within a molecule or between reacting molecules
Me S N2 Me Nu C R RO H H Me Me2CuLi RO Me H H R
Geometrical constraints placed upon ground and transition states by orbital overlap considerations. Fukui Postulate for reactions:
"During the course of chemical reactions, the interaction of the highest filled (HOMO) and lowest unfilled (antibonding) molecular orbital (LUMO) in reacting species is very important to the stabilization of the transition structure."
Nu:
C R
Br
Br:
RO H
major
p. p.
minor
A + B A(:) + B(+)
Lewis Acid
A A
B B
Lewis Base
FMO concepts extend the donor-acceptor paradigm to non-obvious families of reactions Examples to consider
Me R C R Br
S N1
+
R R C Me + Br:
H2
2 Li(0) Mg(0)
2 LiH CH3MgBr
CH3I +
rate decreases as R becomes more electronegative "Organic chemists are generally unaware of the impact of electronic effects on the stereochemical outcome of reactions." "The distinction between electronic and stereoelectronic effects is not clear-cut."
1-02-Introduction-1
9/12/03 4:44 PM
D. A. Evans
Chem 206
OAc
SnBr4 Me SiMe3
O Me
Me
AlCl3
OAc
SnBr4 BnO
p. p.
BnO
O EtO2C O EtO2C (R)2CuLi Bu OTBS O OTBS diastereoselection 8:1 O Ph N O only diastereomer Bu OTBS OAc OAc O H Ph N O H N N N N O OAc OAc H H N R R O TBS Al R O Yakura et al Tetrahedron 2000, 56, 7715 O Ph 60-94% AcO AcO H H N O only diastereomer Ph
Bu3Al
R3 O Al O
EtO2C
EtO
Yakura's rationalization:
1-03-Introduction-1a
9/15/03 8:14 AM
D. A. Evans
Chem 206
Linear Combination of Atomic Orbitals (LCAO): Orbital Coefficients Rule Two: Each MO is constructed by taking a linear combination of the individual atomic orbitals (AO): Bonding MO Antibonding MO = C11 + C22 = C*11 C*22
Let's combine two hydrogen atoms to form the hydrogen molecule. Mathematically, linear combinations of the 2 atomic 1s states create two new orbitals, one is bonding, and one antibonding:
Rule one: A linear combination of n atomic states will create n MOs. (antibonding) E Energy H 1 p. p. E (bonding) 1s 1s H 2
The coefficients, C1 and C2, represent the contribution of each AO. Rule Three: (C1)2 + (C2)2 = 1
The squares of the C-values are a measure of the electron population in neighborhood of atoms in question Rule Four: bonding(C1)2 + antibonding(C*1)2= 1 In LCAO method, both wave functions must each contribute one net orbital Consider the pibond of a C=O function: In the ground state pi-CO is polarized toward Oxygen. Note (Rule 4) that the antibonding MO is polarized in the opposite direction.
Let's now add the two electrons to the new MO, one from each H atom:
(antibonding) E1
Energy
(antibonding)
H 1
1s E2
1s
H 2 Energy
(bonding)
(bonding)
D. A. Evans
Bonding Generalizations
Chem 206
Bond strengths (Bond dissociation energies) are composed of a covalent contribution ( Ecov) and an ionic contribution ( Eionic). Bond Energy (BDE) = Ecovalent + Eionic (Fleming, page 27)
When one compares bond strengths between CC and CX, where X is some other element such as O, N, F, Si, or S, keep in mind that covalent and ionic contributions vary independently. Hence, the mapping of trends is not a trivial exercise.
For Bonds:
Better than
This is a simple notion with very important consequences. It surfaces in the delocalized bonding which occurs in the competing anti (favored) syn (disfavored) E2 elimination reactions. Review this situation. An anti orientation of filled and unfilled orbitals leads to better overlap. This is a corrollary to the preceding generalization. There are two common situations.
For example, consider elements in Group IV, Carbon and Silicon. We know that C-C bonds are considerably stronger by Ca. 20 kcal mol-1 than C-Si bonds.
C C C CC CSi C
better than
Si
Si
X A
lone pair HOMO
C-SP3 CC
C-SP3
* CX LUMO
X Better than
lone pair HOMO
* CX LUMO
C-SP3 CSi
This trend is even more dramatic with pi-bonds: CC = 65 kcal/mol CSi = 36 kcal/mol SiSi = 23 kcal/mol Weak bonds will have corresponding low-lying antibonds.
Formation of a weak bond will lead to a corresponding low-lying antibonding orbital. Such structures are reactive as both nucleophiles & electrophiles A Y
Y
* CX LUMO
X C
Better than
X C
CY HOMO
* CX LUMO
D. A. Evans
Chem 206
Donor Acceptor Properties of C-C & C-O Bonds Consider the energy level diagrams for both bonding & antibonding orbitals for CC and CO bonds.
* C-C * C-O
Hierarchy of Donor & Acceptor States Following trends are made on the basis of comparing the bonding and antibonding states for the molecule CH3X where X = C, N, O, F, & H.
-bonding States: (CX)
CH3CH3 CH3H CH3NH2 CH3OH
C-SP
C-SP3 O-SP
3
very close!!
CH3F
poorest donor
p. p.
The greater electronegativity of oxygen lowers both the bonding & antibonding C-O states. Hence:
CC is a better donor orbital than CO CO is a better acceptor orbital than CC
For the latest views, please read Alabugin & Zeidan, JACS 2002, 124, 3175 (pdf)
CH3CH3 CH3NH2 CH3OH CH3F
best acceptor
C-SP3
C-SP3 C-SP2
The following are trends for the energy levels of nonbonding states of several common molecules. Trend was established by photoelectron spectroscopy.
Nonbonding States
CC
better donor
CC
The greater electronegativity of CSP2 lowers both the bonding & antibonding CC states. Hence: CSP3-CSP3 is a better donor orbital than CSP3-CSP2 CSP3-CSP2 is a better acceptor orbital than CSP3-CSP3
1-06-donor/acceptor states 9/12/03 5:16 PM
D. A. Evans
Hybridization vs Electronegativity
Chem 206
Electrons in 2S states "see" a greater effective nuclear charge than electrons in 2P states. This becomes apparent when the radial probability functions for S and P-states are examined: The radial probability functions for the hydrogen atom S & P states are shown below.
100 % 100 %
N
4.5
SP
Radial Probability
Pauling Electronegativity
Radial Probability
1 S Orbital
N N
3.5
SP3
SP2
C 3
SP
2 S Orbital
2 S Orbital 2 P Orbital
p. p.
3 S Orbital 3 P Orbital
2.5
SP2
SP3
20
25
30
35
40
45
50
55
% S-Character
CH (56)
S-states have greater radial penetration due to the nodal properties of the wave function. Electrons in S-states "see" a higher nuclear charge. Above observation correctly implies that the stability of nonbonding electron pairs is directly proportional to the % of S-character in the doubly occupied orbital
Least stable Most stable
Pka of Carbon Acid
55
50
45
C H (44)
6 6
40
CSP3
CSP2
CSP
35
PhCC-H (29)
30
The above trend indicates that the greater the % of S-character at a given atom, the greater the electronegativity of that atom.
1-07-electroneg/hybrization 9/12/03 4:49 PM
25 20 25 30 35 40 45 50 55
% S-Character
D. A. Evans
Chem 206
The interaction of a vicinal bonding orbital with a p-orbital is referred to as hyperconjugation. This is a traditional vehicle for using valence bond to denote charge delocalization.
R H H C
+
C
R+ H H H H C C H H
The graphic illustrates the fact that the C-R bonding electrons can "delocalize" to stabilize the electron deficient carbocationic center. Note that the general rules of drawing resonance structures still hold: the positions of all atoms must not be changed.
p. p.
1.431
[F5SbFSbF5]
+
C
100.6
1.608
Me
Me Me
+
C
H H
+
C
H H
1.528
CR
CR
110
Me Me Me
1.530
Take a linear combination of CR and CSP2 p-orbital: "The new occupied bonding orbital is lower in energy. When you stabilize the electrons is a system you stabilize the system itself."
1-08-Hyperconj (+)-1 9/12/03 4:53 PM
D. A. Evans
"Negative" Hyperconjugation
Syn Orientation
R
Chem 206
antibonding CR R: H H C X+ H H antibonding CR R: R X+ H H C filled hybrid orbital X
Delocalization of nonbonding electron pairs into vicinal antibonding orbitals is also possible R H H C
R C X
R H H H H
H X H H H
Anti Orientation
R
Since nonbonding electrons prefer hybrid orbitals rather that P orbitals, this orbital can adopt either a syn or anti relationship to the vicinal CR bond.
H H
H H
Nonbonding e pair
Spectroscopic Probe
X-ray crystallography X-ray crystallography Infrared Spectroscopy Infrared Spectroscopy NMR Spectroscopy NMR Spectroscopy
CR
As the antibonding CR orbital decreases in energy, the magnitude of this interaction will increase Note that CR is slightly destabilized
D. A. Evans
Chem 206
Now carry out the same analysis with the same 2 orbitals present in the trans isomer.
The interaction of filled orbitals with adjacent antibonding orbitals can have an ordering effect on the structure which will stabilize a particular geometry. Here are several examples: Case 1: N2F2 F N N This molecule can exist as either cis or trans isomers F F N N F There are two logical reasons why the trans isomer should be more stable than the cis isomer. The nonbonding lone pair orbitals in the cis isomer will be destabilizing due to electron-electron repulsion. The individual CF dipoles are mutually repulsive (pointing in same direction) in the cis isomer. In fact the cis isomer is favored by 3 kcal/ mol at 25 C. Let's look at the interaction with the lone pairs with the adjacent CF antibonding orbitals. The cis Isomer F
filled N-SP2 F antibonding NF NF (LUMO) filled N-SP2 (HOMO)
filled N-SP2
N F
NF (LUMO)
In this geometry the "small lobe" of the filled N-SP2 is required to overlap with the large lobe of the antibonding CF orbital. Hence, when the new MO's are generated the new bonding orbital is not as stabilizing as for the cis isomer.
Conclusions
Lone pair delocalization appears to override electron-electron and dipole-dipole repulsion in the stabilization of the cis isomer. This HOMO-LUMO delocalization is stronger in the cis isomer due to better orbital overlap. Important Take-home Lesson Orbital orientation is important for optimal orbital overlap.
Note that by taking a linear combination of the nonbonding and antibonding orbitals you generate a more stable bonding situation. Note that two such interactions occur in the molecule even though only one has been illustrated.
1-10- N2F2 9/12/03 4:59 PM
This is a simple notion with very important consequences. It surfaces in the delocalized bonding which occurs in the competing anti (favored) syn (disfavored) E2 elimination reactions. Review this situation.
D. A. Evans
Chem 206
The interaction of filled orbitals with adjacent antibonding orbitals can have an ordering effect on the structure which will stabilize a particular conformation. Here are several examples of such a phenomon called the gauche effect: Hydrazine
H N H N H H
anti
The closer in energy the HOMO and LUMO the better the resulting stabilization through delocalization. Hence, N-lone pair NH delocalization better than NH NH delocalization. Hence, hydrazine will adopt the gauche conformation where both N-lone pairs will be anti to an antibonding acceptor orbital. The trend observed for hydrazine holds for oxygen derivatives as well Hydrogen peroxide
H O O H anti
Hydrazine can exist in either gauche or anti conformations (relative to lone pairs).
H N H
H H
H N H H
gauche
There is a logical reason why the anti isomer should be more stable than the gauche isomer. The nonbonding lone pair orbitals in the gauche isomer should be destabilizing due to electron-electron repulsion. In fact, the gauche conformation is favored. Hence we have neglected an important stabilization feature in the structure. HOMO-LUMO Interactions Orbital overlap between filled (bonding) and antibonding states is best in the anti orientation. HOMO-LUMO delocalization is possible between: (a) N-lone pair NH; (b) NH NH
H filled N-SP3 (HOMO) N N NH (LUMO) NH (HOMO) H NH (LUMO) N N H NH (LUMO)
H2O2 can exist in either gauche or anti conformations (relative to hydrogens). The gauche conformer is prefered.
H O
O H
gauche H
Major stabilizing interaction is the delocalization of O-lone pairs into the CH antibonding orbitals (Figure A). Note that there are no such stabilizing interactions in the anti conformation while there are 2 in the gauche conformation. Figure A Figure B
OH (LUMO) (HOMO) filled O-SP3
Note that you achieve no net stabilization of the system by generating molecular orbitals from two filled states (Figure B). better stabilization
NH (HOMO)
Problem: Consider the structures XCH2OH where X = OCH3 and F. What is the most favorable conformation of each molecule? Illustrate the dihedral angle relationship along the CO bond.
D. A. Evans
Chem 206
http://www.courses.fas.harvard.edu/~chem206/
Kirby, A. J. (1982). The Anomeric Effect and Related Stereoelectronic Effects at Oxygen. New York, Springer Verlag. Box, V. G. S. (1990). The role of lone pair interactions in the chemistry of the monosaccharides. The anomeric effect. Heterocycles 31: 1157. Box, V. G. S. (1998). The anomeric effect of monosaccharides and their derivatives. Insights from the new QVBMM molecular mechanics force field. Heterocycles 48(11): 2389-2417. Graczyk, P. P. and M. Mikolajczyk (1994). Anomeric effect: origin and consequences. Top. Stereochem. 21: 159-349. Juaristi, E. and G. Cuevas (1992). Recent studies on the anomeric effect. Tetrahedron 48: 5019. Plavec, J., C. Thibaudeau, et al. (1996). How do the Energetics of the Stereoelectronic Gauche and Anomeric Effects Modulate the Conformation of Nucleos(t)ides? Pure Appl. Chem. 68: 2137-44. Thatcher, G. R. J., Ed. (1993). The Anomeric Effect and Associated Stereoelectronic Effects. Washington DC, American Chemical Society.
Stereoelectronic Effects-2
Anomeric and Related Effects Electrophilic & Nucleophilic Substitution Reactions The SN2 Reaction: Stereoelectronic Effects Olefin Epoxidation: Stereoelectronic Effects Baeyer-Villiger Reaction: Stereoelectronic Effects Hard & Soft Acid and Bases (Not to be covered in class)
Problem 121
http://evans.harvard.edu/problems/
Sulfonium ions A and B exhibit remarkable differences in both reactivity and product distribution when treated with nucleophiles such as cyanide ion (eq 1, 2). Please answer the questions posed in the spaces provided below. KCN
Et
+ PhCH2CN
(1)
D. A. Evans
MeCH2CN
(2)
D. A. Evans
The Anomeric Effect
Chem 206
It is not unexpected that the methoxyl substituent on a cyclohexane ring prefers to adopt the equatorial conformation. H OMe H
OMe Gc = +0.6 kcal/mol What is unexpected is that the closely related 2-methoxytetrahydropyran prefers the axial conformation: H O OMe Gp = 0.6 kcal/mol O H OMe
Since the antibonding CO orbital is a better acceptor orbital than the antibonding CH bond, the axial OMe conformer is better stabilized by this interaction which is worth ca. 1.2 kcal/mol. Other electronegative substituents such as Cl, SR etc also participate in anomeric stabilization. H 1.781 H O Cl H O O Cl 1.819 Cl
This conformer preferred by 1.8 kcal/mol Why is axial CCl bond longer ?
That effect which provides the stabilization of the axial OR conformer which overrides the inherent steric bias of the substituent is referred to as the anomeric effect. Let anomeric effect = A Gp = A = Gc + A Gp Gc
O Cl
H O HOMO
CCl
A = 0.6 kcal/mol 0.6 kcal/mol = 1.2 kcal/mol Principal HOMO-LUMO interaction from each conformation is illustrated below: H
There is also a rotational bias that is imposed on the exocyclic COR bond where one of the oxygen lone pairs prevers to be anti to the ring sigma CO bond H O O R O R favored R O O
OMe
H OMe
A. J. Kirby, The Anomeric and Related Stereoelectronic Effects at Oxygen, Springer-Verlag, 1983 E. Jurasti, G. Cuevas, The Anomeric Effect, CRC Press, 1995
D. A. Evans
Chem 206
Prediction: The IR CH stretching frequency for aldehydes is lower than the closely related olefin CH stretching frequency. For years this observation has gone unexplained. R R C H CH = 2730 cm CF3
-1
R C C R
Prediction: As X becomes more electronegative, the IR frequency should increase O Me CH3 Me O CBr3 Me O
O H
CH = 3050 cm -1
C=O (cm-1)
Sigma conjugation of the lone pair anti to the H will weaken the bond. This will result in a low frequency shift.
1720
1750
1780
Infrared evidence for lone pair delocalization into vicinal antibonding orbitals.
The NH stretching frequency of cis-methyl diazene is 200 cm-1 lower than the trans isomer. Me H N N Me
filled N-SP2 H antibonding NH
Prediction: As the indicated pi-bonding increases, the XCO bond angle should decrease. This distortion improves overlap.
R C X * CX O lone pair O
R C X O
NH = 2188 cm -1 Me N N H NH = 2317 cm -1
Me N
filled N-SP2
antibonding NH H
Evidence for this distortion has been obtained by X-ray crystallography Corey, Tetrahedron Lett. 1992, 33, 7103-7106
..
The low-frequency shift of the cis isomer is a result of NH bond weakening due to the anti lone pair on the adjacent (vicinal) nitrogen which is interacting with the NH antibonding orbital. Note that the orbital overlap is not nearly as good from the trans isomer. N. C. Craig & co-workers JACS 1979, 101, 2480.
D. A. Evans
Chem 206
Observation: CH bonds anti-periplanar to nitrogen lone pairs are spectroscopically distinct from their equatorial CH bond counterparts
H H H H
N H
Me3C G = 0.35kcal/mol
N HOMO CH
Spectroscopic Evidence for Conjugation Infrared Bohlmann Bands Characteristic bands in the IR between 2700 and 2800 cm-1 for C-H4, C-H6 , & C-H10 stretch Bohlmann, Ber. 1958 91 2157 Reviews: McKean, Chem Soc. Rev. 1978 7 399 L. J. Bellamy, D. W. Mayo, J. Phys. Chem. 1976 80 1271 NMR : Shielding of H antiperiplanar to N lone pair H10 (axial): shifted furthest upfield H6, H4: = Haxial - H equatorial = -0.93 ppm Protonation on nitrogen reduces to -0.5ppm H. P. Hamlow et. al., Tet. Lett. 1964 2553 J. B. Lambert et. al., JACS 1967 89 3761
2-03-Anomeric Effect-3 9/16/03 2:43 PM
Bn N Me
1.457
Me
1.453
N N Bn
1.459
D. A. Evans
Chem 206
1B
2B 1A Phosphate-1A p. p.
Thymine Adenine
Phosphate-1B
R
O
R
O
P
O
O O R
O O R
O R P O O R
Phosphate-2A Phosphate-2B
Gauche-Gauche conformation
O
R P
O
O O R
Oxygen lone pairs may establish a simultaneous hyperconjugative relationship with both acceptor orbitals only in the illustrated conformation.
Plavec, et al. (1996). How do the Energetics of the Stereoelectronic Gauche & Anomeric Effects Modulate the Conformation of Nucleos(t)ides? Pure Appl. Chem. 68: 2137-44.
D. A. Evans
Chem 206
Let us now focus on the oxygen lone pair in the hybrid orbital lying in the sigma framework of the C=O plane. * CO
O R R O
(E) Conformer
G = +4.8 kcal/mol
C R
In the (Z) conformation this lone pair is aligned to overlap with * CO.
The (E) conformation of both acids and esters is less stable by 3-5 kcal/mol. If this equilibrium were governed only by steric effects one would predict that the (E) conformation of formic acid would be more stable (H smaller than =O). Since this is not the case, there are electronic effects which must also be considered. These effects will be introduced shortly. Rotational Barriers: There is hindered rotation about the =COR bond. These resonance structures suggest hindered rotation about =COR bond. This is indeed observed:
O R O R' R O O R'
Energy
(E) Conformer
R R O C O
In the (E) conformation this lone pair is aligned to overlap with * CR.
* CR
O
R O C
barrier ~ 10-12 kcal/mol
O R O R O R
G ~ 2-3 kcal/mol
Since * CO is a better acceptor than * CR (where R is a carbon substituent) it follows that the (Z) conformation is stabilized by this interaction.
O R
O R R O
Rotational barriers are ~ 10-12 kcal/mol. This is a measure of the strength of the pi bond.
O 1 Et CH3CH2 O O O 2
Lone Pair Conjugation: The oxygen lone pairs conjugate with the C=O.
versus
R
O
C R
The filled oxygen p-orbital interacts with pi (and pi*) C=O to form a 3-centered 4-electron bonding system.
2) Lactone 2 is significantly more prone to enolization than 1? In fact the pKa of 2 is ~25 while ester 1 is ~30 (DMSO). Explain. 3) In 1985 Burgi, on carefully studying O O O the X-ray structures of a number of lactones, noted that the O-C-C () & O O O O-C-O () bond angles were not equal. Explain the indicated trend in bond = 12.3 = 6.9 = 4.5 angle changes.
SP2 Hybridization
Oxygen Hybridization: Note that the alkyl oxygen is Sp2. Rehybridization is driven by system to optimize pi-bonding.
D. A. Evans
Three-Center Bonds
Case 3: 2 p-Orbitals; 1 s-orbital
Chem 206
Consider the linear combination of three atomic orbitals. The resulting molecular orbitals (MOs) usually consist of one bonding, one nonbonding and one antibonding MO. Case 1: 3 p-Orbitals pi-orientation
antibonding
antibonding
nonbonding
Energy
nonbonding
bonding
Do this as an exercise
CH2
H 2C
CH
bonding
D. A. Evans
Chem 206
Electrophilic substitution at saturated carbon may occur with either inversion of retention Inversion
+ M
R Nu C H H X:
C H H
Ra El(+) H Rb C M
+ Nu
Ra C H
Ra Nu C Rb H M+
Given the fact that the LUMO on the electrophile is the CX antibonding orblital, Nucleophilic attack could occur with either inversion or retention.
Rb
Inversion
R Nu
Retention
Ra El(+) Ra C M H Rb C M
+
Retention
R X H H C
Ra H Rb C El M+
C H H
LUMO
H Rb
El +
HOMO
Ra Ra C H Rb
C M H Rb
HOMO
Inversion
LUMO
El(+)
C
antibonding HOMO
X
bonding Br2 H Br
Retention Examples
Li H
CO2 CO2Li H
Nu
Fleming, page 75-76
predominant inversion
predominant retention
D. A. Evans
The reaction under discussion:
R R C H X
Chem 206
Nu:
Nu
X:
1 and 2 containing deuterium labels either on the aromatic ring or on the methyl group were prepared. A 1:1-mixture of 1 and 2 were allowed to react. If the rxn was exclusively intramolecular, the products would only contain only three deuterium atoms:
O S O O CH3 SO3 D3C Nu
The NuCX bonding interaction is that of a 3-center, 4-electron bond. The frontier orbitals which are involved are the nonbonding orbital from Nu as well as CX and CX: CX
D 3C
Nu:
exclusively intramolecular
(CD3ArNuCH3)
CH3
O S
O O CD3
SO3 H 3C Nu
(CH3ArNuCD3
energy
Nu:
C X
Me
Nu:
exclusively intramolecular
CD3
CX RCH2X
Nu
Experiments have been designed to probe inherent requirement for achieving a 180 NuCX bond angle: Here both Nu and leaving group are constrained to be part of the same ring.
R R
2 If the reaction was exclusively intermolecular, products would only contain differing amounts of D-label depending on which two partners underwent reaction. The deuterium content might be analyzed by mass spectrometry. Here are the possibilities: 1 + 1 D3-product 2 CD3ArNuCH3 D'3-product 2 + 2 2 CH3ArNuCD3 1 CD3ArNuCD3 1 CH3ArNuCH3 Hence, for the strictly intermolecular situation one should see the following ratios D0 : D3 : D'3 : D6 = 1 : 2 : 2 : 1. 1 + 2 The product isotope distribution in the Eschenmoser expt was found to be exclusively that derived from the intermolecular pathway! Other Cases: exclusively intermolecular
(CH3)2N SO3CH3 (CH3)3N
Nu:
C X
C H H X
H H
Nu
D6-product D0-product
"tethered reactants"
The Eschenmoser Experiment (1970): Helv. Chim Acta 1970, 53, 2059 The reaction illustrated below proceeds exclusively through bimolecular pathway in contrast to the apparent availability of the intramolecular path.
O S O O CH3 SO3
SO3
CH3
SO3CH3 N(CH3)2
SO3
Nu:
N(CH3)3
Nu
Hence, the NuCX 180 transition state bond angle must be rigidly maintained for the reaction to take place.
D. A. Evans
SO3CH3 N(CH3)2
(CH3)2N
Chem 206
+
SO3
SO3
SO3CH3
N(CH3)3
(CH3)3N
exclusively intermolecular
8- membered cyclic transition state
174 174
00000 00000000 00000 00000000 00000 00000 00 00 00 00 0000 00 00 0000 00000 0000 00000
Approximate representation of the transition states of the intramolecular alkylation reactions. Transition state CO and CN bond lengths were estimated to be 1.5x(CX) bond length of 1.4
D. A. Evans
The General Reaction:
R R O
Chem 206
R O OH R
+
R R R
+
R OH
Me O
O H
HOMO CC
LUMO *OO
Reaction rates are governed by olefin nucleophilicity. The rates of epoxidation of the indicated olefin relative to cyclohexene are provided below: OH
OH OAc
1.0
0.6
0.05
0.4
The indicated olefin in each of the diolefinic substrates may be oxidized selectively.
Me Me Me Me Me Me Me
H Me Me
Me
O H
E. J. Corey, JACS 101, 1586 (1979) For a more detailed study see P. Beak, JACS 113, 6281 (1991) View from below olefin
2-10 Epoxidation-1 9/16/03 2:58 PM
For theoretical studies of TS see R. D. Bach, JACS 1991, 113, 2338 R. D. Bach, J. Org. Chem 2000, 65, 6715
D. A. Evans
The General Reaction:
R R
Chem 206
+
R R
R R
+
R R note labeled oxygen is transferfed
HOMO CC
LUMO *OO
chiral catalyst
O Me
O R2 R1 R2
O R
(Oxone)
Ph
Ph
Ph
Ph
>95% ee
84% ee
92% ee
oxone
O Me
O Me O CF3
co-distill to give ~0.1 M soln of dioxirane in acetone co-distill to give ~0.6 M soln of dioxirane in hexafluoroacetone
oxone
O F 3C
Me
Me Me
O O
1 (1) 2
Me O
Curci, JOC, 1980, 4758 & 1988, 3890; JACS 1991, 7654. Transition State for the Dioxirane Mediated Olefin Epoxidation
O R R O O R R
O R2
(2)
O Me O Me
R1
R2
planar
>90% ee
spiro
rotate 90
Part A (8 points). Provide a mechanism for the epoxidation of ethylene with dimethyldioxirane (1). Use three-dimensional representations, where relevant, to illustrate the relative stereochemical aspects of the oxygen transfer step. Clearly identify the frontier orbitals involved in the epoxidation. Part B (7 points). Now superimpose chiral ketone 2 on to your mechanism proposed above and rationalize the sense of asymmetric induction of the epoxidation of trisubstituted olefins (eq 2). Use three-dimensional representations, where relevant, to illustrate the absolute stereochemical aspects of the oxygen transfer step.
stabilizing Olp * C=C cis olefins react ~10 times faster than trans Houk, JACS, 1997, 12982.
D. A. Evans
O C RL RS + RCO3H RCO2H
Chem 206
CMe3 Me O H O R O O
The major product is that wherein oxygen has been inserted into theRLCarbonyl bond. O kR kR / KMe R
R O O C R Me + CF3CO3H O C Me
H
Favored
CMe3 O Me O OH O R
Migrating group
major
O Me O CMe3
kMe
C R O
Me
minor
PhCH2
RS OH C RL O O
Disfavored
Me O
Migrating group
The Intermediate
O OH Me O CMe3
Me3C O
1. The RLCOO dihedral angle must be180 due to the HOMO LUMO interaction -RLCOO. 2. The COOC' dihedral angle will be ca. 60 due to the gauche effect (O-lone pairsCO). This gauche geometry is probably reinforced by intramolecular hydrogen bonding as illustrated on the opposite page:
2-12- Baeyer Villiger Rxn 9/16/03 5:33 PM
Conformer B
Steric effects destabilize Conformer B relative to Conformer A; hence, the reaction is thought to proceed via a transition state similar to A. For relevant papers see: Crudden, Angew. Chem. Int. Ed 2000, 39, 2852-2855 (pdf) Kishi, JACS 1998, 120, 9392 (pdf)
D. A. Evans
Chem 206
O Me
+ RCO3H CMe3
Me3C O H
Me O
- MeCO2H
O O H O R O
Favored
H
Me
Conformer A
H
Disfavored
Me O Me3C O R OH O
Migrating group
O Me
1
CMe3
2 3
Conformer B
Steric effects destabilize Conformer B relative to Conformer A; hence, the reaction is thought to proceed via a transition state similar to A. For relevant papers see: Crudden, Angew. Chem. Int. Ed 2000, 39, 2852-2855 (pdf) Kishi, JACS 1998, 120, 9392 (pdf)
2-13- Baeyer Villiger Rxn-2 9/16/03 5:41 PM
B. Breit
FMO-Theory/HSAB Principle 1
Hard and Soft Acids and Bases (HSAB-Principle)
Reading Assignment: Fleming, Chapter 3, p33-46 Pearson, JACS 1963, 85, 3533.
Chem 206
FMO-Theory and Klopman-Salem equation provide an understanding of this empirical principle: Hard Acids have usually a positive charge, small ion radii (high charge density), energy rich (high lying) LUMO. Soft Acids are usually uncharged and large (low charge density), they have an energy poor (low lying ) LUMO (usually with large MO coefficient). Hard Bases usually have a negative charge, small ion radii (high charge density), energy poor (low lying) HOMO. Soft Bases are usually uncharged and large (low charge density), energy rich (high lying) HOMO (usually with large MO coefficient).
Hard Acids prefer to interact with hard bases Soft acids prefer to interact with soft bases.
Softness: Polarizability; soft nucleophiles have electron clouds, which can be polarized (deformed) easily. Charged species with small ion radii, high charge density.
Hardness:
Soft-Soft
E E
Hard-Hard
Acid
B. Breit
FMO-Theory/HSAB Principle 2
Chem 206
Klopman-Salem Equation for the interaction of a Nucleophile N (Lewis-Base) and an Electrophile E (Lewis-Acid).
E =
Q: Charge density : Dielectricity constant R: distance (N-E) c: coefficient of MO : Resonance Integral E: Energy of MO
Soft-Soft Interactions: Coulomb term small (low charge density). Dominant interaction is the frontier orbital interaction because of a small E(HOMON/LUMOE). formation of covalent bonds Hard-Hard Interactions: Frontier orbital term small because of large E(HOMON/LUMOE). Dominant interaction is described by the Coulomb term (Q is large for hard species), i.e. electrostatic interaction. formation of ionic bonds Hard-Soft Interactions: Neither energy term provides significant energy gain through interaction. Hence, Hard-Soft interactions are unfavorable.
B. Breit
FMO-Theory/HSAB Principle 3
HSAB principle - Application to Chemoselectivity Issues
(c) SN2 vs E2
Chem 206
CO2R
hard O soft C C
soft MeI
C-Alkylation
Me OTMS
CO2R
S N2
hard TMSCl
E2
O-Alkylation
(d) Ambident Nucleophiles (b) 1,2- vs. 1,4-addition to ,-unsaturated carbonyl compounds + 0.29
O H H
- 0.48
O
soft Ag S C N hard Na
soft MeI
H3 C
C O
S-Alkylation
+ 0.62 LUMO-coefficients
hard RCOX
N-Acylation
hard soft
O
hard MeLi
N-Alkylation
O hard
O-Alkylation
D. A. Evans
Chem 206
http://www.courses.fas.harvard.edu/~chem206/
The Primary Literature Baldwin, J. Chem. Soc., Chem. Comm. 1976, 734, 736. Baldwin, J. Chem. Soc., Chem. Comm. 1977 233. Baldwin, J. Org. Chem. 1977, 42, 3846. Baldwin, Tetrahedron 1982, 38, 2939.
Lecture Number 3
Useful LIterature Reviews Johnson, C. D. (1993). Stereoelectronic effects in the formation of 5and 6-membered rings: the role of Baldwin's rules. Acc. Chem. Res. 26: 476-82. (Handout) Beak, P. (1992). Determinations of transition-state geometries by the endocyclic restriction test: mechanisms of substitution at nonstereogenic atoms. Acc. Chem. Res. 25: 215. (Handout)
+
HO O
D. A. Evans
3-00-Cover Page 9/19/03 8:36 AM
NH2NH2 OMe Me
HN NH O
D. A. Evans, J. Johnson
Chem 206
endo
C. Nucleophilic ring closures sub-classified according to hybridization state of electrophilic component: (tetrahedral = tet; trigonal = trig; digonal = dig) D. Nucleophilic ring closures further subclassified according to size of the fomed ring. For example:
5-exo-tet
X Y
5-exo-trig
X Y
5-exo-dig
X Y
Nomenclature
Classes of Ring Closing Processes A. Exo-cyclization modes identified by the breaking bond being positioned exocyclic to the forming cycle.
exo
X Y
= 180
X Y
X X
Y Y B. Endo-cyclization modes identified by the breaking bond being positioned endocyclic to the forming cycle.
endo
= 109
Y
Will come back to this case later
X Y X = first-row element N, O
* 120 *
D. A. Evans, J. Johnson
Chem 206
Tetrahedral Carbon
All exo cyclization modes are allowed: (n-exo-tet, n = 3)
exo
In this simple model, the transition-state leading to 1 involves the diaxial orientation of nucleophile and leaving group. This orientation affords the best overlap of the anti-bonding CY orbital and the nonbonding electron pairs on the nucleophile O. In the formation of the diastereomeric epoxide 2, the proper alignment of orbitals may only be achieved by cyclization through the less-favored boat conformer. Accordingly, while both cyclizations are "allowed", there are large rate differences the the rates of ring closure. While the FRST-PLATTNER RULE deals wilth the microscopic reverse, in the opening of epoxides by nucleophiles, the stereoelectronic arguments are the same.
C Y
C Y
There are stereoelectronic issues to consider for n-exo-tet cyclizations Formation of 3-Membered Rings (3-exo-tet)
H H H
X C H2
CH2 C H2
C H2
+ Y
faster
H H H Me3C
O
Y
slower
H O
Nu-
Nu HO
O H H
chair
boat
"The diaxial nucleophilic ring cleavage of epoxides" For more information on epoxide cleavage see Handout 03A.
D. A. Evans, J. Johnson
Chem 206
Tetrahedral Carbon
Endo cyclization modes that are disallowed (n-endo-tet, n = 39)
8-endo-tet disfavored Rxn exclusively intermolecular 8-endo-tet disfavored Rxn exclusively intermolecular 9-endo-tet borderline 84% intermolecular, 16% intramolecular
O O
NMe3+
endo
Y C(SP3)
SO2OMe NMe2
SO3 NMe3+
The stereoelectronic requirement for a 180 XCY bond angle is only met when the endo cyclization ring size reaches 9 or 10 members. Case 1: Eschenmoser, Helvetica Chim. Acta 1970, 53, 2059.
O S O O CX3 O S O O S O OCX3 O S O SO2OMe NMe2
SO3 NMe3+
Conclusions
Allowed endo cyclization modes will require transition state ring sizes of at least nine members.
CY3
O Cl OOH n
-
CX2 O
Beak states that the conclusions made with carbon substitution also hold for oxygen atom transfer.
Beak, P. (1992). Determinations of transition-state geometries by the endocyclic restriction test: mechanisms of substitution at nonstereogenic atoms. Acc. Chem. Res. 25: 215.
CY3
CY3
D. A. Evans, J. Johnson
Chem 206
Trigonal Carbon
Endo cyclization modes that are disallowed (3 to 5-endo-trig)
n-endo-trig X Y X C Y MeO2C NH2 CO2Me
X = first-row element The 5-endo-trig cyclization is a watershed case distance from reacting centers: 2.77 Case 1: Baldwin, J. Chem. Soc., Chem. Commun., 1976, 734.
CO2Me OH base
X
CO2Me O
however
CO2Me SH
It is possible that a "nonvertical" trajectory is operational like that suspected in C=O addition
CO2Me
Second row atom relaxes the cyclization geometrical requirement Case 2: Baldwin, J. Chem. Soc., Chem. Commun., 1976, 736.
MeO2C NH2 CO2Me
X
MeO2C HN
CO2Me
5-endo-trig 0%
MeO2C HN O
5-exo-trig 100%
D. A. Evans, J. Johnson
Case 2: continued...
MeO2C NH2 CO2Me
X
Chem 206
5-endo-trig 0%
MeO2C HN O
CH3CO2H
+ N
OH
5-exo-trig 100%
R HC N
1
CO2Me KO Bu R2 CO2Me
t
CO2Me R1 HN R CO2Me
2
CO2Me R 3:1
1
HN
CO2Me R2
Ph
Case 3:
O Ph OMe NH2NH2 65 oC Ph HN NH O
R O R
(CH2OH)2 H+
R R
O O
O Ph MeI OK
Ph NH
R O R
(CH2OH)2
R HO
R O
OH
H+ H2O
R R O
OH
( )2
( )2
5-endo-trig
5-endo-trig
H+
R O
disfavored ?
R R O O
R Ph CO2Me NH2 Ph O HN NH HO
OH 5-exo-tet
( )2
favored ?
5-exo-trig
Johnson, C. D. (1993). Stereoelectronic effects in the formation of 5- and 6-membered rings: the role of Baldwin's rules. Acc. Chem. Res. 26: 476-82.
D. A. Evans, J. Johnson
More Exceptions
Chem 206
Bu
X Y
NaH
HO
DMF, 60 C Y F H Cl Br Cond
Y O
X F F
Yield 80 17 15
O MeO
O MeO N
MeO O MeO N
Cl Br
5-endo-trig
Ichikawa, et al Synthesis 2002, 1917-1936, PDF on Course Website Numerous other cases are provided in this review.
Br
H O
MeO2C N O
OMe
MeO2C N Ts
CO2Me
Ts
5-exo-trig
TsHN
5-endo-trig
Favored
H O
Not Observed
5-endo-trig
O O
5-exo-trig
5-endo-trig
Chem. Comm 2088, 28 Review: "5-Endo-Trig Radical Cyclizatons" Ishibashi, et al Synthesis 2002, 695-713, PDF on Course Website
Not Observed
Favored
D. A. Evans, J. Johnson
Chem 206
C C
C Y
Br
X
MO
Me Me O
(1)
The overlap for C-alkylation is poor due to geometrical constraints of 5-membered ring
However:
Me Me O Me Br
KOt-Bu or LDA
The relaxed geometrical constraint provided by the added CH2 group now renders the 6-membered cyclization possible
Given the failure of the enolate alkylation shown above (eq 1), explain why these two cyclizations are successful.
Br NHAr O R O Ar NH R OMs base O N Ar base N O R Ar R
MO
Br
CO2Me
D. A. Evans, J. Johnson
Rules for Ring Closure: SP2 & SP Carbon & Related Systems
Chem 206
MO R
X Y
(Enolendo)-Exo-trig
O R
X YM
Nu120 120 E+
Baldwin: - 3 and 4-Exo-dig are disfavored - 5 to 7-Exo-dig are favored - 3 to 7-Endo-dig are favored
X MO R Y
(Enolexo)-exo-trig
O R
X YM
H _
Ab initio SCF 4-31G calculations for the interaction of hydride with acetylene:
H
2.13 127 o 148o H
Favored: 3-7-(enolexo)-exo-trig
H O Me O
I
5-(Enolendo)-Exo-trig
Me Me O
6-(Enolendo)-Exo-trig
Me O H
H 156o 1.22
1.5-2.0
110o -120o
STO-3G minimal basis set H Dunitz, Helv Chim. Acta 1978, 61, 2538.
favored
Me O Me O Me
III
H O
Me Me O
II
N
2.92 104o
ON
+
+
N
O
93
2.44
o
N
o
Caution: Baldwin's conclusions assume that the RDS is ring closure; however, it is well known (by some!) that the rate determining step is dehydration in a base-catalyzed aldol condensation.
86
D. A. Evans, J. Johnson
Chem 206
CH2R N
C-
R
Saegusa, J. Am. Chem. Soc. 1977, 99, 3532. _
5-endo-dig
:X
Spiro dihydrofuranones:
O Li HO MeO
n n = 1,2
Li+
OMe
KOtBu
OMe
X
For an opposing viewpoint to Baldwin's view of nucleophile trajectories, see Menger's article on directionality in solution organic chemistry: Tetrahedron 1983, 39, 1013.
O Me Me HO Ph NaOMe MeOH Me Me O Ph O
Developing negative charge on the central allenic carbon is in the same plane as the OMe group
Magnus, J. Am. Chem. Soc. 1978, 100, 7746.
5-endo-dig
O
5-exo-dig
O R OH
R = H, OMe
NaOMe
X
5-endo-trig
R O Ph
Li
Ph
Li
Ph
4-endo-dig
X
Li
Li
Ph
D. A. Evans, J. Johnson
Chem 206
Trost, J. Am. Chem. Soc., 1979, 101, 1284. Proposes E-olefin geometry, E/Z > 95:5
5-exo-dig
O O CO2Me
:
R R'
30-40 kcal/mol ?
R R'
:
OH
HO2C H
Hirsutic Acid C
O Me
Baldwin's Rules are an effective first line of analysis in evaluating the stereoelectronics of a given ring closure Baldwin's Rules have provided an important foundation for the study of reaction mechanism Competition studies between different modes of cyclization only give information about relative rates, and are not an absolute indicator of whether a process is "favored" or "disfavored" Structural modifications can dramatically affect the cyclization mode; beware of imines and epoxides
EXO Tet Trig Dig X X Tet ENDO Trig X X X X X X Dig
OTBS 1) RCOCl
2) AgBF4 86%
Me C-
N+ C O
Me R
Works for varying ring sizes and R groups; acylnitrilium ion can also work as an electophile in a Friedel-Crafts type of reaction 5-endo-dig Livinghouse, Tetrahedron 1992, 48, 2209.
O H N O Me R
3 4 5 6 7
D. A. Evans
Chem 206
http://www.courses.fas.harvard.edu/~chem206/
A.M. 1964, Harvard University Ph.D. 1967, Harvard University Physical and Theoretical Chemistry.
Reading Assignment for week A. Carey & Sundberg: Part A; Chapters 2 & 3
R. W. Hoffmann, Angew. Chem. Int. Ed. Engl. 2000, 39, 2054-2070 Conformation Design of Open-Chain Compounds (handout)
D. A. Evans
4-00-Cover Page 9/22/03 9:01 AM
D. A. Evans
Chem 206
The following discussion is intended to provide a general overview of acyclic conformational analysis
One can see from the space-filling models that the Van der Waals radii of the hydrogens do not overlap in the eclipsed ethane conformation. This makes the steric argument for the barrier untenable. One explanation for the rotational barrier in ethane is that better overlap is possible in the staggered conformation than in the eclipsed conformation as shown below. In the staggered conformation there are 3 anti-periplanar CH Bonds
eclipsed conformation
H E = +3.0 kcal mol-1 (R = H) Van derWaals radii of vicinal hydrogens do not overlap in ethane E = +3.4 kcal mol-1 (R = Me) C H C
CH HOMO
H
C C
* CH LUMO
CH
p. p.
CH
R H C H H
In propane there is a discernable interaction
H H
H
C
H
C
* CH LUMO CH
For purposes of analysis, each eclipsed conformer may be broken up into its component destabilizing interactions. Incremental Contributions to the Barrier. Structure ethane propane Eclipsed atoms E (kcal mol -1) 3 (HH) 2 (HH) 1 (HMe) +1.0 kcal mol -1 +1.0 kcal mol -1 +1.4 kcal mol -1
Following this argument one might conclude that: The staggered conformer has a better orbital match between bonding and antibonding states. The staggered conformer can form more delocalized molecular orbitals. J. P. Lowe was the first to propose this explanation
"A Simple Molecuar Orbital Explanation for the Barrier to Internal Rotation in Ethane and Other Molecules" J. P. Lowe, JACS 1970, 92, 3799 Me Me Me
Calculate the the rotational barrier about the C1-C2 bond in isobutane
D. A. Evans
Chem 206
X
H C H H H H H
H H C
X X
Using the eclipsing interactions extracted from propane & ethane we should be able to estimate all but one of the eclipsed butane conformations
Me C H Me H
Observation: While the anti conformers are favored for X = Cl, Br, the gauche conformation is prefered for 1,2-difluroethane. Explain. Discuss with class the origin of the gauche stabiliation of the difluoro anaolg. Recent Article: Chem. Commun 2002, 1226-1227 (handout)
staggered conformation
H H
Me H C MeH
eclipsed conformation
E=?
G = RT Ln K G = 2.3RT Log10K
2.3RT = 1.4 (G in kcal Mol1 )
E est = 3.8 kcal mol -1 The estimated value of +3.8 agrees quite well with the value of +3.6 reported by Allinger (J. Comp. Chem. 1980, 1, 181-184)
At 298 K:
pKeq = Log10Keq
E1
E2
H H
Me H C MeH H H
H H
Me C
pKeq 0 1 2
H Me A
Ref = 0
+3.6
Me Me G
+5.1
+0.88
Chem 206
Me C H H H
From the torsional energy profile established by Allinger, we should be able to extract the contribution of the MeMe eclipsing interaction to the barrier:
H H C H H Me H H Me Me C HH
staggered conformation Me
eclipsed conformation
gauche(+) or g+ 15%
gauche(-) or g15%
Let's extract out the magnitide of the MeMe interaction 2 (HH) + 1 (MeMe) = +5.1 1 (MeMe) = +5.1 2 (HH) p. p. 1 (MeMe) = +3.1
General nomenclature for diastereomers resulting from rotation about a single bond (Klyne, Prelog, Experientia 1960, 16, 521.)
RR C 0 R R C -60
R C
sp sc sc
+60
Incremental Contributions to the Barrier. Eclipsed atoms 2 (HH) 1 (MeMe) E (kcal mol -1) +2.0 +3.1
R Eclipsed Butane conformation
ac
R C -120
ac
+120 R C R 180 R C R
ap
From the energy profiles of ethane, propane, and n-butane, one may extract the useful eclipsing interactions summarized below: Hierarchy of Eclipsing Interactions
X
X Y
Y H
H
H
Symbol sp + sc (g+) + ac
H H
C H
H Me Me Me
n-Butane Conformer E2 G E1 A E1 G
ap (anti or t) - ac - sc (g-)
D. A. Evans n-Pentane
Chem 206
Rotation about both the C2-C3 and C3-C4 bonds in either direction (+ or -):
Me Me H Me H
g+g+ g+t
Me H Me Me
tg-
H Me
g+g-
Me H
H Me
Me Me H
t,t
Me Me Me H H
H Me
Me
tg+
Me H
X
g-t 1 g-g+
p. p.
1 (t,t) Anti(2,3)-Anti(3,4)
2 (g+t) Gauche(2,3)-Anti(3,4)
G = +5.5 kcal mol -1 G = X + 2Y where: X = 1,3(MeMe) & Y = 1,3(MeH) 1,3(MeH) = Skew-butane = 0.88 kcal mol -1 1,3(MeMe) = G 2Y = 5.5 1.76 = + 3.7 kcal mol -1
1 1 5 3
3 (g+g+)
Me
Me
Me
Me
Me
Me
Me
Me
From prior discussion, you should be able to estimate energies of 2 & 3 (relative to 1). On the other hand, the least stable conformer 4 requires additional data before is relative energy can be evaluated.
It may be concluded that in-plane 1,3(MeMe) interactions are Ca +4 kcal/mol while 1,2(MeMe) interactions are destabliizing by Ca 2.2 kcal/mol.
D. A. Evans
Acyclic Conformational Analysis: Natural Products Lactol & Ketol Polyether Antibioitics
Chem 206
The conformation of these structures are strongly influenced by the acyclic stereocenters
Me O HO R O OH H Me Me OH O H O O Me OH Et Et OH Me
R Me R Me Me Me
R'
R'
or
Me H RR'
g -g -
Me H R'
Me H H Me
tt
Me
Me
Et
R'
Me
or
Me
Me H H R'
tg
H H R H
gt
Ferensimycin B, R = Me Lysocellin, R = H
The conformation of these structures are strongly influenced by the acyclic stereocenters and internal H-bonding
Alborixin R = Me; X-206 R = H
Internal H-Bonding
OH Me Me Me Me O O OR Bourgeanic acid Me Me C O OH R Me OH H Me O OH O OH OH O Me Me Me H O Me Me OH O Et Me OH
D. A. Evans
Chem 206
Internal H-Bonding
Me Me O C O OH Me OH H Me O OH O OH OH O Me Me Me O Me Me OH O Et
p. p.
"The Total Synthesis of the Polyether Antibiotic X-206". Evans, D. A.; Bender, S. L.; Morris, J. J. Am. Chem. Soc. 1988, 110, 2506-2526.
D. A. Evans
Chem 206
p. p.
D. A. Evans
Chem 206
Simple olefins exhibit unusal conformational properties relative to their saturated counterparts
Propane versus Propene
109 H H H H Me H H H H H 120 CH2
staggered conformation
C H H
eclipsed conformation
G = +4 kcal mol-1
Me
Hybridilzation change opens up the CCC bond angle The Propylene Barrier
p. p.
H H C H CH2 H H CH2 C H
staggered conformation
CH2 C H H H
H H
Me CH2 C H
eclipsed conformation
= 50 staggered conformation
=0
+2.0 kcal/mol
= 180
H H C H H C Me H
eclipsed conformation
H X H C H H
+0.49 kcal
= 120
= 180
H X C H H
=0
Conforms to ab initio (3-21G) values: Wiberg, K. B.; Martin, E. J. Am. Chem. Soc. 1985, 107, 5035.
K. Wiberg, JACS 1985, 107, 5035-5041 K. Houk, JACS 1987, 109, 6591-6600
Y H Me Me
H
H
H H
C H
H Me
~ 3.1
~ 3.7
~3.9
~ 7.6
It may be concluded that in-plane 1,3(MeMe) interactions are Ca +4 kcal/mol while 1,2(MeMe) interactions are destabliizing by Ca +3 kcal/mol.
0000 0000 000 0000 0000 0000 000 0000 0000 0000 000 0000 00 0 00 0 0 00 0 0 00 0 0000 00000000 0000 0000 00000000 0000 0000 00000000 0000
minimized structure
D. A. Evans
Chem 206
http://www.courses.fas.harvard.edu/~chem206/
OTs 1
EtO n-C4H9 H
+ 98:2
OH O Me
CH2OBn
Me
diastereoselection 8:1
Reading Assignment for week A. Carey & Sundberg: Part A; Chapters 2 & 3
R. W. Hoffmann, Angew. Chem. Int. Ed. Engl. 2000, 39, 2054-2070 Conformation Design of Open-Chain Compounds (handout) R. W. Hoffmann, Chem. Rev. 1989, 89, 1841-1860 Allylic 1-3-Strain as a Controlling Element in Stereoselective Transformations (handout) F. Weinhold, Nature 2001, 411, 539-541 "A New Twist on Molecular Shape" (handout)
Me
Me
PhNCO Et3N
Me
Me
NO2
D. A. Evans
D. A. Evans
Chem 206
Simple olefins exhibit unusal conformational properties relative to their saturated counterparts
Propane versus Propene
109 H H H H Me H H H H H 120 CH2
staggered conformation
C H H
eclipsed conformation
G = +4 kcal mol-1
Me
Hybridilzation change opens up the CCC bond angle The Propylene Barrier
p. p.
H H C H CH2 H H CH2 C H
staggered conformation
CH2 C H H H
H H
Me CH2 C H
eclipsed conformation
= 50 staggered conformation
=0
+2.0 kcal/mol
= 180
H H C H H C Me H
eclipsed conformation
H X H C H H
+0.49 kcal
= 120
= 180
H X C H H
=0
Conforms to ab initio (3-21G) values: Wiberg, K. B.; Martin, E. J. Am. Chem. Soc. 1985, 107, 5035.
K. Wiberg, JACS 1985, 107, 5035-5041 K. Houk, JACS 1987, 109, 6591-6600
Chem 206
1-butene
4
2-propen-1-ol
H H H C C OH H H
H H H C C Me
H H
E (kcal/mol)
E (kcal/mol)
0 -180
-90
90
180
0 -180
-90
90
180
(Deg)
The Torsional Energy Profile = 50
Me H H H C H C H H H C H
(Deg)
The Torsional Energy Profile
H H C H C OH H
= 180
H C Me H H H
= 60
HO C H C H H
= 180
=0
C H Me H C
H H H
= 120
H C H C
OH H H
+1.32 kcal
H H C H C
Me H H
+1.33 kcal
H
+2.00 kcal
=0
C H HO C
H H H
+1.18 kcal
+0.49 kcal
=0
= 120
= 180
+0.37 kcal
= 180
=0
Conforms to ab initio (3-21G) values: Wiberg, K. B.; Martin, E. J. Am. Chem. Soc. 1985, 107, 5035.
Chem 206
2-methyl-1-butene
4
2-methyl-2-propen-1-ol
4
H H H C C Me
H Me
H H H C C OH
H Me
E (kcal/mol)
E (kcal/mol)
0 -180
-90
90
180
0 -180
-90
90
180
(Deg)
The Torsional Energy Profile = 180 = 50
Me H H H C H C Me H H C H H H C H C H Me Me
(Deg)
The Torsional Energy Profile = 180 = 60
HO C Me H H H H C H C OH Me
= 120
OH
=0
C H Me =0 H C
= 110
H Me H
+1.39 kcal
H H C H C
Me Me H
+2.68 kcal
=0
C H HO = 180 =0 H C
H Me H
+1.16 kcal
H H
+2.01 kcal
Me
C H
C H
+0.06 kcal
+0.21 kcal
= 180
Chem 206
(Z)-2-pentene
4 4
(Z)-2-buten-1-ol
H Me H C C OH H H
H Me
E (kcal/mol)
E (kcal/mol)
C Me
0 -180
-90
90
180
0 -180
-90
90
180
(Deg)
H Me C H Me C H H
(Deg)
The Torsional Energy Profile =0
Me C H HO C H H H Me
= 180
H C H C H OH H
+3.88 kcal
= 180 = 90
Me Me H C H C H H Me H H C H C Me H
+1.44 kcal
Me
= 120
OH C H C H H
+0.86 kcal
+0.52 kcal
= 180 =0
=0
= 180
Values calculated using MM2 (molecular mechanics) force fields via the Macromodel multiconformation search. 5-04-2-pentene/ z-2-buten-1-ol 9/23/03 3:00 PM
Chem 206
(Z)-2-hydroxy-3-pentene
4
Me OH Me
4.6 kcal/mol
HO
H C Me H
E (kcal/mol)
Me
3
Me
100
H OH
Me H
C H
0.3-0.4 kcal/mol
H Me H C C OH
-90 0 90 180
Me H
30
0 -180
(Deg)
The Torsional Energy Profile
OH
60
Me
=0
H Me C H HO C H Me
Me C H Me
2.7 kcal/mol
C OH
H H
= -140
+2.72
????? = -80
HO Me C H C Me H H
+4.68
HO H H C C Me
H Me
30
= 80 Me
Me C C H H
Y X
2
R1
= 150
H C C Me H
R3
*
1
R large
+0.66H
Me
R small
+0.34
=0
+0.40 kcal
HO = 180
D. A. Evans
Chem 206
F. Johnson, Chem. Rev. 1968, 68, 375; Allylic Strain in Six-Membered Rings R. W. Hoffmann, Chem. Rev. 1989, 89, 1841-1860 (handout) Allylic 1-3-Strain as a Controlling Element in Stereoselective Transformations Houk, Hoffmann JACS 1991, 113, 5006
Consider the illustrated general structure where X & Y are permutations of C, N, and O:
R2
3 Y X 2
R1
OTs 1
+ 98:2
R3
Typical examples:
R2 R3 R1
R2 R large N
R1
R2 R large R + N
R1
R2 R large
R1 N
Relevant enolate
conformations
R large 1
EtO n-C4H9 H
major
O +
p. p.
R small Olefin
R small Imine
In the above examples, the resident allylic stereocenter () and its associated substituents frequently impart a pronounced bias towards reactions occuring at the pi-bond. A(1,3) interaction R2 3 R1 Nonbonding interactions between the allylic Y substituents (Rlarge, Rsmall) & substituents at X R large the 2- & 3-positions play a critical role in R3 2 1 defining the stereochemical course of such R small reactions A(1,2) interaction Representative Reactions controlled by Allylic Strain Interactions
HO H Me HO O R OBn
Hg(OAc)2 NaBH4
A1
B1
critical conformations
C1 H
H OR Me TsO(H2C)4 C C Bu OLi Me
H C
Bu C
(CH2)4OTs
A2
B2
C2
Me
HO Me
minor
H
diastereoselection 10:1 M. Isobe & Co-workers, Tetrahedron Lett. 1985, 26, 5199.
D. A. Evans
O EtO n-C4H9 H O EtO n-C4H9 H
LiNR2 MeI
Chem 206
Ph
NH4Cl
Ph
OM OMe R
R-substituent R = Me diastereoselection 87:13 80:20 40:60
O OMe R
Me3Si
R = Et R = CHMe2
I. Fleming & Co-workers, Chem. Commun. 1985, 318. Y. Yamamoto & Co-workers, Chem. Commun. 1984, 904.
Ph
LiNR2
OBn
MeO
p. p.
RO2C H CO2Me
MeO
LiNR2
RO2C H H CO2Me
Me
OH
Br
95% yield
Me Bn N Boc R
O N OH
S S diastereoselection >95%
TBSOCH2
Me CH2
LiNR2 MeI
H CO2Me
OMe
MeI 86%
Me
Me
R PhMe2Si
OM OEt
R
MeI
O OEt Me
R = Me: diastereoselection 99:1 R = Ph: diastereoselection 97:3
PhMe2Si
I CO2Et R
OLi O-t-Bu
CO2Et
R = H: one isomer
D. A. Evans
s The basic process
S H H
R
Chem 206
H
R
OH
H H
R
H2 B
R
H C R
R
O Me Me
CH2 OBn
B2 H6 H2 O2
O Me Me
CH2 OBn
C R
C R R
C R
Me
Me
Oxidant
MCPBA BH3, H2 O2 E
Ratio, A:E
69:31 34:66
Reference
JOC, 1967, 32, 1363 JOC, 1970, 35, 2654 BnO Me
OH OH Me Me B2 H6 H2 O2 BnO Me Me Me OH
major diastereomer
Me Me
control elements
RM H
Me
Me OTr OH OH 5:1
Diastereoselection;
major diastereomer
Me
Me
Me
Me
Me
Me
Me
Me OTr
OH
OH
OH
OH OTr
OH
OH
OH 4: 1
OH
Diastereoselection;
D. A. Evans
Consider the resonance structures of an amide:
O R3 C N
1
Chem 206
Y X
2
R1 R large
1
The selection of amide protecting group may be done with the knowledge that altered conformational preferences may result:
O O H H
R1 R R
O R3
C N +
R1 R
1
R small
N R
N R O
A(1,3) interactions between the "allylic substituent" and the R1 moiety will strongly influence the torsion angle between N & C1. Favored
O Me C N Me
N H R H O N O H C R H H R
Disfavored
Me Me
Disfavored
H C O R
Favored
p. p.
H R C O N
H strongly favored Me Me
R O 1 A(1,3) interaction between the C2 & amide C R substituents will strongly influence the torsion N angle between C1 & C2. R R
2
R O
1 2
N R + R
H strongly favored
O Me Ph N O
O Me
N H
L L
OM base favored O Me C N H L L H
Me
N L
(Z)-Enolate
H
H O H C L N Me L base disfavored O H
H L
OM C N Me L H Me N L L
N Ph O diastereoselection >95%
(E)-Enolate
D. A. Evans
Chem 206
N Bn
R O
Acylation CO2
Reduction
O Me
N H
In the enolate alkylation process product epimerization is a serious problem. Allylic strain suppresses product enolization through the intervention of allylic strain
H O El C N Me L L O Me C N H El L L Me O C H El N L L
Diastereoselection ~ 97 : 3
Why does'nt the acylation product rapidy epimerize at the exocyclic stereocenter?? R O Me C
favored
H N H R R O R C N Me R R
While conformers B and C meet the stereoelectronic requirement for enolization, they are much higher in energy than conformer A. Further, as deprotonation is initiated, A(1,3) destabilization contributes significantly to reducing the kinetic acidity of the system These allylic strain attributes are an integral part of the design criteria of chiral amide and imide-based enolate systems
O O Me N Bn CH2OH Me N O O O Me N Me OH Me
X-ray structure
D. A. Evans
Discodermolide
Chem 206
hinge Me HO O O H
16
Me
17
Me
Me Me Me OH Me
OH
O O
NH2
Me OH
- immunosuppressive activity - potent microtubule-stabilizing agent (antitumor activity similar to that of taxol)
The conformation about C16 and C17 is critical to discodermolide's biological activity.
D. A. Evans
Chem 206
O H
Me OH
D. A. Evans
Chem 206
HO O O H
16 Me Me Me OH Me OH O O NH2
Me OH
16
D. A. Evans
Chem 206
http://www.courses.fas.harvard.edu/~chem206/
Prelog Strain: van der Waals interactions Baeyer Strain: bond angle distortion away from the ideal Pitzer Strain: torsional rotation about a sigma bond
Lecture Number 6
Conformational Analysis-3
Conformational Analysis of C4 C6 Rings
3 4 5 6 7 8 9 10 11 12 13 14 15
499.8 656.1 793.5 944.8 1108.3 1269.2 1429.6 1586.8 1743.1 1893.4 2051.9 2206.1 2363.5
27.5 26.3 6.2 0.1 6.2 9.7 12.6 12.4 11.3 4.1 5.2 1.9 1.9
9.17 6.58 1.24 0.02 0.89 1.21 1.40 1.24 1.02 0.34 0.40 0.14 0.13
Eliel, E. L., Wilen, S. H. Stereochemistry of Organic Compounds Chapter 11, John Wiley & Sons, 1994.
Ribeiro & Rittner, "The Role of Hyperconjugation in the Conformational Analysis of Methylcyclohexane and Methylheterocyclohexanes" J. Org. Chem., 2003, 68, 6780-6787 (handout)
de Meijere, "Bonding Properties of Cyclopropane & their Chemical Characteristics" Angew Chem. Int. Ed. 1979, 18, 809-826
Baeyer "angle strain" is calculated from the deviation of the planar bond angles from the ideal tetrahedral bond angle. Discrepancies between calculated strain/CH2 and the "angle strain" results from puckering to minimize van der Waals or eclipsing torsional strain between vicinal hydrogens. Why is there an increase in strain for medium sized rings even though they also can access puckered conformations free of angle strain? The answer is transannular strain- van der Waals interactions between hydrogens across the ring.
D. A. Evans
6-00-Cover Page 9/26/03 8:44 AM
Chem 206
H H H
Me
1.517 1.478
1.222
R
1.474
(antibonding)
1.444 1.534
Ph
(bonding)
(bonding)
1 (bonding) de Meijere, "Bonding Properties of Cyclopropane & their Chemical Characteristics" Angew Chem. Int. Ed. 1979, 18, 809-826 (handout)
de Meijere, A.; Wessjohann, L. "Tailoring the Reactivity of Small Ring Building Blocks for Organic Synthesis." Synlett 1990, 20.
Chem 206
H H H H H H H H H H H H H H H H H
Cyclopentane
H H H H H H
Eclipsing torsional strain overrides increased bond angle strain by puckering. Ring barrier to inversion is 1.45 kcal/mol.
H H H H
= 28
CsEnvelope
C2 Half-Chair
CsEnvelope
Two lowest energy conformations (10 envelope and 10 half chair conformations Cs favored by only 0.5 kcal/mol) in rapid conformational flux (pseudorotation) which causes the molecule to appear to have a single out-of-plane atom "bulge" which rotates about the ring.
(MM2)
Since there is no "natural" conformation of cyclopentane, the ring conforms to minimize interactions of any substituents present.
CsEnvelope (MM2)
H H
H H
H H
A single substituent prefers the equatorial position of the flap of the envelope (barrier ca. 3.4 kcal/mol, R = CH3). 1,2 Disubstitution prefers trans for steric/torsional reasons (alkyl groups) and dipole reasons (polar groups). Me Me X
X 1,3 Disubstitution: Cis-1,3-dimethyl cyclopentane 0.5 kcal/mol more stable than trans.
1,2 Disubstitution prefers trans diequatorial to cis by 1.3 kcal/mol for diacid (roughly equivalent to the cyclohexyl analogue.)
H H
A carbonyl or methylene prefers the planar position of the half-chair (barrier 1.15 kcal/mol for cyclopentanone). X
Chem 206
Relative to cyclohexane derivatives, those of cyclopentane prefer an sp2 center in the ring to minimize eclipsing interactions. "Reactions will proceed in such a manner as to favor the formation or retention of an exo double bond in the 5-ring and to avoid the formation or retention of the exo double bond in the 6-ring systems." Brown, H. C., Brewster, J. H.; Shechter, H. J. Am. Chem. Soc. 1954, 76, 467.
Examples:
H H H H H H H H O O NaBH4 H
H OH
k6
H H H
NaBH4
H H OH H
k6 = 23 k5
k5
E = +6.5-7.0 E = +5.5
Conan, J-Y.; Natat, A.; Priolet, D. Bull. Soc. Chim., Fr. 1976, 1935.
O O OEt OH O OEt
95.5:4.5 keto:enol
76:24 enol:keto
Evans, Breit
Chem 206
Keq
H
G = RTlnKeq
Meaxial has 2 gauche butane interactions more than Meequatorial. Expected destabilization: 2(0.88) kcal/mol = ~1.8 kcal/mol; Observed: 1.74 kcal/mol
Me H C H H H H Me H H C Me H C H
AValue
1.74
1.80
2.15
5.0
The "relative size" of a substituent and the associated A-value may not correlate. For example, consider the CMe3 and SiMe3 substituents. While the SiMe3 substituent has a larger covalent radius, it has a smaller A-value:
Me C Me H Me Si Me H Me Sn Me H
The A Value, or -G, is the preference of the substituent for the equatorial position.
Me
Me
Me
AValue
4.5-5.0
2.5
1.1
The Me substituent appears to respond strictly to the decrease in nonbonding interactions in axial conformer. With the more polar substituents, electrostatic effects due to the trigonal ring carbon offset the decreased steric environment.
Rigberio & Rittner, The Role of Hyperconjugation in the Conformational Analysis of Methylcyclohexane and Methylheterocyclohexanes JOC 2003, 68, 6780 Commentary by Ken Houk University of California, Los Angeles Department of Chemistry Dear David, The calculations in the Ribeiro article look fine, but I am not convinced by the interpretation. It does seem to work pretty well for many systems, but not obviously for the isomeric 1,3-dioxane cases they note early on. There seems no explanation of why CH hyperconjugates better than CC. Further, the results with alkyls larger than methyl still require traditional steric arguments. I would say that the equatorial methyl preference has been attributed in part to hyperconjugative effects that occur when the CH bonds are anti-periplanar. But I would not yet go much beyond that! Best regards, (b. 1943) A.B. 1964, Ph.D. 1968, Harvard University; Assistant-Full Professor, Louisiana State University, 1968-1980; Alfred P. Sloan Fellow, 1975-1977; Camille and Henry Dreyfus Teacher-Scholar, 1972-1977; LSU Distinguished Research Master, 1978; Professor, University of Pittsburgh, 1980-1985; Alexander von Humboldt Senior U.S. Scientist Award, 1982; Akron Section, American Chemical Society Award, 1983; Arthur C. Cope Scholar Award, 1988; Director, Chemistry Division, National Science Foundation, 1988-1990; James Flack Norris Award in Physical Organic Chemistry, 1991; Schrdinger Medal, World Association of Theoretically Oriented Chemists, 1998; Tolman Medal, Southern California Section, American Chemical Society, 1999; Fellow of the American Academy of Arts and Sciences, 2002; American Chemical Society Award for Computers in Chemical and Pharmaceutical Research, 2003; International Academy of Quantum Molecular Science, 2003.
D. A. Evans
Chem 206
CF: 1.39
CCl: 1.79
CBr: 1.95
CI: 2.16
F A-value: 0.250.42
Cl A-value: 0.5364
Br Avalue: 0.48-0.67
I A-value: 0.470.61
p. p.
Evans, Breit
Chem 206
G = 1.36 kcal/mol versus 1.74 for cyclohexane Let's now compare look at the carbonyl analog in the 2-position
Me Me3C O H base epimerization Me3C O H Me
G = 0 kcal/mol
G = 1.56 kcal/mol versus 1.74 for cyclohexane However, the larger alkyl groups do not follow the expected trend. Can you explain? (see Eliel, page 732)
CHMe2 Me3C O H base epimerization Me3C O H CHMe2
G = A(Me) A(X)
H X H Me X H
Me
+ 0.88
+ 0.88
Evans, Breit
Me Ph
Chem 206
Case 1:
Me
HH Me H
Me
The prediction:
Observed:
G = 0.32 kcal/mol
The prediction:
Hence, when the two substituents are mutually interacting you can predict neither the magnitude or the direction of the equilibrium. Let's analyze this case. Allinger, Tet. Lett. 1971, 3259
Observed:
G = +2.74 kcal/mol
If the added gauche butane destabilization in the di-equatorial conformer had not been added, the estimate would have been off.
Case 2:
H Me Me OH H OH H H Me Me
The conformer which places the isopropyl group equatorial is much more strongly preferred than would be suggested by A- Values. This is due to a syn pentane OH/Me interaction. Problem: Can you rationalize the stereochemical outcome of this reaction?
00 0000000 0 00 0000000 00
Me
D
n-C4H9
n-C4H9
diastereoselection 89:11
Evans, Breit
Chem 206
The Reference:
N H
G = 0.36 kcal/mol
Me H
Reference:
H Me
Me N N
G = 1.74 kcal/mol
Hydrogen is "bigger" than the Nlone Pair.
Me
Me
G = 3.0 kcal/mol
Me H O Me O
(1)
G = 2.86 kcal/mol
The A-value of Nsubstituents is slightly larger than the corresponding cyclohexane value. Rationalize
H H O H H Me O Me
Me
H H O O Me
(2)
O Me
G = 1.43 kcal/mol
O O
G = 4.0 kcal/mol
(3)
G = 1.95 kcal/mol
O Me H
H Me
O O
Me H
O O
G = 0.8 kcal/mol
H H N H H H N H H H Me N Me H Me
(4)
N
H Me
G = 2.5 kcal/mol
(5)
H
N Me
G = 1.6 kcal/mol
(6) H N
Evans, Breit
Chem 206
Estimate the energy difference between the two methyl-decalins shown below.
Me Me
The steroid nucleus provided the stimulation for the development of conformational analysis, particularly of polycyclic ring systems. D. H. R. Barton was awarded a Nobel prize in 1969 for his contributions in this area.
flexible
H H
rigid
G = 0.5 kcal/mol
rigid The turnover to favor the cis fusion results from the entropic preference for the less ordered cis isomer.
mobile
H H
favored
2.4 kcal/mol
Relative G
G = +6.4 kcal/mol
H
Let's identify the destabilizing gauche butane interactions in the cis isomer
H
3
H
Gauche-butane interactions
2
Me
A B
H
C D
R
A
H Me H
B
H
C D
4 1
A/B Trans
A/B Cis
Rationalize the conformational flexibility of a A/B Trans vs. A/B Cis Steroid!
Evans, Breit
Chem 206
k rel
31
The axial diastereomer is not always slower reacting: Alcohol Oxidation with Cr(6+)
H Me3C OH Me3C OH H
k rel
Me3C
1
H OH Me3C
0.13
OH H
k rel
0.27
k rel
1
Me H OH Me Me Me
3.2
Me OH H
Acid-catalyzed esterification
H CO2H CO2H H
Me
k rel
3.36
k rel
1
H
0.04
CO2H CO2H Me3C H
The rate-determining step is breakdown of the chromate ester. This is an apparent case of strain acceleration
k rel
Me3C
0.05
Ester Saponification
H Me3C CO2Et Me3C CO2Et H
G A
G ref
G B
k rel
20
1
GS GS G G GS Reference Case
For a more detailed discussion of this topic see: Eliel, E. L., S. H. Wilen, et al. (1994). Stereochemistry of Organic Compounds pp 720-726
6-09-Axial-equat react 9/25/03 8:05 PM
GA > G ref
GB < G ref
D. A. Evans
Conformational Transmission
Chem 206
Me
A Me B C Me
base
O H H
ratio: 13 : 87
H H H
base
O H LiO H LiO H
= 56 CCC 111
Given cyclohexane with an identified torsion angle R, if R either increases or decreases wht effects in angle change are transmitted to O, M, and P?
R = 56
base
O H H LiO H H LiO H H
R = 0 15 44 61
[] 41 11 +6
R
ratio: 10 : 90 Operation: 56
LiO H LiO H
P O M
O M P
56 56 56
[] = R( 0) R( 56)
56 56 56 56 H2 15 0* 44 61
base
O H
56
ratio: 92 : 8
Hence, relative to cyclohexane, the following notation for torsion angle change may be denoted: 11 +6 For P For M
D. A. Evans
Operation:
H
Conformational Transmission-2
H H R C R H H H R C R H Me Me O H H H Me Me O H LiO H LiO H
Chem 206
H
base
H
Operation:
H
base
H LiO H LiO H
ratio: 92 : 8
effects reinforcing
effects opposing
A
R
versus
A
R
Question: Which is the more stable C=C isomer in the two THC structures?
Me OH Me OH
Me O C5H11 Me O C5H11
1) C=C will open up ring=B torsion angle B 2) Ring B will resist increase in its ring fusion torsion angle 3) Therefore torsion effects are opposed
Me
R. W. Kierstead, JACS 1967, 89, 5934 Question: Which enol acetate is more stable?
OBz
1) C=C will close down ring=B torsion angle 2) Ring B will accomodate decrease in its ring fusion torsion angle
OBz
OBz
Ac2O TSOH or
O AcO AcO
Chem 206
Twist-Chair (0 kcal/mol)
Ring strain originates in eclipsing interactions and transannular van der Waals interactions Methyl position G 1 2 2.8 3 >4.5 4 -0.3 5 6.1
Underside view of boat-chair C3 & C7 eclipsing interactions Boat (3.02 kcal/mol) Twist-Boat (2.49 kcal/mol) 7
Chem 206
7 1 Transannular strain between C3 & C7 3 Chair-Boat (CB) conformation reference structure Chair-Chair (CC) conformation (+1-1.6 kcal/mol)
Methyl position G
2 2.8
3 >4.5
4 -0.3
5 6.1
Cyclooctane derivatives
Carbonyl is positioned at C3 or C7
LINR2 MeI
Me
Predict stereochemistry
Me
Nu
LiCuMe2
Predict stereochemistry
Disubstitution occurs at C4 or C6
Me
Me
D. A. Evans
Chem 206
http://www.courses.fas.harvard.edu/~chem206/
J. I. Seeman, J. Chem. Ed. 1986, 63, 42-48. J. I. Seeman, Chem Rev. 1983, 83, 83-134. Eliel, pp. 647-655 Carey & Sundberg,Part A, CH 4, pp 187-250
Conformational Analysis-4
s Ground State Torsional Effects (Conformational Transmission) s Conformational Analysis of C6 C8 Rings continued s Transition State Torsional Effects s CurtinHammett Principle (Will not cover in lecture)
s Reading Assignment for week Eliel & Wilen, Stereochemistry of Carbon Compounds" Chapter 11 Configuration and Conformation of Cyclic Molecules (handout) A. Carey & Sundberg: Part A; Chapter 4 "Study & Descrption of Reaction Mechanisms"
K. Houk, Science. 1986, 231, 1108-1117 Theory & Modeling of Stereoselective Organic Reactions (Handout) Monday, September 29, 2003
Martinelli, et.al. Tett. Lett. 1989, 30, 3935 Rationalize the stereochemical outcome of this reaction.
CO2Me Me Me CO2Me Me
Me Me
O O
LiNR2 Me-I
Me Me
O O
diastereoselection is 8:1.
D. A. Evans
7-00-Cover Page 9/29/03 8:57 AM
D. A. Evans
Conformational Transmission
Chem 206
Me
A Me B C Me
base
O H H
ratio: 13 : 87
H H H
base
O H LiO H LiO H
= 56 CCC 111
Given cyclohexane with an identified torsion angle R, if R either increases or decreases wht effects in angle change are transmitted to O, M, and P?
R = 56
base
O H H LiO H H LiO H H
R = 0 15 44 61
[] 41 11 +6
R
ratio: 10 : 90 Operation: 56
LiO H LiO H
P O M
O M P
56 56 56
[] = R( 0) R( 56)
56 56 56 56 H2 15 0* 44 61
base
O H
56
ratio: 92 : 8
Hence, relative to cyclohexane, the following notation for torsion angle change may be denoted: 11 +6 For P For M
D. A. Evans
Operation:
H
Conformational Transmission-2
H H R C R H H H R C R H Me Me O H H H Me Me O H LiO H LiO H
Chem 206
H
base
H
Operation:
H
base
H LiO H LiO H
ratio: 92 : 8
effects reinforcing
effects opposing
A
R
versus
A
R
Question: Which is the more stable C=C isomer in the two THC structures?
Me OH Me OH
Me O C5H11 Me O C5H11
1) C=C will open up ring=B torsion angle B 2) Ring B will resist increase in its ring fusion torsion angle 3) Therefore torsion effects are opposed
Me
R. W. Kierstead, JACS 1967, 89, 5934 Question: Which enol acetate is more stable?
OBz
1) C=C will close down ring=B torsion angle 2) Ring B will accomodate decrease in its ring fusion torsion angle
OBz
OBz
Ac2O TSOH or
O AcO AcO
Chem 206
Twist-Chair (0 kcal/mol)
Ring strain originates in eclipsing interactions and transannular van der Waals interactions Methyl position G 1 2 2.8 3 >4.5 4 -0.3 5 6.1
Underside view of boat-chair C3 & C7 eclipsing interactions Boat (3.02 kcal/mol) Twist-Boat (2.49 kcal/mol) 7
Chem 206
7 1 Transannular strain between C3 & C7 3 Chair-Boat (CB) conformation reference structure Chair-Chair (CC) conformation (+1-1.6 kcal/mol)
Methyl position G
2 2.8
3 >4.5
4 -0.3
5 6.1
Cyclooctane derivatives
Carbonyl is positioned at C3 or C7
LINR2 MeI
Me
Predict stereochemistry
Me
Nu
LiCuMe2
Predict stereochemistry
Disubstitution occurs at C4 or C6
Me
Me
Chem 206
Torsional Strain: the resistance to rotation about a bond Torsional energy: the energy required to obtain rotation about a bond Torsional Angle: also known as dihedral angle Torsional steering: Stereoselectivity originating from transition state torsional energy considerations
H H
G = +3 kcal mol-1
eclipsed
A H O H CH2 C H H H H CH2 H
H H
H O H H H B
staggered conformation
The eclipsed conformation (conformation A) is preferred. Polarization of the carbonyl decreases the 4 electron destabilizing Rotational barrier: 1.14 kcal/mol Houk, JACS 1983, 105, 5980-5988.
+2.0 kcal/mol
eclipsed conformation H
C H
H
Wiberg K. B.; Martin, E. J. Amer. Chem. Soc. 1985, 107, 5035-5041. A
H X H Me H B
Me X H
Conformation A is preferred. There is little steric repulsion between the methyl and the X-group in conformation A.
D. A. Evans
Chem 206
Houk: "Torsional effects in transition states are more important than in ground states"
H*
H H 2C H C H H H H 2C C H
H*
H H H 2C H
H*
H C H H C RL C
Transition states
H-radical and H-anion: antiperiplanar CR orbital stabilized the TS illustrated for Nu addition
C-RL
0 no H*
+
30 60 90 120
+1.6 +4.7
C-Nu homo
Nu
Forming bond
H
2 Kcalmol-1
Same trends are observed for H+ addition Houk, Science 1981, 231, 1108-1117 "The Theory and Modeling of Stereoselective Organic Reactions"
Forming bond
0 +2.4 0
Nu Transition state H H C H H C H
H0
+5.3
C-RL C-Nu
RL
Nu C R H
Houk, JACS 1981, 103, 2438 Houk, JACS 1982, 104, 7162
C-RL
RL
7-06-Torsional effects-2 9/29/03 8:17 AM
C-Nu
D. A. Evans
Chem 206
How do we account for the high selectilvities in the oxidation of the indicated olefin?
OH OH H N N Ph 98 : 2 diastereoselectivity O Ph 99 : 1 diastereoselectivity O O mCPBA H N H
Highly exo selective for electrophilic, nucleophilic and cycloaddition reactions Rate enhancement due to strain
OsO4
endo The Controversy over origin of high exoselectivities Steric effects Least nuclear motion Orbital distortion Schleyer: torsional steering B A
Ph O
B A Favored
Addition from exo face avoids eclipsing A & B hydrogens (better hyperconjugative stabilization of transition state)
Addition from indicated olefin face avoids eclipsing A & B H's (better hyperconjugative stabilization of transition state) Martinelli has carried out further studies on related structures...........
D. A. Evans
Transition State Torsional Effects: Olefin Additions Martinelli: Torsional steering important in selectivity
O mCPBA H
Chem 206
89
99 : 1 diastereoselectivity
major
mCPBA
Me
Me
62
50 : 50 diastereoselectivity
63
O
mCPBA H
major 99 : 1 diastereoselectivity 40
74
Authors propose that diastereoselection controlled by TS torsional effects Martinelli & Houk, J. Org. Chem. 1994, 59, 2204.
7-08-torsional effects-4 9/29/03 8:18 AM
D. A. Evans
Chem 206
Nu:
HE
[H]
Me3C
% Axial Diastereomer
0 10 20 30 40 50 60 70 80 90 100
HE HA
Nu:
Me C CH2Me H
3
The steric hindrance encountered by Nu-attack from the axial C=O face by the axial ring substituents (hydrogens in this case) at the 3-positions is more severe than the steric hinderance encountered from Nu-attack from the equatorial C=O face.
Axial Attack H:
Observation: Increasingly bulky hydride reagents prefer to attack from the equatorial C=O face. The most stereoselective Reductions
O Me3C H H OH OH H Me3C H H
[H]
Me3C
H:
Equatorial Attack
[H]
(R) Ganem, Tet. Let 1981, 22, 3447 Hutchins, JOC 1983, 48, 3412 private communication R = Bn R = Ph
Prediction
K. A. Beaver, D. A. Evans
Leading References:
Chem 206
J. I. Seeman, J. Chem. Ed. 1986, 63, 42-48. J. I. Seeman, Chem Rev. 1983, 83, 83-134. See also Eliel, pp. 647-655
k1, k2 >> kA, kB: If the rates of reaction are faster than the rate of interconversion, A and B cannot equilibrate during the course of the reaction, and the product distribution (PB/PA) will reflect the initial composition.
[PB] = [PA] [B]o [A]o
Me
Me
13
13
MeI
Energy
GAB G1 G2 G
PB
p. p. Do the two different conformers react at the same rate, or different rates? What factors determine the product distribution?
PA
A
Rxn. Coord.
The situation:
Consider two interconverting conformers, A and B, each of which can undergo a reaction resulting in two different products, PA and PB.
In this case, the product distribution depends solely on the initial ratio of the two conformers.
steric hindrance
less stable
Me
more stable
PA
major
k1
kA kB
k2
PB
minor
(1)
H O
MeBr
We'll consider two limiting cases: (1) The rate of reaction is faster than the rate of conformational interconversion (2) The rate of reaction is slower than the rate of conformational interconversion
If the rates of conformationall interconversion and reaction are comparable, the reactants are not in equilibrium during the course of the reaction and complex mathmatical solutions are necessary. See Seeman, Chem. Rev. 1983, 83 - 144 for analytical solutions.
MeBr
Me Me N minor product O Me H
Me Me N O H Me major product
While enolate conformers can be equilibrated at higher temperatures, the products of alkylation at -78 C always reflect the initial ratio of enloate isomers. Padwa, JACS 1997 4565
K. A. Beaver, D. A. Evans
Case 2: Curtin-Hammett Conditons
Chem 206
k1, k2 << kA, kB: If the rates of reaction are much slower than the rate of interconversion, (GAB is small relative to G1 and G2), then the ratio of A to B is constant throughout the course of the reaction.
PA
k1
To relate this quantity to G values, recall that Go = -RT ln Keq or Keq = e-G/RT, k1 = e-G1/RT, and k2 = e-G2/RT. Substituting this into the above equation:
[PB] [PA] = k2 k1 Keq = e-G2/RT e-G1/RT (e-G/RT) = e-G2/RTe-G/RTeG1/RT
kA kB
k2
slow
slow
PB
(1)
(4)
fast
G
Combining terms:
[PB] [PA]
= e-(G2 + G-G1)/RT or
[PB] [PA]
e-G/RT
G1 Energy
GAB
G2
Where G = G2+G-G1
PB
p. p.
A
PA
Curtin - Hammett Principle: The product composition is not solely dependent on relative proportions of the conformational isomers in the substrate; it is controlled by the difference in standard Gibbs energies of the respective transition states.
major
Rxn. Coord.
minor
The Derivation:
d[PB] d[P ] Using the rate equations dt A = k1[A] and dt = k2[B] we can write:
d[PB] d[PA] = k2[B] k1[A]
Within these limits, we can envision three scenarios: If both conformers react at the same rate, the product distribution will be the same as the ratio of conformers at equilibrium. If the major conformer is also the faster reacting conformer, the product from the major conformer should prevail, and will not reflect the equilibrium distribution. If the minor conformer is the faster reacting conformer, the product ratio will depend on all three variables in eq (2), and the observed product distribution will not reflect the equilibrium distribution. This derivation implies that you could potentially isolate a product which is derived from a conformer that you can't even observe in the ground state!
or
d[PB] =
k2[B] k1[A]
d[PA]
(2)
[B] [A]
(3)
d[PB] =
Keq d[PA]
Integrating, we get
[PB] [PA]
k2 K k1 eq
When A and B are in rapid equilibrium, we must consider the rates of reaction of the conformers as well as the equilibrium constant when analyzing the product ratio.
K. A. Beaver, D. A. Evans
Tropane alkylation is a well-known example.
N Me Me N
Chem 206
N i-Pr2N O
less stable
more stable
H Me
i-Pr2N
Li Me
s-BuLi
(-)-Sparteine
faster
13
MeI
13
MeI
slower (-)-Sparteine
13
13
Me + Me N
Me + N
Me
major product
minor product
i-Pr2N
Because sparteine is chiral, these two complexes are diastereomeric and have different properties.
Lisparteine Me
Lisparteine Me
i-Pr2N
p. p.
The less stable conformer reacts much faster than the more stable conformer, resulting in an unexpected major product!
JOC 1974 319
faster
i-Pr2N O
Cl
slower
Oxidation of piperidines:
Me N N Me3C H
i-Pr2N Me
less stable
Me3C
Me
Me
more stable
82 - 87% ee
Keq = 10.5 k1
Me N+ O
slower
H2O2
k2 faster
O Me3C H N + Me
Enantioselectivities are the same, regardless of whether or not the starting material is chiral, even at low temperatures. Further, reaction in the absence of (-)-sparteine results in racemic product. Note that the two alkyllithium complexes MUST be in equilibrium, as the enantioselectivity is the same over the course of the reaction. If they were not equilibrating, the enantioselectivity should be higher at lower conversions.
Me3C
minor product
Ratio: 5 : 95
major product
When the equilibrium constant is known, the Curtin-Hammett derivation can be used to calculate the relative rates of reaction of the two conformers. Substituting the above data into [PB]/[PA] = k2K/k1, the ratio k2/k1 ~ 2.
Note that in this case, the more stable conformer is also the faster reacting conformer! Tet. 1972 573 Tet. 1977 915
This is a case of Dynamic Kinetic Resolution: Two enantiomeric alkyl lithium complexes are equilibrating during the course of a reaction with an electrophile. Beak, Acc. Chem. Res, 1996, 552
K. A. Beaver, D. A. Evans
Chem 206
The asymmetric hydrogenation of prochiral olefins catalyzed by Rhodium is an important catalytic process.
[L2Rh]+
MeO2C
NHAc
MeO2C
NHAc
coordination
MeO2C NH HN
coordination
CO2Me P Ph O Me Me Rh P
Ph
Ph
> 95% ee Enantioselectivities are generally very high when the ligand is a chelating diphosphine. (ee's are given for S,S-CHIRAPHOS)
P Rh P Ph O
minor
major
When a chiral ligand is used, there are two diastereomeric complexes which may be formed:
MeO2C NH P HN P Ph O Me Me Ph O Rh P CO2Me
hydrogen addition
MeO2C P
faster
slower
hydrogen addition
CO2Me
NH Ph O Me Me
HN Ph O
P P Rh H H
p. p.
Rh P
H Rh P H
minor complex 1
H2 fast
major complex
(NMR, X-Ray) H2
slow
migration
P
+S
+S
migration
MeO2C R
NHAc
MeO2C S
NHAc
H Rh P S O Me
CH2Ph CO2Me R NH
PhH2C MeO2C S S HN
P H Rh P O Me
Ph
Ph
observed product
Observations: Complex 2 is the only diasteromer observed for the catalyst-substrate complex (1HNMR, X-Ray crystallography) in the absence of hydrogen The enantioselectivity is strongly dependant on the pressure of H2, and degrades rapidly at higher hydrogen pressures The observed enantiomer is exclusively derived from the minor complex 2
MeO2C R Ph NHAc
reductive elimination
-L2RhS2
-L2RhS2
reductive elimination
MeO2C S
NHAc
Ph
> 95% ee
K. A. Beaver, D. A. Evans
Chem 206
The Curtin-Hammett treatment can be extended to ANY case where different products are formed from two rapidly intereconverting starting materials, whether they are conformers, tautomers or isomers.
k1 kA kB k2
PA
major
PB
minor
"It was pointed out by Professor L. P. Hammett in 1950 (private communication) that ..." David Y. Curtin, 1954 " Because Curtin is very generous in attributing credit, this is sometimes referrred to as the Curtin-Hammett principle rather than the Curtin principle." Louis Plack Hammett, 1970
Stannylene ketals provide an efficient way to acylate the more hindered site of 1,2-diols.
O Cl O 2N Ph O SnBu2 O O 2N O Cl
p. p.
Ph
OCOAr OSnBu2Cl
Ph
O O
Ph Ar OSnBu2Cl
OSnBu2Cl OCOAr
more stable
less stable
Ratio 2:1
TMS-Cl faster Ar= p-NO2C6H4 slower TMS-Cl
Curtin - Hammett Principle: The product composition is not solely dependent on relative proportions of the conformational isomers in the substrate; it is controlled by the difference in standard Gibbs energies of the respective transition states.
Ph
OCOAr OTMS
Ph
OTMS OCOAr
THE TAKE-HOME LESSON: Never assume that the most stable conformation of a compound is the most reactive. It may be, but then again, it may not.
The two stannyl esters are in equilibrium at room temperature, and the more stable isomer is initially formed more slowly. The stannyl esters are allowed to equilibrate before quenching with TMS-Cl, which reacts more rapidly with the less hindered primary alkoxystannane.
JOC 1996, 5257
D. A. Evans
Chem 206
http://www.courses.fas.harvard.edu/~chem206/
OH Me2CH
OH diastereoselection 24:1
Me2CH Me
Me
W. C. Still & J. C. Barrish, J. Am. Chem. Soc. 1983, 105, 2487. Me NHCONHPh Ph
m-CPBA CH2Cl2, 0 C 75 %
Me O
NHCONHPh Ph
Diastereoselection = 95 : 5
Web Problem 163: The following is an idea that has been proposed to you by a fellow student. The proposal is based on the fact that boranemethyl sulfide complex is an effective hydroboration reagent (eq 1). It is proposed that homoallylic sulfides such as that illustrated below should be capable of "directing" the hydroboration process from this substituent through the borane-substrate complex.
H 2B
-SMe2
(1)
Me2SBH3 + SMe
Me2S +Me2S
Me
BH3
directed hydroboration
Me
S
(2)
???
Me Me
BH2
Me
D. A. Evans
8-00-Cover Page 10/1/03 8:02 AM
Part A. In order to begin your critique, you must possess a good working knowledge of the details of the hydroboration of olefins with boranemethyl sulfide. Provide a clear depiction of the transition state for the hydroboration process using ethylene as the olefinic substrate and boranemethyl sulfide as the hydroborating agent. Part B. Now, based on your knowledge of the hydroboration reaction and the principles learned thus far in Chem 206, critique the idea proposed in Eq 2. You must concisely state the logic upon which you base your assessment. Pictures speak a thousand words.
D. A. Evans
Chem 206
Hydrometallation
R C C R H H
Halogenation
M H
M H
M = B, Al, etc
R C C R H H
R C C R H H
Br
Br
H R C C H Br
Br
Hydrogenation
R C C R H H
M-catalyst
H H
R C C R H H
+ Hg(OR)2
RO R H R C C H HgOR
RO2H
ROH
R C C R H H O Os O O O
RSX
RO R H R C C H SR
OsO4
N2
R C C R H H R2 C R C C R H H R R O
Attributes: Each process may proceed via an bridged intermediate where X is the initiating electrophile Olefin substitution may disrupt bridging
X R C C R H H
M-catalyst + R2C=N2 N2
+ R2C=C=O
N2
R C C R H H
+ HX
R C C H X
H C C R X
Attributes: Each process adds to the C=C via a stereospecific process Intermediates may be involved in some of the indicated reactions
Attributes: Process may proceed via an bridged intermediate where H+ is the initiating electrophile Olefin substitution, reaction conditions as well as halide type may disrupt bridging
H R C C R H H
D. A. Evans
The basic process
S H B H H
R
Chem 206
H
R
H 2B
R
H C
O Me
CH2OBn Me
R
OMe O Me Me Me OH
B2H6 H2O2
+ R
Oxidant
MCPBA BH3, H2O2
Ratio, A:E
69:31 34:66
Reference
JOC, 1967, 32, 1363 JOC, 1970, 35, 2654
p. p.
BnO Me Me Me
OH Diastereoselection = 3:1
OH
RL RM Me
H2O2
OH major diastereomer
control elements
A(1,3) allylic strain Steric effects; RL vs RM Staggered transition states RM TrO Me H RL H C B H C H H CH2OR
Me
Me
Me
ThexylBH2, then BH3
Me OTr
TrO OH OH OH
H RM
H B C RL H H C CH2OR Me
OH
OTr
Diastereoselection;
5:1 Me OTr
major
minor
Me
Me
Me
Me
Me
Me
Me
TrO
OH
OH
OH
OTr
OH
OH
OH
OH 4: 1
OH
Diastereoselection;
Houk, "Theoretical Studies of Stereoselective Hydroboration Reactions" Tetrahedron 1984, 40, 2257 (Handout)
D. A. Evans
Chem 206
R H H R R RL H C H Me Me RL OH
R2BH H2O2
H OH
Me RL
RM Me C
B H C
Me RL RM OH
TS2
minor
H H
B RM C
R2BH H2O2
Houk's rules: Orient RL anti-periplanar to incoming reagents to avoid TS eclipsing: Case I: Borane
H H H H B RM C H C RL A(1,2) Strain H Me
BH3 H2O2
RM RL Midland finds that TS1 favored for R2BH reagents, but TS1 ~ TS2 for BH3 Others have found that TS1 favored over TS2 for BH3
TS2
major
Me RL RM OH
p. p. A
H RM Me C RL from Lecture 4:
Representative Examples
favored for BH3 Me Me Me OH H CH2 H
9-BBN H2O2
TS1
minor
B H C
H H H
BH3 H2O2
Me Me H H R2BH
CH2OH H
RL RM
Me Me
= 50
Me H C H
OH R
OH
R Me
H2O2
=0
H C H Me
=0
= 110
H C Me H +0.06 kcal +1.39 kcal H C H H C H Me Me
+2.68 kcal
Me
D. A. Evans
Case I: Dialkylboranes
H R R
Chem 206
TS1
major
RM Me C
TS1
minor
minor
TS2
H H
TS2
major
H H
favored for BH3 OMe Me A Me O OH H OMe Me Me Me O B C 9 O Me C-9 C10 Me D O E O O Me OMe Me OMe F Me OH OMe Me O BH3SMe2 85% OMe O O N Me O
1 5 5
p. p.
HO2C
Me H
Lonomycin A
Me OH
10 9
OH
XP
Me Me OH
10 9
O OMe H
Me
Me
H H B RO H C H
H H C RL H Me RO Me H C RL B H C H H H
diastereoselection 92 : 8 OMe Me O XP
1 5
TS1 favored
R
TS2 disfavored
R
Me Bn
O OMe H
Me
Me
Me OH
10 9
OH
R H H
B RO C
H C RL
H Me
RO Me
H C RL
B H C
R H H
9-BBN 60%
Me
O OMe H
Me
Me
diastereoselection > 95 : 5
TA1 disfavored
TA2 favored
D. A. Evans
Chem 206
Me H O O
For each of the examples shown below, attempt to rationalize the stereochemical outcome of the reaction in terms of one of the models presented in the discussion.
1. 9-BBN 2. H2 O2 , NaOH
Me OH Et Et Me O Et H O Et OH
B2H6 H2O2
Me R Et Me
Me
Diastereoselection = 7:1 O O
Et Et
CO2H CH2 Me
Me
"one isomer"
Y. Kishi & Co-workers, J. Am. Chem. Soc. 1978, 100, 2933.
1. 9-BBN 2. H2 O2 , NaOH
H Me
Me O Me O Me
Me
Diastereoselection = 10:1 Me
BH3 .THF
O Me O
Me Me Me OH CH2
p. p.
Mori, K. Tetrahedron 1976, 32, 1979
HO
B2H6 / [ O ]
OH
Me
diastereoselection 12:1
OH Diastereoselection = 19:1 Me
B2H6 / [ O ]
OH
Me
OH Diastereoselection = 32:1 Me
Me Me
B2H6 / [ O ]
OH
Me
OH BH3.THF
B2H6 / [ O ]
OH
Me
OH Diastereoselection = 4.6:1
D. A. Evans
CH2 Me3C BH3.THF
Chem 206
OH H O H OH O Me
BH3.THF
BnO HO
Diastereoselection = 2.1:1
CH2 Me3C Me Me
BH3.THF Me3C Me
Diastereoselection = 1.2:1
H N H O
CH3
OH
p. p.
Me3C
CH2 Me
OH
Diastereoselection = 3.3:1
BH3.THF Me O H H CO2Me
Me OH
Me
O H CO2Me
CH2
Diastereoselection = 2.4:1
55% yield with the diastereomeric alcohol produced in an unspecified amount. Recycling of the minor isomer further provided 15% of the desired material
CH2 Me
BH3.THF Me
OH Me
Me
NNHAr
Diastereoselection = 4.9:1 (Compare with H.C. Brown's case, with 9-BBN; 1.5:1)
Me Me H
Me
OH
D. A. Evans
Chem 206
O R
R O CH2 R
A B
Claisen Rearrangement
A B
favored product p. p.
A B
favored
R OH
CH2I2
R O Zn CH2I
CH2 R OH
Simmons-Smith Reaction
Directed Reactions
Review: Hoveyda, Evans, Fu Chem. Reviews 1993, 93, 1307
MCPBA
Hydroxyl-directed Reactions
Cl CO3H
ratio 92 : 8
O OH
t-BuOOH VO(acac)2
ratio 98 : 2
A B
Et2Zn CH2I2
ratio 90 : 10
Me
M(I) + H2
Agenda
Directed Reductions
Hydrogenation Hydride reduction
Me
OH
(Ir+) Stork JACS 105, 1072 (1983) (Rh+) Evans JACS 106, 3866 (1984)
D. A. Evans
A. Rao in Comprehensive Organic Synthesis, Trost, Ed., 1992, Vol 7, Chapter 3.1
H Me OH
Me
reagent
X Me Me OH
s General Reaction:
X = O, CH2
R R O R O OH q R R O
+
R R R
q O
R
+
R OH
maj
Reag
H Me OH C H Me H
Reag
Me C C OH H H
HOMO CC LUMO CC
H Me
min TSminor
R R O O O
H
R O O
TSmajor
q O
O
H
q O
q O
R C C H R C H H H R
q O
C C H H
R C C H H R
Selectivity 71 : 29 95 : 5 > 99 : 1
Estimate ~ 50 ~ 120 ?
HOMO CC LUMO: OO
s Reaction rates governed by olefin nucleophilicity. The rates of epoxidation of the indicated olefin relative to cyclohexene are provided below: OH
OH OAc
The transition state bite angles for the above reactions are either not known or have been only crudely estimated. The "best guesses" are provided.
1.0
0.6
0.05
0.4
s The indicated olefin in each of the diolefinic substrates may be oxidized selectively.
Me Me Me Me Me Me Me
H Me Me
D. A. Evans
Chem 206
R O
O
H
R O
O
R C C
R R C H C H O R
H O R
O R H C C
H O
C H2
C H2
C H2
CF3 O O H C C H2 C H R R O C H2 O
H
CF3 O
O
H
CF3 O
O
C C H R R
O C H2
O H C C H
OH
OTBS
OH O H O O Me3C OH
OTBS
24 : 1
100 : 1
Me3C OTBS
1:8
12 : 1
5:1
Me3C
100 : 1
Me3C
1:4
1:6
D. A. Evans
Chem 206
Substrate
O HN HO Me HO
Major Product
O HN Me
Selectivity
Substrate
OH O
Major Product
OH Me OH
Selectivity
9:1
O HO O HN Ph HN HO O Ph
"highly selective"
Me
OH
HO Et Me Me
HO Et
"highly selective"
O Me Me
p. p.
O O R O O R
"highly selective"
HO
16 : 1
HO Me O Me
a. R = NH2 b. R = NHBn
3:1 5:1 10 : 1
HO
1:1
HO Me O Me
c. R = NMe2
Me Me
a. R = OCONHBn b. R = OCONMe2
>20 : 1 >20 : 1
HO HOH2C HO O HOH2C
21 : 1
R RO
R RO
a. R = CONH2 b. R = CONHBn
5:1
AcO
AcO
c. R = CONMe2
Chem 206
The literature precedent: Sheng, Zajecek, J. Org. Chem. 1970, 35, 1839
TBHP
OR RO O V O O OH O O
80 oC Catalyst
OH
OH
VO(acac)2 Mo(CO)6
4:1 1:1
ROH OR RO O V OR O HO
ROOH
HO
O Me Me
VO(acac)2 TBHP 80 C
Me Me OH
Me O
Regioselection 20:1
p. p.
OH
Mo(CO)6 TBHP 80 C
O
Relative Rates (Diastereoselectivities) for the Epoxidation of Cyclohexene Derivatives JACS 1973, 95, 6136 Substrate krela,b (diastereoselectivityc ) peracid
1.00
OH O-OtBu O OAc
t-BuOOH
HO HO
t-BuOH
O
Mo(CO)6
1.00
VO(acac)2
1.00
2 1 3 RO 4 O
tBu O V O tBu O O
OR V
0.55 (92 : 8)
4.5 (98 : 2)
>200 (98 : 2)
--
slow
RO V O O
11.0 (98 : 2)
10.0 (98 : 2)
The relative rate data apply only to a given column. Values in parenthesis refer to the ratio of syn:anti epoxide.
D. A. Evans
Allylic Alcohols:
Me OH
Reagent
Chem 206
OH Me O Me
+
OH Me O Me
Me O
OH Me
threo +
Me
OH Me
erythro
Me
Me
Me
Ratio 95 : 5 71 : 29 84 : 16
H H OH Me OH
t BuOOH
Ratio 64 : 36 29 : 71 62 : 38 64 : 36
OH
OH R1
O R1
R2 SiMe3
R1
R2 SiMe3
TSminor
R2 Bu Me
OH
Yield 84 % 70 %
Ratio 99 : 1 99 : 1
H C5H11
TSmajor
H Me
C H
Me H
H Me
C HO
H H
TSminor
EtO OEt OH
O O Me Me
VO(acac)2 60 %
O
EtO OEt OH
O O Me Me
only isomer
t-BuOOH
Me Me
OH
Reagent
Me Me O
OH Me
threo +
Me Me O
OH Me
erythro
O EtO OEt O Me Me
VO(acac)2 60 %
O
EtO OEt
O O Me Me
only isomer
Me
K. Oshima & Coworkers Tetrahedron Lett. 1980, 21, 1657, 4843. K. B. Sharpless & Coworkers Tetrahedron Lett. 1979, 20, 4733.
Ratio 95 : 5 86 : 14 95 : 5 100 : 0
Me HO OH
Boeckman, JACS 1977, 99, 2805.
t-BuOOH VO(acac)2 60 % HO
O Me OH
Diastereoselection = 7 : 1
Me
NHCONHPh Ph
m-CPBA CH2Cl2, 0 C 75 %
Me O
NHCONHPh Ph
+
Me O
NHCONHPh Ph
Diastereoselection = 95 : 5
D. A. Evans
Chem 206
OH R2
Me
Me
Control Elements
A(1,3) Strain Directed Rxn
H H Me H O L HV
R1
R2 Me i-Pr
OH R2 +
Yield 92 % 97 %
Syn diastereomer
OH t-BuOOH VO(acac)2
C6H13 Me
O R1 Me
O R1 Me
OH
p. .
Et
Me
t-BuOOH VO(acac)2
O Et
OH Me +
O Et
OH Me
R1 C6H13 Me Me
OH Me O Et Me C5H11 t-BuOOH VO(acac)2 Me
R2 Me Me C5H11
OH Me C5H11
Yield 73 % 70 % 81 %
O
+ Me
Ratio 70 : 1 85 : 1 16 :1
OH Me C5H11
Diastereoselection 12 : 1
Control Elements
Directed Rxn
Me
H O
L HV
L' O R O H Et Me
OH
Diastereoselection = 211 : 1
Prediction
H R2 O R1 H L HV L' O R H L O R1 HV
Substrate
L' O R O H Me OH Me OH Me Me OH Hex R
Product
OH Me OH Me Me OH Hex
Selectivity
O
2:1
O H
Me
R2 H
4.6 : 1
Anti diastereomer
Syn diastereomer
1.4 : 1
R = (CH2)7CO2Me
D. A. Evans
Chem 206
Me Et OH
iPr
OH
Me
diastereoselection ~ 9 : 1
H H R O Et Et H V Me R OH O Me
A
H O
O
O R
B
Me
OH Et
Me OH
Et
p. .
Me Et Me
CHMe2
O Me Et Me
OH CHMe2 Ar OH
A
Ar O Et
Diastereoselection 8:1
OH Me Et
Ar = p-MeOPh
diastereoselection ~ 20 : 1
H Et Me Me R O H V Me O O R OH R O Me O CHMe2 Et Me Ph O Me H R O H V Me O O R R OH O Et Me O Me N OBn Me O OH Et VO(acac)2 TBHP C6H6, RT OH Et Me Me A O Me OH H B O OH
OH
Me
diastereoselection ~ 6 : 1
O XN
OH
O Et
Me
Et
OBn HOAc O
Me
diastereoselection 20 : 1 (89 %)
XN OBn
D O
Et Me OH
D. A. Evans
Chem 206
http://www.courses.fas.harvard.edu/~chem206/
Olefin Bromination
Reading Assignment for week A. Carey & Sundberg: Part B; Chapter 4 "Electrophilic Additions to CC Multilple Bonds"
Hoveyda, Evans, & Fu (1993). Substrate-directable chemical reactions. Chem. Rev. 93: 1307-70 (Handout) J. M. Brown, Angew. Chem. Int. Edit. 26, 190-203 (1987) (Handout) Investigation of the early Steps in Electrophilic Bromination through the Study of the Reaction of Sterically Encumbered Olefins R. S. Brown, Accts. Chem. Res. 1997, 30, 131 (handout) Bromoniun Ions or -Bromocarbocations in Olefin Bromination. A Kinetic Approach to Product Selectivities M-F. Ruasse, Accts. Chem. Res. 1990, 23, 87 (handout) Friday, October 3, 2003
D. A. Evans
9-00-Cover Page 10/2/03 3:38 PM
D. A. Evans
Chem 206
Relevant Review articles: J. M. Brown, Angew. Chem. Int. Edit. 26, 190-203 (1987).
Polar functional groups may play a role in controlling the diastereoselectivity of the hydrogenation process; however, the control elements were not well-defined.
CHMe2 CHMe2 O
General Mechanism
M
M(0)
R C + H
C R H
R C H
only isomer
CH3
H C R H
M(0) +
M R H C C
H R H R C H
H C R H
however
CHMe2 OH H CH3
R C H
p. .
Historically, primary stereochemical control designed around analysis of steric environment in vicinity of C=C. However, the influence of polar effects was documented
trans:cis = 55:45
O O
CO2Et
CO2Et HO H H H H
H2 Pd-C EtOH
OMe
10% Pd-C
OMe
H2
HO H H OH H
Steric Control
sole product
LiAlH4
Pd(0)
O O CH2OH
Pd(II)
O
trans : cis 85 : 15
CH2OH O HO H H
H H
H2 Pd-C EtOH
OMe
5% Pd-Al2O3
OMe
H2
OH H
Directed ?
12 : 1
trans : cis 5 : 95
D. A. Evans
Chem 206
The first rational attempt to identify those FGs which will direct the reaction
H O CH3O R O H2, 5% Pd-C CH3O
10
O Rh R O Ph2P
(CH2)n Schrock & Osborne, J. Am. Chem. Soc. 91, 2816 (1969)
BF4
PPh2 Py
Ir
PF6
PCy3
cis : trans 95 : 5 93 : 7 75 : 25 55 : 45 18 : 82 15 : 85 14 : 86 10 : 90
S H2 Ph2P Rh
S
BF4
H2
S H Rh H Ph2P
S = solvent
PPh2
(CH2)n
PPh2
16-e
18-e-
H. Thompson & Co-workers, J. Am. Chem. Soc. 95, 838 (1973) The first rational attempt to associate catalyst with substrate:
CH2OH
S H MeO
Rh Ph2P
S PPh2
Reductive Elimination
H H
Oxidative Addition
H
(+S)
Rh
H 2C Ph2P
S PPh2
H Rh Ph2P
S PPh2
D. A. Evans
Chem 206
S 2H2 Rh Ph2P
+
S Rh
S
BF4
H2
S H Rh H PPh2 CH3
CH2Cl2
CH3
+2 S
BF4
Ph2P
PPh2
PPh2
16-eP P H2 Rh HA HB H C H H OH C
18-e
- Ph2P
Catalyst
Rh(DIPHOS-4)+ +
R2 CH2
OH
R2 H
Ir(pyr)PCy3
p. .
P Rh P P R2 CH3 OH P Rh CH3 H R2 OH
OH
Rh + H2
OH CH3 CH3
CH2OH
Rh + H2
CH2OH
65 : 1
CH3 19 : 1
Me
Me
Me
H Me Me
OH Me
}
OH Me
HA
HA H H
O R2
+ H
Retigeranic Acid Me
Rh H2
+
OH Me Me
That H atom lying parallel to the pi-system (HA) should migrate preferentially if the dihydride is an intermediate.
Me
H Me
OH
75 : 1 (95%)
Rh(DIPHOS-4)+ H2 800 psi THF THF is important to success of rxn to buffer the Lewis acidity of the catalyst which causes elimination of ROH under normal conditions
D. A. Evans
Chem 206
Polar functional groups other than OH may also direct the process
CO2Me Rh(DIPHOS-4)+ H 2C H2 CH3 CO2Me
diastereoselection 91 : 9
X OMe NC4H8
CH3
H2
diastereoselection 89:11
CH3
CH3
p. .
Ir(pyr)Pcy3+ H2 Me
A.G. Schultz and P.J. McCloskey, J. Org. Chem., 1985, 50, 5907.
diastereoselection >99:1
H Me OCH3 15 psi H2 Ir(pyr)Pcy3+ CH3 R.H. Crabtree and M.W. Davis, J. Org. Chem., 1986, 51, 2655. OCH3
J.M. Brown and S.A. Hall, J. Organomet. Chem., 1985, 285, 333. Me O N N H O H Ir(pyr)Pcy3+ H2 H Me O N N H O CONC4H8 N CH3 CH2OMe O CH3 Ir(pyr)Pcy3+ H2 CH3 N CH2OMe O CH3 H CH3
diastereoselection >99:1
diastereoselection >99:1
15 psi H2 Ir(pyr)Pcy3+
CONC4H8
diastereoselection >99:1
diastereoselection >99:1
CH3
CH3
A.G. Schultz and P.J. McCloskey, J. Org. Chem., 1985, 50, 5907. A.G. Schultz and P.J. McCloskey, J. Org. Chem., 1985, 50, 5907.
D. A. Evans
Chem 206
OH H2 R2 Me R1
anti > 93 : 7
favored
OH R2 CH2 P P + Rh R1
anti
OH P R2 CH3 R1 P + Rh R2 H
P P Rh C R1 OH C CH3 H H2 R2 Me
+
OH R1
H H
H C P Rh P C + OH
R1 CH2R2 H2 R2 Me
OH R1 OH R CH2 Me O N O O Me Ph H2 Rh(DIPHOS-4)+ R Me OH
syn > 91 : 9
p. .
disfavored
syn
COXn Me
D
P P P + Rh P R2 H OH R2 Me P P + Rh H C P Rh P C + OH R1 Me H2 R2 Me OH R1 Rh C R1 + OH C CH3 H OH H2 OH R2 Me R1 R Me Me O
anti
low pressure
Me N O O Ph OH R Me Me COXn
favored
H2 Rh(DIPHOS-4)+
syn
syn
R2 H
D
R1
R = (CH3)2CH R = Ph R = CH3
disfavored
anti T
R = (CH3)2CH R = Ph
D. A. Evans
Chem 206
favored
OH R Me Me
Me Et Me O Me
syn
disfavored
P P + Rh
P H O+ P Rh CH2 R Me C Me C H H
OH H2 R Me Me
EtO2C Me HO Me Me H2 Rh +
Catalyst
Me
Ratio
+
Rh(DIPHOS-4)
EtO2C HO Me Me
85 : 15 65 : 35 98 : 2 (90%)
Rh()(BINAP) + Rh(+)(BINAP)
+
p. .
HO Me Me
OTBS
HO Me Me
OTBS
A
HO Me Me HO
syn
OH
OH Me O Me H O
Me OH
B Olefin A A B
OTBS
anti
Catalyst (H2 Pressure) Rh(DIPHOS-4)+ (1000 psi) Ir(pyr)PCy3+ (15 psi, 2.5 mol%)
syn : anti 95 : 5 73 : 27
Me CH3O2C Me Me Me OH
Diastereoselection: 94 : 6 (93%) with Dow, Shih, Zahler, Takacs, JACS 1990, 112, 5290
}
D. A. Evans
R R R Br2 R
Olefin Bromination-1
R Br C
Chem 206
Introduction
R
Bromonium ion origin of the anti (trans) selectivity first suggested by Roberts, JACS 1937, 59, 947 +
R R R
Br R
R R
R R
Reaction is first order in alkene At low concentrations of Br2, rxn is also first order in Br2 At higher concentrations of Br2 in nonpolar solvents rxn is second order in Br2. Substituent Effects on Bromination Rates
Br2
Br R R Br
R Br C
Br R
First X-ray Structure of a bromonuium ion: Brown, JACS 1985, 107, 4504
Alkene
CH2=CH2 CH3CH=CH2 n-PrCH=CH2 i-PrCH=CH2 t-BuCH=CH2 (CH3)2C=CH2 cis-CH3CH=CHCH3 trans-CH3CH=CHCH3 (CH3)2C=CHCH3 (CH3)2C=C(CH3)2
krel
1 61 70 57 27 5470 2620 1700 130,000 1,800,000 Br-3 Br-2 C C 2 eq Br2 -2 eq Br2
Br3 Br
p. .
Br-4
X-ray structure
Stereochemical outcome versus structure (Br2 in HOAc @ 25) Alkene
H Me H Me H Ph H Br-1
% anti addition
Alkene
H Me
% anti addition
2.116 2.194
100%
Me Me Ph Me H H
83%
100%
H H Ph Me Me Me
63%
1.497
73%
Me Ph H
68%
D. A. Evans
Olefin Bromination-2
Overall Reaction Mechanism
Second Order Kinetics
Chem 206
Calculated Geometries of Substituted Bromonium Ions Ruasse, Chem Commun. 1990, 898 More recent calculations: Sigalas, Tetrahedron 2003, 59, 4749
Br
2.01
Br
1.88
Br
2.70 1.51 2.05
Products
H H
1.47
H H
H H
Me Me
Me Me
1.51
Me Me
Br2
Note; the CBr bond lengths in previous X-ray structure are 2.116 . Bromonium Ions undergo fast exchange with olefins Brown, Accts. Chem. Res. 1997, 30, 131 p. . Unprecedented until 1991 (Bennet, JACS 1991, 113, 8532)
(-complex)
Br2
Br Br3 -complex
Products
AdC CAd X
Br3 Me3C H Br H
exclusive product
X = Br: exchange rate: 2 x 106 M1 s-1 AdC CAd X = I : exchange rate: 8 x 106 M1 s-1
Diaxial opening of bromonium ions may be viewed as an extension of the Furst-Plattner Rule for epoxide ring opening (Lecture-3).
H Me3C H Br H MeOH Me3C H H H Me3C H H OMe H H Br Me3C H Br Br OMe H H
R R R
R R R
R R
47%
+ Br
R R complex R R R R
+ Br
R R TS R R
+ Br
53%
It appears that bromine attack from both olefin faces occurs wilth near equal probability.
D. A. Evans
Olefin Bromination-3
Chem 206
Bromination of Cyclohexene Derivatives Pasto, JACS 1970, 92, 7480 Diaxial opening of bromonium ions may be viewed as an extension of the Furst-Plattner Rule for epoxide ring opening. (Lecture-2)
H H
Me
Case A
MeOH PyrBr+ Br3 H Me3C H MeOH Me3C H Me3C H Br
H H Br Me3C H Br
OMe H H
H R
47%
53%
Case B p. .
PyrBr+ Br3 Me3C H Me MeOH OMe Me3C H Br Me H H Me
How to generate either epoxide from a conformationaly biased olefin exclusive product
H Me RCO3H H O Me Epoxidation controlled by steric effects imposed by cis-fused ring
Br + Me3C H H Me Me3C
H anti-Reactive
Br H
Br Me3C H
not Me H observed
OMe H H O
Me base H Br H H H
Me Me Br OH minor major H
syn-Unreactive
H H OH
From Case A, one assumes that both bromonium ions are formed; however, for the syn isomer to react, ring opeing must proceed against the polarization due to Methyl substituent.
D. A. Evans
Oxymercuration Pasto, JACS 1970, 92, 7480 The basic process:
H R C C H H XHgX ROH XHg H C R C H H OR NaBH4 H
Olefin Oxymercuration-1
Chem 206
Diaxial opening of bromonium ions may be viewed as an extension of the Furst-Plattner Rule for epoxide ring opening. (Lecture-2) Case A
MeOH PyrBr+ Br3 H Me3C H Br H MeOH Me3C H H H Me3C H H OMe H H H Br Me3C H Br Br OMe H H
Kinetics: Halpern, JACS 1967, 89, 6427 Reduction: Pasto, JACS 199, 91, 719 Overview: B rown, JOC 1981, 46, 3810.
47%
Me3C
53%
p. .
HgOAc
Case B
PyrBr+ Br3 Me3C Me MeOH OMe Me3C H Br Me H Br H anti-Reactive H Me
R=H R = Me
Me3C H Me Hg(OAc)2 THF, H2O Me3C
41% 100%
48%
OH H Me
exclusive product
exclusive product
syn-Unreactive Br + Me H H HOMe
H+
Me3C H
Br H OMe Me
HgH
not observed
nonstereoselective radical chain process O O CO2 Formate is an excellent source of hydride ion for late transition and heavy main-group metals
syn-Unreactive
R Hg
H
From Case A, one assumes that both bromonium ions are formed; however, for the syn isomer to react, ring opeing must proceed against the polarization due to Methyl substituent.
D. A. Evans
Chem 206
http://www.courses.fas.harvard.edu/~chem206/
Bromoniun Ions or -Bromocarbocations in Olefin Bromination. A Kinetic Approach to Product Selectivities M-F. Ruasse, Accts. Chem. Res. 1990, 23, 87 (handout) Investigation of the early Steps in Electrophilic Bromination through the Study of the Reaction of Sterically Encumbered Olefins R. S. Brown, Accts. Chem. Res. 1997, 30, 131 (handout)
OR
OR
O Me
OR
OR
O Me
O OH HgX Me Me
16
Hoveyda, Evans, & Fu (1993). Substrate-Directable Chemical Reactions. Chem. Rev. 93: 1307-70 (Handout)
XHg Me BnO
O O O Me Me Me H O Me
Me OH
D. A. Evans
10-00-Cover Page 10/6/03 8:35 AM
85%, dr = 93 : 7
Me
Ionomycin Synthesis (with Dow & Shih, JACS 1990, 112, 5290)
D. A. Evans
Olefin Oxymercuration-1
Oxymercuration Pasto, JACS 1970, 92, 7480
Chem 206
Diaxial opening of bromonium ions may be viewed as an extension of the Furst-Plattner Rule for epoxide ring opening. (Lecture-2) Case A
MeOH PyrBr+ Br3 H Me3C H MeOH Me3C H H Me3C H Br H Me3C H Me Me3C H PyrBr+ Br3 H OMe H H H Br Me3C H Br Br OMe H H
Kinetics: Halpern, JACS 1967, 89, 6427 Reduction: Pasto, JACS 199, 91, 719 Overview: B rown, JOC 1981, 46, 3810.
47%
53%
p. .
HgOAc
Case B
R=H R = Me
Me3C H Me Hg(OAc)2 THF, H2O Me3C
41% 100%
48%
OH H Me
exclusive product
Me H
HgOAc Me H
H anti-Reactive
HgX
not observed
Me3C
exclusive product
HgH
nonstereoselective radical chain process O O CO2 Formate is an excellent source of hydride ion for late transition and heavy main-group metals
R Hg
H
From Case A, one assumes that both bromonium ions are formed; however, for the syn isomer to react, ring opeing must proceed against the polarization due to Methyl substituent.
D. A. Evans
Oxymercuration Examples
s Acyclic allylic alcohols:
OH OBn O H H H OC6H11 Giese, Tet. Lett. 1985, 26, 1197 : = 96 : 4 R
Hg(OAc)2 R'OH
Chem 206
OH
NaBH4
OH HgOAc R R'OH HOH MeOH HOH HOH Me OR' R -Et -Et -Ph -tBu H C H H RL X RL OH HgOAc Ratio 76 : 24 93 : 07 88 : 12 98 : 02 OH yield 65% 72% 66% 70%
BnO BnO
R OR'
H R' AcNH H O
X Hg HO
Hg(OAc)2
H OBn
H O HO HO Me H
HO Me H
Hg HO H C RL Me
H C H Me HOH RL
OH
OH Me
O-acetate participation will turn over the stereochemical course of the rxn
OAc Et
Hg(OAc)2 HOH NaBH4
XHgCH2 N BnO2 C
Me H
H N BnO2 C H
OAc Et Me Et OH erythro
Hg(OAc)2
COOMe
With more electrophilic Hg(II) salt, more polar solvents, and longer rxn times, the rxn may be rendered reversible.
BnO
BnOH NaBH4
diastereoselection = 83 : 17 (79%)
D. A. Evans
Oxymercuration Examples
Proposed Mechanism
Lewis acid catalyzes formation of hemiketal
H R' R O HgCl H OH Me O Me H
5% Yb(OYt)3
Chem 206
H O O
Me Me
OH R
+ H
O R'
HgClOAc 5% Yb(OYt)3
O R Me
Yb(X2)
Yb(X2)
Me O HgCl R H O O X R Hg
OH R
+ Me
O Me
H Me
HgClOAc 5% Yb(OYt)3
O R
H O O
Me Me R
H H O O HgCl
Me Me
p. .
Mechanistic Observations:
Me OH R + Me O Me
HgClOAc acetone, 2h rt
Yb(X2)
rate-determining step
Yb(X2)
low diastereoselectivity
Me O HgCl R H H O O Me
HgClOAc
O R
X Me
Hg R
H O O H
Me Me
~1:1-mixture of diastereomers Product formed in low yield. much recovered starting material
Lewis acid addends were surveyed. the logic for this step was two-fold: (A) Lewis acid would promote the formation of the putative hemiketal imtermediate. (B) Lewis acid would promote reversability of the oxymercuration process
Yb(X2)
Yb(X2)
Leighton presumes that mercurium ion formation is rate-determining under kinetic conditions. At higher temperatures and longer reaction times the products are shown to interconvert. ClHg H R O H O Me Me YbX3
HOAc, 5% Yb(OYt)3
OH Me3C
+ Me
O Me
Me O Me3C
Me O HgCl
Cl
Hg H R H O O H
Me Me
YbX3 Cl Hg R H H O O H Me Me
Erel = 0
OAc
D. A. Evans
Chem 206
Ionomycin Synthesis (with Dow & Shih, JACS 1990, 112, 5290)
Me Me OH O O O
Me OH
B
Me
C
Me
D
Me
E
H Me O
F
O Me
OH
Me H
OH OH
O Me OH Me
OH OH O Ca
aldol
Et Me O
D E
Me OH
Me
+
H
H O
F
O Me O Me Me OR
C1-C16 Subunit
Me OR
A
O Me OMe Me
Me Me OH Me Me R H O Me H O Me
Me Me OH
Me
Me
Me Me Me OH
OR
C17-C37 Subunit
Et
HO Me Me R OH OH
p. .
Me O
1
Me H
O OH
OH OH
Me
Me
16
Me Me
A
OR OH
OR
O Me H Me H HO
H R1
16
OH
Me H
Me
O O Me
Me
HO Me H
Me Me OH
H H
OR OH
9
HgX H Me R2
Me BnO O
O Me Me
RL
HgX2 RDS
Me RO2C H H
O Me H
CO2R X RO H Hg C RL H C Me H
H RL
OR
HgX+
RDS
Me
85%, dr = 93 : 7
H R1 H Me H HO Me R2 H Hg H X O O Me Me XHg Me BnO O Me H O Me Me Me Me OH
H H O
7
OR
9
Me H
RL
Me
HgX
D. A. Evans
Chem 206
Other electrophilic olefin addition reactions afford the same stereochemical outcome
X OH
Hg(OAc)2
HO H
Hg C n-Bu
H C H Me n-Bu
OH
OH Me O RO Me OH
I2, HOH/THF
A HO Me
HCO3
I C CH2
n-Bu
Me
H Me
HO Me -O2C C
H C H Me
RDS
H Me
R=H -O2C
OH
I2, HOAc
HO H C
CH2
H C H Me
OH
HOAc
OAc Me
n-Bu
Me
RDS
n-Bu
HO
I Me Me O
HO
I Me Me O
p. .
n-Bu
OH
Me
I2, HOAc
HO H
H C Me H
HOAc
R = OMe
n-Bu
t-BuOOH VO(acac)2
Ratio 96 : 4 (85%) O
K2CO3 MeOH
RDS
O MeO
OH O Me MeO
OH O Me
This is an exceptional approach to the creation of either syn or anti 1,3-dioxygen relationships Evans, Kaldor, Jones, J. Am. Chem. Soc. 1990, 112, 7001.
Me
Me
Other cases:
O OH Me
TIPSO
OH Me Me
I2, THF, 4 C 0.25 M KH2PO4,
TIPSO
OH
OH Me
HO
Me
n-Bu3SnH, toluene, 25 C TsOH, (CH3)2C(OCH3)2, 25 C
I Me TIPSO O Me O Me HO
OH
O HO
I2, HOH/THF HCO3
Me O HO
Me
Me
67% overall
HO
OH
diastereoselection 96 : 4
Me O
Me
D. A. Evans
Chem 206
Hypothesis-B: Stereocontrol through Reversal of Bromonium Ion Intermediate Me RL H OH Me RL bromonium ion-olefin exchange Me Me RL RL Ar H Br H C O Me Me Et H D O H Me Br Ar H C O Me Me Et H D O H Me
E O HO
Me CH2OH
Me H
Et H
Br
Kishi, JACS 1979, 101, 259, 260, 262 Still, JACS 1980, 103, 2117-2121
OH
Br
Ring D disfavored
p. .
Me D OH E HO O Me
R H Me
Br
OH Me
H
50%
H Me H
Me RL H OH Me RL H
RL H OH Me RL Br
O Me O
Me Me RL H OH H
RL Me RL H OH
Me
RL Incorrect Stereochemistry Br
Me
El(+)-induced heterocyclization
Cardillo, Tetrahedron 1990, 46, 3321-3408 Bartlett, Asymmetric Synthesis 1984, 3, Chap 6, 411-454
D. A. Evans
A complete turnover in olefin diastereofacial selectivity is observed when adding internal and external nucleophiles I2
Chem 206
HO I Me O O Bu I
Addition product
OH
OH Me
O HO
OH Me
H
I2
Me OH O OH
R H H HO
Me H
R H H HO I2
Me RDS H
R H H HO I+
Me H
OH2
OH
I2
Bu
OH Me
Bu
Me
H 2O
Disfavored complex
p. .
General Observation:
For electrophiles that react via onium intermediates (I2, Br2, Hg(OAc)2, PhSeCl), the major diastereomer from electrophile-induced cyclization is opposite to that observed in the analogous intermolecular electrophilic addition. For a review of elctrophilic induced olefin cyclization reactions see: G. Cardillo & M. Orena, Tetrahedron 1990, 46, 3321.
RDS
Me H H
OH
I + Me H R
Favored complex
HO
H O
I OH Me Bu I Me OH
Cyclization reactions: Intramolecular attack on a complex (not an onium ion) Analysis of the stereoselectivity of electrophilic addition to chiral olefins: 1. Relative abundances of conformational minima 2. Relative reactivities of the available forms 3. Stereoselectivies of the individual conformers
O
Cyclization product
Houk: Argument for the "inside alkoxy effect" in complex formation complex cyclizes if R contains a Nu and its formation is rate determining Onium ion formation is rate determing in the addition reactions "The presence or absence of an internal nucleophile acts to determine the stereochemical outcome of the reaction by modifying the nature (timing) of transition state.
D. A. Evans
Chem 206
CH3 OH
For a recent general review of the Simmons-Smith reaction see: Charette & Beauchemin, Organic Reactions, 58, 1-415 (2001)
CH2 I2 , Zn-Cu OH
>99:1
S. Winstein, JACS 1959, 81, 6523; 1961, 83, 3235; 1969, 91, 6892
CH2 I2 + Zn R = OMe: >99:1 Dauben, JACS 1963, 85, 468 R = OAc: 4:1
Sawada, JOC 1968, 33, 1767 R R
ICH2 ZnI
ZnI CH2 I
ICH2 ZnI
+ ZnI2
R
9:1
>99 : 1
NHSO2 Ar
These results suggest that the transition state might be binuclear. Construct a reasonable transition structure which accomdates the data
NHSO2 Ar
Me CH2
diastereoselection 20:1
R'
Yamamoto, JACS, 1985, 107, 8254 Mash, JACS, 1985, 107, 8256 Yamamoto, Tetrahedron, 1986, 42, 6458
A. S. Kim, D. A. Evans
Radical Lead Tetraacetate Mechanism
Redox- Thallium.1
Vinyl and Aryl C-H Oxidations Thallium
Chem 206
CHO
(TFA)2Tl
CHO
CHO
Tl(TFA)3, TFA
N H N H
H RCH2 Me OH
LTA
Me RCH2 Me O R
OAc
RCH2
OAc
42%
OH
N Ac
19% (racemic)
O Me Me Me
33%
20%
Phenolic Oxidations:
O Me
For a review of oxidative aryl couplings, see: Dinsmore, C. Evening Seminar, February 1993.
LTA
HO
Me O O
Immer, Helv. Chim. Acta 1962, 45, 753.
Me O
45-72%
H
TTFA 75%
HO O
CF3COO
LTA
HO
OAc O O OAc
O Br O O O O OAc HO
Cocker, JCS, 1965, 6.
28%
O O Me Me
42%
Ph
Me O
Me
N Ph
TTFA 56%
N O Br O
Me
AcO
AcO
A. S. Kim, D. A. Evans
Oxythallation of Ketones (Enols) with Ring Contraction TTN
O Me CO2Me
Redox- Thallium.2
TTN = Tl(NO3)3 Oxythallation of Double and Triple Bonds
Chem 206
Me
MeOH
O
84%
Tl(ClO4)3
McKillop and Taylor, JACS, 1973, 95, 3340. McKillop and Taylor, JOC, 1978, 43, 3773.
COMe
AcOH 88-92%
OMe OMe
TTN MeCN
O
ONO2
85%
OMe
McKillop and Taylor, JOC, 1972, 37, 3381.
84%
OMe
86%
COOH
O O
84%
O COOH
Salaun, Tet., 1974, 30, 1423.
1) TTN/HClO4 2) NaH,
n-Pentyl O
O n-Pentyl
(MeO)2P(O)
70%
O
Corey, TL, 1971, 4753.
CO2Me
Me Me Me HO2C H
O
Jones, JACS, 1976, 98, 8476.
Tl(OAc)3 83%
Me
Inoue, Bull. Chem. Soc.
Me
A. S. Kim, D. A. Evans
Oxidative Rearrangements of Styrenes TTN = Tl(NO3)3
Redox- Thallium.3
Oxidative Rearrangements of Chalcones
MeO
Chem 206
OMe Me O
H Me MeO
McKillop and Taylor, JACS, 1973, 95, 3635.
Me
OH
TTN
OH OH
MeOH 74%
O
Eade,Aust. J. Chem. 1978, 31, 2699.
OBn
OM e
75%
HO
OBn
Me
OH
O O
2TTN
OH O O
MeOH 65%
OMe
1) TTN, MeOH
MeO
2) H3O+ 100%
MeO
McKillop and Taylor, TL, 1977, 1827.
OH
OO
2TTN
OH HO
MeOH 53%
A. S. Kim, D. A. Evans
Oxidation of Nitrogen Compounds
R N N H R R' HN N COR
Redox- Thallium.4
TTN = Tl(NO3)3
Chem 206
CO2Me
+ N2
TTN MeOH
R O R'
McKillop and Taylor, JACS 1971, 93, 4918.
TTN MeOH
R O R'
McKillop and Taylor, JACS 1971, 93, 4918.
OMe
MeO
MeO
NO2
Fujita, JCSCC, 1976, 202.
MeO
O SEt
Ph
OMe OMe
Fujita, TL, 1978, 4115.
Ph
Me S S S
Me S
S
Smith, Synth. Commun. 1979, 9, 301.
D. A. Evans, T. B. Dunn
Chem 206
http://www.courses.fas.harvard.edu/~chem206/
s Woodward-Hoffmann Theory R. B. Woodward and R. Hoffmann, The Conservation of Orbital Symmetry, Verlag Chemie, Weinheim, 1970. s Frontier Molecular Orbital Theory I. Fleming, Frontier Orbitals and Organic Chemical Reactions, John-Wiley and Sons, New York, 1976. s Dewar-Zimmerman Theory T. H. Lowry and K. S. Richardson, Mechanism and Theory in Organic Chemistry, 3rd Ed., Harper & Row, New York, 1987. s General Reference R. E. Lehr and A. P. Marchand, Orbital Symmetry: A Problem Solving Approach, Academic Press, New York, 1972.
Lecture Number 11
Pericyclic Reactions1
s Introduction to Pericyclic Reactions s Electrocyclic Reactions s Sigmatropic Reactions s Cycloaddition Reactions
O O
s Reading Assignment for week: Carey & Sundberg: Part A; Chapter 11 Concerted Pericyclic Reactions Fleming: Chapter 4 Thermal Pericyclic Reactions
Ph
heat
Ph
Travis Dunn
heat
CO2Me
Chem 206
Three theories are commonly used to explain and predict pericyclic reactions. We will only concern ourselves with two of these theories. 1) Fukui: Frontier Molecular Orbital Interactions s Much easier to use than the original orbital symmetry arguments s HOMO/LUMO interactions 2) Dewar-Zimmerman: Aromatic Transition States s The easiest to apply for all reaction types, but it is not as easy to
understand why it it valid
heat rarely observed 4 electrons Pericyclic reactions are stereospecific: A A A A heat A A heat
s First theory to explain and predict the outcome of many reactions s Correlation diagrams
On the three methods:
"There are several ways of applying the orbital-symmetry principle to cycloaddition reactions, three of which are used more frequently than others. Of these three, we will discuss two: the frontier-orbital method and the Mbius-Hckel method. The third, called the correlation diagram method, is less convenient to apply than the other two." Jerry March in "Advanced Organic Chemistry"
A A
Reactions behave differently depending on the conditions used (i.e. thermal versus photochemical conditions): A A A
11-01-Peri 10/11/00 7:53 AM
heat A
A A
Cyclobutene
or h
Butadiene
or h
1,3,5-Hexatriene 1,3-Cyclohexadiene
Chem 206
A sigmatropic rearrangement is the migration of a sigma bond from one position in a conjugated system to another position in the system, accompanied by reorganization of the connecting pi bonds. The number of pi and sigma bonds remains constant. The rearrangement is an [m,n] shift when the sigma bond migrates across m atoms of one system and n atoms of the second system. Examples:
2 2 3 1
[1,3]-shift
2 3 1
3 4 5
R1 R2
[1,5]-shift
R2 R1 H
[2+2]
R
1 2 3 3' 2'
R
1 2 3 3' 2'
X
[4+2] +
[3,3]-shift
X R
1'
1'
H
+
R
+
H H
O
+
[4+1]
O S O
H N N H
+
R N2 R'
+
H H
R R'
C O
[4+1]
O
Ene Reaction:
CR2
[2+1]
R R H
+
Electrocyclic Reactions
Butadiene to cyclobutene: A 4-electron (4q) system
Chem 206
Ring closure can occur in two distinct ways. This has consequences with regard to: s The orbital lobes that interact s The disposition of substituents on the termini Conrotatory Closure: The termini rotate in the same direction Me B B A B A B A A B A A B Me Me H H Me
Me
conrotation
heat
Me
conrotation
heat
Me
Me
disrotation
Me
H H
Me
Me B A Me Me
disrotation
Me
A A A B A B B A B B
Me Me It was also noted that changing the "reagent" from heat to light reversed this reactivity pattern. Under photochemical conditions 4 electron systems undergo disrotatory motion, while 6 electron systems undergo conrotatory motion. Me
disrotation
Empirical Observations: It was noted that butadienes undergo conrotatory closure under thermal conditions, while hexatrienes undergo disrotatory closure under thermal conditions. The microscopic reverse reactions also occur with the same rotational sense (i.e. cyclobutenes open in a conrotatory sense when heated, and cyclohexadienes open in a disrotatory sense when heated.)
Me Me Me Me
controtation
h Me
h Me Me
D. A. Evans, T. B. Dunn
Conjugated pi systems
Chem 206
6 p-orbitals
C nonbonding
C nonbonding
bonding
There are no nodal planes in the most stable bonding MO. With each higher MO, one additional nodal plane is added. The more nodes, the higher the orbital energy.
Chem 206
Photochemical Activation: When light is used to initiate an electrocyclic reaction, an electron is excited from 2 to 3. Treating 3 as the HOMO now shows that disrotatory closure is allowed and conrotatory closure is forbidden. 4 3 2 1 4 3 Me 2 1
h Me H H Me
Photon Me absorption
3 (HOMO)
Me
Me
Me H
H Me
Me H
H Me
H Me
H Me
2 (diene HOMO)
Me Me
3 (new HOMO)
H Me
H Me
H Me
2 (diene HOMO)
Me
Me
Me H
3 (new HOMO)
Destructive overlap
A similar analysis for the hexatriene system proves that under thermal conditions, disrotation is allowed and conrotation is forbidden.
We have so far proven which ring closures are allowed and which are forbidden. Do we now have to go back and examine all the ring openings?
NO!
The principle of microscopic reversiblity says that if the reaction is allowed in one direction, it must be allowed in the other direction.
11-05-electrocyclic/FMO 10/11/00 7:56 AM
Chem 206
The Dewar-Zimmerman analysis is based on identifying transition states as aromatic or antiaromatic. We will not go into the theory behind why this treatment works, but it will give the same predictions as FMO or Orbital Symmetry treatments, and is fundamentally equivalent to them.
Disrotatory Closure
Conrotatory Closure
One Phase Inversion Zero Phase Inversions Hckel Topology Mbius Topology 4 electrons in system 4 electrons in system Antiaromatic and Aromatic and Forbidden Allowed Note that I can change the phase of an abitrary orbital and the analysis is still valid! Connect Orbitals
Disrotatory Closure
Conrotatory Closure
s Assign the transition state as aromatic or antiaromatic, based on the number of electrons present. System Hckel Mbius Aromatic 4q + 2 4q Antiaromatic 4q 4q + 2 Two Phase Inversions Hckel Topology 4 electrons in system Antiaromatic and Forbidden Three Phase Inversions Mbius Topology 4 electrons in system Aromatic and Allowed
s If the transition state is aromatic, then the reaction will be allowed thermally. If the transition state is antiaromatic, then the reaction will be allowed photochemically.
11-06-electrocyclic/DZ 10/11/00 7:57 AM
Chem 206
The Stereochemical issues: The migrating group can migrate across the conjugated pi system in one of two ways. If the group migrates on the same side of the system, it is said to migrate suprafacially with respect to that system. If the group migrates from one side of the pi system to the other, it is said to migrate antarafacially with respect to that system. Suprafacial migration: The group moves across the same face. B A B A A B A B
s Construct TS by considering an allyl anion and the proton (or radical pair): H X Y X H H Y X Y
B X
H Y X
H Y X
H Y
Antarafacial migration: The group moves from one face to the other.
Proton 1S (LUMO)
bonding antibonding bonding
B A B A
B B A A B A B X
X
2 (allyl anion HOMO)
Y
bonding
Suprafacial Geometry
Antarafacial Geometry
s The analysis works if you consider the other ionic reaction, or consider a radical reaction. In each case it is the same pair of orbitals interacting. s The suprafacial migration is forbidden and the bridging distance too great for the antarafacial migration. Hence, [1,3] hydrogen migrations are not observed under thermal conditions. s Under photochemical conditions, the [1,3] rearrangement is allowed suprafacially. How would you predict this using FMO?
[1,3]-Sigmatropic Rearrangements
Chem 206
s Construct TS by considering an allyl anion and the methyl cation: Retention at carbon H C H H
bonding
Inversion at carbon
2p on Carbon
H C H H X
H H
bonding
antibonding bonding
H H
s The analysis works if you consider the other ionic reaction, or consider a radical reaction. In each case it is the same pair of orbitals interacting. s Under photochemical conditions, the [1,3] rearrangement is allowed suprafacially with retention of stereochemistry. s The stereochemical constraints on the migration of carbon with inversion of configuration is highly disfavored on the basis of strain. Such rearrangements are rare and usually only occur in highly strained systems. Using a similar analysis, one can prove that [1,5] hydrogen and alkyl shifts should be allowed when suprafacial on the pi component and proceeding with retention. Please refer to Fleming for more applications of FMO theory to [1,n] sigmatropic shifts.
Zero Phase Inversions Hckel Topology Six Electrons Allowed thermally Orbital interactions in the Completing the circuit parent system across the bottom face
Chem 206
[3,3] Rearrangements:
A thermally allowed reaction in either of two geometries, the "chair" or the "boat" geometry. Depicted below is the "chair" geometry. You should be able to work out the details of the "boat" geometry yourself. X Z X & Z = C, O, N etc The FMO Analysis: Bring two Allyl radicals together to access for a possible bonding interaction between termini.
The toggle algorithm is a simple way to take one reaction of each class that you remember is allowed (or forbidden) and derive if the reaction is allowed or forbidden under new conditions.
X Z
X Z
bonding bonding
Rearrangement Conditions Component 1 Component 2 [1,3] [1,3] [1,3] [1,5] Two Phase Inversions Hckel Topology Six Electrons Allowed Thermally Heat Heat Light Heat Suprafacial Antarafacial Antarafacial Suprafacial Suprafacial Suprafacial Suprafacial Suprafacial
Each incremental change in the "input" registers changes the "output" register by one. Multiple changes simply toggle the output back and forth. What is the prediction in the last line?
Cycloaddition Reactions
The [4+2] Cycloaddition: Dewar-Zimmerman
Chem 206
In a cycloaddition, a pi system may be attacked in one of two distinct ways. If the pi system is attacked from the same face, then the reaction is suprafacial on that component. If the system is attacked from opposite faces, then the reaction is antarafacial on that component.
The most well known cycloaddition is the Diels-Alder reaction between a four pi component (the diene) and a two pi component (the dienophile). An exhaustive examination of this reaction is forthcoming, so we will limit ourselves to a simple examination.
Suprafacial attack
Antarafacial attack Zero Phase Inversions Hckel Topology Six Electrons Allowed thermally
The [2+2] Cycloaddition: FMO Analysis For the [2+2] cycloaddition two different geometries have to be considered. Suprafacial/Suprafacial
HOMO
Antarafacial/Suprafacial
bonding
HOMO
Summary:
s There are three fundamentally equivalent methods of analyzing pericyclic reactions: Two are much simpler than the third. s Fukui Frontier Molecular Orbital Theory s Dewar-Zimmerman Hckel-Mbius Aromatic Transition States s Woodward-Hoffmann Correlation Diagrams
LUMO
bonding
bonding
antibonding
LUMO
Forbidden
Allowed
s Some methods are easier to use than others, but all are equally correct and no one is superior to another. Conclusions drawn from the correct application of one theory will not be contradicted by another theory. s The principle of microscopic reversibility allows us to look at a reaction from either the forward direction or the reverse direction. s There is a general trend that reactions will behave fundamentally different under thermal conditions and photochemical conditions.
The simplest approach (Supra/Supra) is forbidden under thermal activation. The less obvious approach (Antara/Supra) is allowed thermally but geometrically rather congested. It is believed to occur in some very specific cases (e.g. ketenes) where the steric congestion is reduced.
11-10-Cycloaddition 10/11/00 7:59 AM
D. A. Evans
Chem 206
http://www.courses.fas.harvard.edu/~chem206/
C. Palomo, "Asymmetric Synthesis of -Lactams by Stauginger Ketene-Imine Cycloaddition Reaction, Eur. J. Org. Chem. 1999, 3223-3235. R R N O R N O S N O R N3 R N R O N R O R R R Correlate with R S N O con N3 R N R N3 H S N
N3
con
Lecture Number 12
Pericyclic Reactions2
Electrocyclic Reactions Cheletropic Reactions
O O O
Reading Assignment for week: Carey & Sundberg: Part A; Chapter 11 Concerted Pericyclic Reactions Fleming: Chapter 4 Thermal Pericyclic Reactions
Ph heat Huisgen, TL, 1964, 3381.
Ph
D. A. Evans
12-00-Cover Page 10/13/03 9:03 AM
Evans, Breit
Electrocyclic Reaction - Selection Rules Ground State (Thermal process) 4n e(n = 1,2...) 4n+2 e(n = 0,1,2...) conrotatory disrotatory
Ground State Conrotatory
Electrocyclic Processes-1
Chem 206
Con
HOMO
Examples
Excited State
1
Disrotatory
Con
LUMO HOMO
Disrotatory
Conrotatory
Conrotatory
Disrotatory
42
45
Disrotatory Conrotatory
Conrotatory
H
29
27
H
Disrotatory
Conrotatory
Disrotatory
Disrotatory
Conrotatory
Ph Ph O O O O
R Con R R R R
Con
Ph O
Ph
R Sterically favored
Evans, Breit
Chem 206
Donor substituents prefer conout mode Pi acceptor substituents prefer conin mode
Torquoselectivilty is defined as the predisposition of a given R substituent for a given conrotatory motion Houk et al. Acc. Chem. Res 1996, 29, 471
R R
con in
View the 2 conrotatory modes by looking at the breaking sigma bond from this perspective
H
con
H
out
R R H H
Examples:
Donor substituents prefer conout mode Pi acceptor substituents prefer conin mode
R R H
Outward Motion +
R H H H
Inward Motion
con
R = Me R = CHO
only none
none only
H H LUMO + p
H H
H H H LUMO + p
CH2OBn CHO H H
CH2OBn
con +
CHO
CH2OBn
A
CHO
H H HOMO + p
H H
H H HOMO + p
H H H
ratio: >20:1
Me CN Me CN CN
con
Me
ratio: 4:1
As conrotation begins the energy of the breaking sigma bond rises steeply. Hyperconjugation with a pi* orbital, while possible in both A & B, is better in B. (Houk)
destabilizing 4 electron interation for donor substituents stabilizing 2 electron interation for acceptor substituents
Evans, Breit
Chem 206
Does solvolysis proceed via cation 1 followed by rearrangement to 2 (Case 1), or does it proceed directly to 2 (Case 2)?
2 +X
TsO H
Me
TsO H
H Me
H Me
relative rate 1
LUMO
4
DePuy, Accts. Chem. Res. 1967, 1, 33
40,000
+
R
H A H A
R Dis
H A C H C A
HOMO
X
LUMO
H Me H C Me Me
HOMO Dis
Me H Me C C H
HOMO Dis
+
Me H
H H
Me Me
Evans, Breit
Solvolysis Summary
TsO H TsO H
Chem 206
dis-out
favorable H Me R A
relative rate
40,000
3
Ring-fused Cyclopropyl Systems When the cis substiltutents on the cyclopropyl ring are tied together in a ring the following observsations have been made
TsO H H H TsO H H
nonbonding
1 cation anion
favored
relative rate: > 10+6 H TsO H H TsO H H H H 2C CH2
dis-in
H 2C
A
R
Con R
B B C A C A
C A B
disavored
dis-out
Observation
Ar N
CO2Me ()
dis-in
Ar N
H CO2Me
()
MeO2C
Evans, Breit
Electrocyclic Processes-3
The Nazarov Reaction
O OH +H+ A A A A A H+ A O R Con?? A A
Chem 206
R Dis?? A A
Denmark, S. E. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 5; pp 751.
O O +H
+
nonbonding
predict stereochemistry H H
2
Eight-Atom Electrocyclizations (8 electrons)
1
Cation Anion
A Dis?? A A
A Con?? A
Pentadienyl Cation
A LUMO Con H
C
A
HOMO A
C
H
Let's use the "Ready" shortcut to find the homo: Nodes will appear at single bonds
symmetry of homo
Pentadienyl Anion
A H Dis A
C
A H
C
A
Evans, Breit
Cheletropic Processes-1
Chem 206
[4+2]
+
[4+1] S
O O C C HOMO R R C C LUMO R R
S O
General
Reversion Addition Y
+
LUMO
HOMO
-system
Y X Z
-system
X Z
C C
Cycloreversion only
Frontier Orbitals
0 p (empty)
Y X Z
E 0
2
sp2 (filled) 2
R C R
Evans, Breit
Cheletropic Processes-2
Chem 206
O S O S
O S O
O O S
-SO2
4e in pi system
1 filled
Me
2 filled
R1
R2 Z
Me suprafacial
O S O Me Me O S O Me
-SO2
O Me Me S O suprafacial Me
Clough, J. M. The Ramberg-Backlund Rearrangement.; Trost, B. M. and Fleming, I., Ed.; Pergamon Press: Oxford, 1991; Vol. 3, pp 861. "The Ramberg-Backlund Rearrangement.", Paquette, L. A. Org. React. (N.Y.) 1977, 2 5, 1.
+
R
2
SO2
O S O S
O O
HOMO
empty (LUMO)
empty (LUMO)
O S O S
O S O LUMO
O O S
O O
LUMO
2 filled
1 filled
Similar to carbene geometry
D. A. Evans
Sigmatropic Rearrangements-1
[1,3] Sigmatropic Rearrangements (C migration)
consider the 1,3-migration of Carbon X Consider the orbitals needed to contruct the transition state (TS). :X R X X H H
bonding
Chem 206
CH3 Y CH3 X H3 C X Y Y
Sigmatropic rearrangements are those reactions in which a sigma bond (& associated substituent) interchanges termini on a conjugated pi system Examples:
[1,3] Sigmatropic rearrangement R X [2,3] Sigmatropic rearrangement R X [3,3] Sigmatropic rearrangement X [1,5] Sigmatropic rearrangement Y: X R Y X
Inversion at carbon
R C H X X
H H
bonding
The stereochemical constraints on the suprafacial migration of carbon with inversion of configuration is highly disfavored on the basis of strain.
Me C H
3
D H
1 3
X
Me
antibonding
X X
H H
Y 2 (allyl HOMO)
Suprafacial Geometry
Antarafacial Geometry
These rearrangements are only seen in systems that are highly strained, an attribute that lowers the activation for rearrangement.
D. A. Evans
Sigmatropic Rearrangements-2
[1,5] Sigmatropic Rearrangements (C migration)
5 3
Chem 206
/h
R = H, CR3
2 1
4
[1,5] (C migration): Stereochemical Evaluation
Me Me
RETENTION 230-280C
Me H Me [1,5s]H- shift Me
nonbonding
h
Me
[1,5s]C- shift
2
DewarZimmerman Analysis: Retention
1
thermal photochemical
H
R H H
R R H H H H H
either, or
D. A. Evans
Sigmatropic Rearrangements-3
The Wittig Rearrangement [1,2]
Chem 206
"[2,3]-Wittig Sigmatropic Rearrangements in Organic Synthesis.", Nakai, T.; Mikami, K. Chem. Rev. 1986, 86, 885. Marshall, J. A. The Wittig Rearrangement.; Trost, B. M. and Fleming, I., Ed.; Pergamon Press: Oxford, 1991; Vol. 3, pp 975.
Li O R BuLi O R
R
olefin radical cation transition state
R Li O Li
stepwise
R
CR homoylsis
consider as cycloaddition
CR homoylsis
R
antibonding
R H R Allyl radical
ketyl radical
R
olefin radical anion transition state Allyl radical
D. A. Evans
Chem 206
http://www.courses.fas.harvard.edu/~chem206/
Nakai, T.; Mikami, K. Org. React. (N.Y.) 1994, 46, 105-209. Hoffmann, Angew. Chem. Int. Ed. 1979, 18, 563-572 (Stereochemistry of) Nakai, Chem. Rev. 1986, 86, 885-902 (Wittig Rearrangement) Evans, Accts. Chem. Res. 1974, 7, 147-55 (Sulfoxide Rearrangement) Vedejs, Accts. Chem. Res. 1984, 17, 358-364 (Sulfur Ylilde Rearrangements)
Pericyclic Reactions3
Introduction to Sigmatropic Rearrangements [2,3] Sigmatropic Rearrangements
Reading Assignment for week: Carey & Sundberg: Part A; Chapter 11 Concerted Pericyclic Reactions Fleming: Chapter 4 Thermal Pericyclic Reactions
Paquette, L. A. (1990). Stereocontrolled construction of complex cyclic ketones by oxy-Cope rearrangement. Angew. Chem., Int. Ed. Engl. 29: 609.
D. A. Evans
13-00-Cover Page 10/15/03 8:53 AM
PPh3
S=PPh3
For study on this [2,3] rxn See Baldwin JACS 1971, 93, 6307
D. A. Evans
Sigmatropic Rearrangements-1
[1,3] Sigmatropic Rearrangements (C migration)
consider the 1,3-migration of Carbon X Consider the orbitals needed to contruct the transition state (TS). :X R X X H H
bonding
Chem 206
CH3 Y CH3 X H3 C X Y Y
Sigmatropic rearrangements are those reactions in which a sigma bond (& associated substituent) interchanges termini on a conjugated pi system Examples:
[1,3] Sigmatropic rearrangement R X [2,3] Sigmatropic rearrangement R X [3,3] Sigmatropic rearrangement X [1,5] Sigmatropic rearrangement Y: X R Y X
Inversion at carbon
R C H X X
H H
bonding
The stereochemical constraints on the suprafacial migration of carbon with inversion of configuration is highly disfavored on the basis of strain.
Me C H
3
D H
1 3
X
Me
antibonding
X X
H H
Y 2 (allyl HOMO)
Suprafacial Geometry
Antarafacial Geometry
These rearrangements are only seen in systems that are highly strained, an attribute that lowers the activation for rearrangement.
D. A. Evans
Sigmatropic Rearrangements-2
[1,5] Sigmatropic Rearrangements (C migration)
5 3
Chem 206
/h
R = H, CR3
2 1
4
[1,5] (C migration): Stereochemical Evaluation
Me 5 Me
RETENTION 230-280C
Me H
nonbonding
5 1 [1,5s]H- shift Me
1 Me
[1,5s]C- shift
Me
2
DewarZimmerman Analysis: Retention
1
thermal photochemical
H
R H H
R R H H H H H
either, or
D. A. Evans
Chem 206
[1,2] Sigmatropic Rearrangements: Carbon [1,2]-Sigmatropic rearrangements to cationic centers allowed. Wagner-Meerwein Rearrangement R + + R
"[2,3]-Wittig Sigmatropic Rearrangements in Organic Synthesis.", Nakai, T.; Mikami, K. Chem. Rev. 1986, 86, 885. Marshall, J. A. The Wittig Rearrangement.; Trost, B. M. and Fleming, I., Ed.; Pergamon Press: Oxford, 1991; Vol. 3, pp 975.
Li O R BuLi O R
consider as cycloaddition
FMO analysis
R Li O Li
R
olefin radical cation transition state
stepwise
consider as cycloaddition
FMO analysis
FMO analysis R
C antibonding
R H
R
olefin radical anion transition state Allyl radical
D. A. Evans
Chem 206
OH Me Me Me Me
BuLi
O Me Me Me Me
OH
Me R3
Me Me
temp Me
Me
Me
Me
Me
Y:
25 C
~70%
~30%
X & Y = permutations of C, N, O, S, Se, P; however X is usually a heteroatom Attributes: Stereoselective olefin construction & chirality transfer Representative X-Y Pairs: NO (amine oxides) SC (sulfur ylids) OC (Wittig rearrangement) NC (nitrogen ylids) SS (disulfides) SP, SN, SO (sulfoxides) OP (phosphites) NN, Cl+C (haloium ylids) PC, CC (homoallylic anions).
BuLi
S S
p. p.
An important early paper: Baldwin, J. Chem. Soc., Chem. Comm. 1970, 576 General Reviews:
Trost, Ed., Comprehensive Organic Synthesis 1992, Vol 6, Chapter 4.6: Nakai, T.; Mikami, K. Org. React. (N.Y.) 1994, 46, 105-209. Hoffmann, Angew. Chem. Int. Ed. 1979, 18, 563-572 (Stereochemistry of) Nakai, Chem. Rev. 1986, 86, 885-902 (Wittig Rearrangement) Evans, Accts. Chem. Res. 1974, 7, 147-55 (sulfoxide Rearrangement) Vedejs, Accts. Chem. Res. 1984, 17, 358-364 (Sulfur Ylilde Rearrangements)
BuLi N Me N Me
Me Me
X - O, Y = C; Wittig Rearrangement:
Me O Ph R O Ph
BuLi
Me
BuLi
Me O
Me Li+ Ph
R O Li+ Ph
O H Ph
Me
Me
Buchi, JACS 1974, 96, 7573 Mander, JOC 1973, 38, 2915 important extension lacking CN FG; Sato, JACS 1990, 112, 1999
D. A. Evans
X - O, Y = C; Wittig-like Rearrangements
R2 R1 OH OMe H NMe2 OMe R1 O C: NMe2 R3 140 C R1 O C R2 R3
Chem 206
R2 R3 O keq < 1 R1 + S
R2
R3
S Ar
OH
+ NMe2 R2 R3
In thinking about this rearrangement, also consider the carbenoid resonance form as well
R2 R3 R1 Se Ar
R2 R3 Ts
selenophile R1
R3
X - O, Y = C; An all-carbon Rearrangement p. p.
R1 O N N note that the product contains the retrons for the enolate Claisen rearrangement Smith, Chem. Commun. 1974, 695; Smith, JOC 1977, 42, 3165 R2 R3 Cu(I) N2 O : H O C ROH R2 R1 O OR R3 R1 R2 R3 R1 R2 R3
+ Se
N Ts
NHTs Hopkins, Tet Let. 1984, 25, 15 Hopkins, JOC 1984, 49, 3647 Hopkins, JOC 1985, 50, 417
X - S, Y = N; Related Rearrangement
Na+ TsNCl
TsO S Ph
TsO Ts N S Ph
[2,3]
TsO
X - N, Y = O; Meisenheimer Rearrangement
R2 R1 Me N + O R3 R1 Me N Me Tanabe, Tet Let. 1975, 3005 O R2 R3 Zn/HOAc R1 R2 R3 OH
N Ts
TsO
N Ts
Me
D. A. Evans
Chem 206
Me
Me O
Me
Rb
H
disfavored
Y
X Rb
Ra Y :X
R1 Ar S O
R2
p. p.
Ra & Rb prefer to orient in pseudo-equatorial positions during rearrangement; nevertheless, this is a delicately balanced situation Starting olefin: Cis favored
Ra X Y: Rb X Y
H
RLi R1X R2 Ar S
Ra
H
Ra :X Y Rb
The preceeding transition state models do not explain some of the results: Cis selectivity has been observed: Still JACS 1978, 100, 1927.
R Me O SnBu3 Me n-BuLi -78 C R ratio, 65:35 OH R Me OH
Rb
highly disfavored
Y
Rb
Ra
H
Rb Ra Y :X
Conclusions
Olefin geometry dictates sense of asymmetric induction in rearrangement (Z) Olefin rearrangements might exhibit higher levels of 1,3 induction Product olefin geometry can be either (E) or (Z) from (E) starting material Product olefin geometry will be (E) from (Z) starting material
D. A. Evans
Starting olefin: (E) Trisubstituted
R1 Y H R2 X Y: R1 H Me R2
Chem 206
favored
Me R1
Me H Me Me R2 R1 Y :X n-Bu
Me SnBu3 halogen
disfavored
Y
R2
Still says that the TS is early, so that the 1,2 interactions in the TS are most important. destabilizing
O H 2C Li H H C 4H 9 C4H9 Me H LiO CH2 n-Bu Me
p. p.
R1Me interaction can destabilize the (E) transition state while (Z) TS might be destabilized by R1 interactions with both X-Y and allyl moiety. (E)-path Starting olefin: (Z) favored
Me R1 X Y: R2 X Y H R2 R1 Me H :X Y R1 Me R2 Me n-Bu O CH2Li
Me
(Z)-path
H2 C
O Li
H Me R1 CH2 LiO
highly disfavored
X Y
R2
R1 H Me
Me R2 R1 Y :X
(Z) selectivity has also been observed by others: Sato JACS 1990, 112, 1999.
Me LHMDS, NH3 -70 C Me N +Me Me XMe CsF in HMPA Me
X-
Me NMe2
Conclusions
Olefin geometry dictates sense of asymmetric induction in rearrangement (Z) Olefin rearrangements might exhibit higher levels of 1,3 induction Product olefin geometry can be either (E) or (Z) from (E) starting material Product olefin geometry will be (E) from (Z) starting material
N+ CH2TMS Me
Me
D. A. Evans
Chem 206
(E)-path
Me R1 Ar S O
favored
S Ph Me
O Ph
R1
(Z)-path disfavored
Ph O
S
H
Me
In contrast to the previous cases exhibiting (Z) selectivity rearrangements (E)-selective rearrangments has been observed: p. p.
Me n-BuLi N N S Me N N
Me S Li
Me
Me
R R +S C H R R
pKa ~ 18 (DMSO
Me Br
Me
N N
Me
Me
Me C5H11 HO (E):(Z) > 95:5 (74%) CO2H Nakai, Tet Let 1981, 22, 69
Me
Me [2,3]
Me OH Et2NH, MeOH 25 C Me
Me CO2H
Me
N N Me
S Me
() H OH
CO2Me
D. A. Evans
Chem 206
RL
(E)-path
RL RM (RL = large) X Y:
RL
RM
(Z)-path
Y
X
H
One might project that the (E) path will be moderately favored with selectivity depending on size difference between RL & RM p. p.
Me Me Me S Me Me Rautenstrauch, Helv. Chim Acta 1971, 54, 739 Me Me Me OMe H NMe2 OMe Buchi, JACS 1974, 96, 5563 OH 140 C Me O C: NMe2 O Me Me Me poorly selective NMe2 Me Me Me Me Li/NH3 Me Me Me Me
n-BuLi
Me Me Me Me S
Me
Me Me F
Me Me
Me S Li Me Me Me Me SLi Me Me Me
benzyne MgBr Me Me + S Ph This rxn is probably not as stereoselective as advertised Me Me Me Me Me [2,3] For related [2,3] rxns See Baldwin JACS 1968, 90, 4758 Baldwin JACS 1969, 91, 3646 Me Me Me Me
Me
(E):(Z) = 3:2
Me
SPh Me Me
Me
Squalene
Me
Me
Me
D. A. Evans
Chem 206
Me CO2H
Allylation
Me Me S CO2H
O CH2OR O ROCH2 Me N
BuLi
96% de (61%) HO O XC
Me
DBU, -78 C
Me O S+
BF4 HBF4 CH2Cl2
O O S O O N2 ROCH2 N CH2OR
BuLi Cp2ZrCl2
Me HO O Katsuki, Tet Lett 1986, 27, 4577 XC 97% syn; 96% de (43%)
Me
Me
p. p.
Me Me Me S Me
+
Me
Me O O Me S Me O O Me
Me O S Me Bu3Sn O
Me
Me
Me C 3H 7
66%, 94:4
OH
OBOM
Me O O Me S Me O O Me
Me O S Me O
Bu3Sn
Me Me C 3H 7 Me OBOM
n-BuLi, THF, -78 C
Me
Me
Me C 3H7
OH
OBOM
diastereoselection > 100:1 (64%) Kallmerten TL 1993, 34, 753. Kallmerten TL 1993, 34, 749. Kallmerten SynLet 1992, 845.
Me
64%, 4:93
See these papers for other applications
D. A. Evans
Chem 206
Me O O HO ratio 79 : 6 HO Me
Me O O Me
N Me N S Me O Ph OMe HO
Na2S, MeOH
O SnBu3
Ph
H 2C O H C O C
p. p.
MeO
N Me
C5H11
HSPh, KOt-Bu
O CO2Et C5H11
15
TBSO
Me
n-BuLi, -78 C
CO2Et H
SPh
SPh
1) MCPBA 2) P(OMe)3
O CO2H C5H11 OH
steps
O CO2Et
15
Me
OH Taber J. Am. Chem. Soc. 1977, 99, 3513. Kondo Tet. Lett. 1978, 3927.
D. A. Evans
Chem 206
Me Me HO O Me
H H
Me
Me HO C: H O Me
H Me3C H S Ph
N2=CHCO2Et
X :Y
X: favored
Candidate processes:
R3 OH H OMe NMe2 OMe R3
140 C
SPh H CO2Et
R3 O NMe2 CMe3 S O Ph
Cu(I) catalysis 25 C
C: NMe2
p. p.
S C N
R3 SMe NHTs
NaH 65 C
25 C (MeO)3P MeOH
R3 S SMe CMe3 N Me Me Me Me Me +
Me3C H
OSPh
Me3C
OH
C: SMe
The synthesis:
Me Me O MgBr H Me S
Note that rearrangement is not required to proceed via the carbenoid. propose altenate mechanism
C CN H
-10 C
Me
Me3C H
N CN
Me Bakkenolide-A
HgCl2, HOH MeS H2SeO3
Me
H
Me
S C SMe
NHTs
D. A. Evans
Chem 206
Me Me HO
S N2
Cu(O)
CO2Et +S
Me
CO2Et
CO2Et
50%
KOt-Bu
TfO S 72%
CO2Et
DBU
S +
S EtO2C
72%
p. p.
O
Me
HO Me
Me O Et O
OH Methynolide has been synthesized by Vedejs using this ring-expansion methodology Me Vedejs, JACS 1989, 111, 8430
Me Me 54% Me N Me Ph O
+ N Me Me
Me N+ CH2 N Me H
O Ph
nonselective N-alkylation
Me Me 78% Me N O
N Me
D. A. Evans
Chem 206
http://www.courses.fas.harvard.edu/~chem206/
T. S. Ho, Tandem Organic Reactions 1992, Chapter 12 (Cope, Claisen) Paquette, L. A. (1990). Stereocontrolled construction of complex cyclic ketones by oxy-Cope rearrangement. Angew. Chem., Int. Ed. Engl. 29: 609.
Pericyclic Reactions4
[3,3] Sigmatropic Rearrangements: Introduction Cope Rearrangements & Variants Claisen Rearrangements & Variants
Reading Assignment for week: Carey & Sundberg: Part A; Chapter 11 Concerted Pericyclic Reactions Fleming: Chapter 4: Thermal Pericyclic Reactions
K. Houk, Transition Structures of Hydrocarbon Pericyclic Rxns Angew Chem. Int. Ed. Engl. 1992, 31, 682-708 K. Houk, Pericyclic Reaction Transition States: Passions & Punctilios, Accts. Chem. Res. 1995, 28, 81-90 Angew Chem. Int. Ed. Engl. 1992, 31, 682-708 CMe3
diastereoselection >87:13
CMe3 Ireland, JOC 1983, 48, 1829
O H Me H Me
D. A. Evans
Me
D. A. Evans
General Reviews:
Chem 206
S. J. Rhoades, Organic Reactions 1974, 22, 1 (Cope, Claisen) S. R. Wilson, Organic Reactions 1993, 43, 93 (oxy-Cope) T. S. Ho, Tandem Organic Reactions 1992, Chapter 12 (Cope, Claisen) Trost, Ed., Comprehensive Organic Synthesis 1992, Vol 5, Chapter 7.1: (Cope, oxy-Cope, Anionic oxy-Cope) Chapter 7.2, Claisen
X Z X Z X Z
?
X
p. p.
X
X & Z = C, O, N etc
X
The Boat and Chair geometries for these transition structures are well defined.
O O
Bring two allyl radicals together to access for a possible bonding interaction between termini.
X X
bonding bonding
D. A. Evans
Chem 206
favored
H Me Me
Doering/Roth Experiments: Tetrahedron 18, 67, (1962): The Geometry of the transltion state (boat vs chair) can be analyzed via the rearrangement of substituted 1,5-dienes:
Me Me
trans-trans: 90%
cis-cis: 10%
Threo isomer
Me Me Me Me
Me
trans-cis: < 1%
Meso isomer Measure product composition from rearrangement of each diene isomer p. p.
Me Me H Me H Me H less favored H Me H disfavored H Me H Me H Me Me Me H Me H Me disfavored H H H H H Me Me Me trans-trans H H 60 C Reese Chem. Commun. 1970, 1519
equilibrium stongly favors this isomer
favored
H H Me
Me
favored
Me Me
trans-trans
H Me
Me H H
disfavored
H H
Me
trans-trans: 0.3%
H H Me Me
cis-cis
Me
trans-cis
favored
trans-cis
H
120 C
D. A. Evans
Chem 206
O Me
Me Me
heat xylene
OMe
Me
90% Me Me
LDA MeI
Li (PhS)Cu
Me 1.5 equiv
Me O Me Me Me (EtO)2P
Li
OMe
Me
H2 (Ph3)3RhCl LDA
Me
OMe Me
Me
EtNH2/THF
O Me
p. p.
Me
Me
(EtO)2PCl
-himachalene
O Me CHO Vogel Angew. Chem. Int. Ed. 1963, 2, 739
favored Wittig
CO2Et Me
60-70%
+ S(O)Me2
k1
HO
HO
k2
k2 = 10 + 10 k1
10 + 17
Marvell, Tet. Lett. 1970, 509 Energetically, how much does tautomerization give you? keq ~ 10+5 G = 1.4(pKeq) = 1.4X(-5) = -7 kcal/mmol
D. A. Evans
Chem 206
OX OH
Half-life (66 yrs) no rxn 1.2 hrs 1.4 min 11 hrs 4.4 min 10 C 66 C
OH
Me
66 C THF
OLi ONa OK
Me
4 3 6
1 6
O
3
OK (HMPT) O K
-+
OH
Me XO Me MeO
Me Me Me
Me
Me
p. p.
HO
66 C THF
No Rxn
GOH
pka (TS)
O
GO ??
GO
HO
GO = GOH+ 2.3RT [ pka TS pka SM] GO = GOH GO + 2.3RT [18 29] (in DMSO) 1.4 [ 11]
HO
Effect probably comes from both reactant destabilization & transition state stabilization
GO = GOH +
~ 15 kcal/mol
D. A. Evans
Chem 206
[3,3]
X R
[1,3]
X R
O C
ketyl
Y R
X Y R
X Y
[2,3]
[1,2]
X ene
H
In DMSO:
C C
Y X
Y X H HO C H H BDE = 90.7 (BDE = 91.8 expt) H NaO C H H BDE = 80.6 H KO C H H BDE = 79.0 H O C H H BDE = 74.2
C C
C C C
Y X
C X C
D +16.5 kcal/mol
C X
Related papers: Evans, Baillargeon, Tet Lett. 1978, 36, 3315, 3319
X C
X C
X C
X C
RH
D. A. Evans
MeO OMe MeO OMe
Chem 206
Periplanone-B Synthesis
Me
O MgX
OH
NaH 75%
O
H H
OMe OMe H2 C
H OH
KH THF
ROH2C Me
Me
Jung, JACS 1978, 100, 4309 Jung, JACS 1980, 102, 2463
OH
ROH2C
Me
KH, THF
OR
KH THF 2 steps
Me H Me Me O Me
OH Me
O Me
50 C 50 % yield
OH OH
Me OH
[3,3] 7823 C
Me
H Me
Me
Me
poitediol
dactylol
Dieckmann
CH2OR
53%
J. Leighton, D. A. Evans
Me
Oxy-Cope Problems
Me Me Me O Me Me
Chem 206
Me H
?
Me Me H
-amorphene
THPO
Me Me Gregson, R. P.; Mirrington, R. N. J. Chem. Soc., Chem. Commun. 1973, 598. Et Me By incorporating a carbonyl group into this structure generate all possible oxy-Cope retrons. Which is (are) the most reasonable? Brub, G.; Fallis, A. G. Tetrahedron Lett. 1989, 30, 4045.
THPO
Propose a three step synthesis of B from A. Koreeda, et al. J. Org. Chem. 1980, 45, 1172. Me Me OH MeO Me Me OH OMe KHMDS THF, 20 C 51% KHMDS THF, 20 C 88% Me Me O H H OMe H H Me Me O H
H H Me O H
By incorporating a double bond into this structure generate all possible oxy-Cope retrons. Which is (are) the most reasonable? Ireland, et al. J. Org. Chem. 1981, 46, 4863. O Et H H OMe OMe
H H By incorporating a double bond into this structure generate all possible oxy-Cope retrons. Which is (are) the most reasonable? Paquette, L. A. et al. Tetrahedron Lett. 1987, 28, 31. MeO Me H
Me
H Propose detailed mechanisms for these reactions. Rationalize the different behavior of these enol ether isomers. Paquette, L. A.; Reagan, J.; Schreiber, S. L.; Teleha, C. A. J. Am. Chem. Soc. 1989, 111, 2331-2332. O O Me HO O mesitylene, N Me Me 72 h 48% H O O O Me O Me Me
O H Li O
Me
H Me
Propose a synthesis of A using the illustrated dihydropyran synthon. Oplinger, J. A.; Paquette, L. A. Tetrahedron Lett. 1987, 28, 5441.
Propose a detailed mechanism paying particular attention to issues of chemo- and stereoselectivity. Jacobi, P. A.; Selnick, H. G. J. Org. Chem. 1990, 55, 202.
D. A. Evans
General Reviews:
Chem 206
S. J. Rhoades, Organic Reactions 1974, 22, 1 (Cope, Claisen) Trost, Ed., Comprehensive Organic Synthesis 1992, Vol 5, Ch 7.2 Ziegler, Accts. Chem. Res. 1977, 10, 227 (Claisen) Bennett, Synthesis 1977, 589 (Claisen) Blechert, Synthesis 1989, 71 (HeteroCope) R. K. Hill, Asymmetric Synthesis vol 3, Ch 8, p503 (chirality transfer) Ziegler, Chem Rev. 1989, 89, 1423 (Claisen)
Claisen
O R
SN2'
The Reaction:
O R
O R
H ~ 20 kcal mol-1
X R
2
There is good thermodynamic driving force for this reaction. Bonds Broken: C-C (65 kcal mol ) & C-O (85 kcal mol ) Bonds Made: C-O (85 kcal mol-1) and C-C (85 kcal mol-1) R
-1 -1
X O
1 O
X R
2
H (kcal mol-1) 16 31 30
(Benson estimates)
Control of stereocenter 2 evolves into a decision how to establish the hydroxyl-bearing stereocenter
X O
OH H 77%
~ 30
O O
OR ~ 20
O
180-200 oC
O
Cope
O H 91%
OH
~ 20 kcal/mol
~ 30 kcal/mol
OR
O
OH
E:Z = 6.7:1
Heteroatom substitution at the indicated position increases exothermicity as well as reaction rate
65%
D. A. Evans
Chem 206
AcOHg
O OEt
75%
Watanabe, Conlon, JACS 1957, 79, 2828 Bronsted acids can also serve as catalysts O CH2 Cp2Ti AlMe2 Cl Ph O 96% Ph CH2 O
p. p.
H Me3C H2C
R B H Me3C H2 C
Use of Tebbe's Reagent: Evans, Grubbs, J. Am. Chem. Soc. 1980, 102, 3272. (review) S. H. Pines, Organic Reactions 1993, 43, 1 H
A H R
Me3C H2C R
The Ireland approach to the bicyclic acid A: Exocyclic Olefins: House, JOC 1975, 40, 86
OEt O O heat CMe3 O Me3C H H heat CMe3 Me3C H OEt Me3C O OEt HO H Me Me Me X O Claisen
X=H
H Me O Me
HO Me Me H
HO Me Me
Me
ratio 52:48
O Me3C
Me O H H HO Me Me
OH Me
EtOCH=CH2 Hg(OAc)2
Me OH
HH
Me H
ratio 75:25
HO Me Me
53% overall
O H
for exoocyclic olefins, overlap between developing sigma and pi bonds is equally good from either olefin diastereoface. In this instance, steric effects dominate & this system shows a modest preference for "equatorial attack." A related case is provided below.
The new stereocenter () introduced via the rearrangement had the wrong configuration!
D. A. Evans
Chem 206
Claisen Rearrangement as vehicle for stereoselective olefin synthesis Consider the following rearrangement:
H ke CHO Me O
Faulkner suggests that the installation of other substituents on Claisen transition states will lead to enhanced reaction diastereoselection:
H ke X
110 C
O X O X Et Me O X O Et X
Et Me
O Me ka H
e
Me
e
Et
(E)
H Me
(Z) a
a
Faulkner & Perrin (Tet. Lett. 2783 (1969) have made the correlation between G for rearrangement & G for the corrresponding cyclohexane# equilibria:
Me
p. p.
Me
H O H Me
#
Me H Me H O
(E):(Z) found
90:10 >99:1 >99:1 >98:2 Faulkner, Tet Let 1969, 3243 Faulkner, JACS 1973, 95, 553 Johnson, JACS 1970, 92, 741
G = +1.5 kcal/mol
G = +1.75 kcal/mol
They then suggest that there is a good correlation between cyclohexane "A-values" & G for the rearrangement process. Their case is fortified by the following expamples: CHO
110 C
O R2 R1
R2
CHO X
O OPMB Et Me
R2 R1 (E) R1 (Z)
R1
Me Me Et
R2
Et iPr Et
(E):(Z) found
90:10 93:07 90:10
(E):(Z) predicted
91:9 94:6 91:9 Faulkner, JACS 1973, 95, 553
procedure
Y = Ac, Ireland Y = H, Johnson Y = H, Eschenmoser
conditions
LDA, TMSCl HC(OMe)3, H+ MeC(OMe)2NMe2
X
TMSO MeO Me2N
T, C
-78+55 130 80
(E):(Z) ratio
97:3 94:6 97.5:2.5
D. A. Evans
Chem 206
http://www.courses.fas.harvard.edu/~chem206/
Pericyclic Reactions5
s Claisen Rearrangements & Variants
Enders, D.; Knopp, M.; Schiffers, R. "Asymmetric [3.3]-sigmatropic rearrangements in organic synthesis." Tetrahedron: Asymmetry 1996, 7, 1847-1882 Ziegler, F. E. "The Thermal Aliphatic Claisen Rearrangement." Chem. Rev. 1988, 88, 1423. Gajewski, J. J. "The Claisen rearrangement. Response to solvents and substituents: The case for both hydrophobic and hydrogen bond acceleration in water and for a variable transition state." Acc. Chem. Res. 1997, 30, 219-225. Tietze, L. F. "Domino reactions in organic synthesis." Chem. Rev. 1996, 96, 115-136. Parsons, P. J.; Penkett, C. S.; Shell, A. J. "Tandem reactions in organic synthesis: Novel strategies for natural product elaboration and the development of new synthetic methodology." Chem. Rev. 1996, 96, 195-206. Pereira, S.; Srebnik, M. "The Ireland-Claisen rearrangement." Aldrichimica Acta 1993, 26, 17.
s Reading Assignment for week: Carey & Sundberg: Part A; Chapter 11 Concerted Pericyclic Reactions Carey & Sundberg: Part B; Chapter 6 Cycloadditions, Unimolecular Rearrangements Thermal Eliminations Fleming: Chapter 4 Thermal Pericyclic Reactions
Wipf, P. Claisen Rearrangements.; Trost, B. M. and Fleming, I., Ed.; Pergamon Press: Oxford, 1991; Vol. 5, pp 827. New Aspects of the Ireland and Related Rearrangements, Tetrahedron 2002, 58, 29052928 (handout)
Me
OH Me
h
O OTMS
D. A. Evans
15-00-Cover Page 10/20/03 9:40 AM
Me h
D. A. Evans
General Reviews:
Chem 206
S. J. Rhoades, Organic Reactions 1974, 22, 1 (Cope, Claisen) Trost, Ed., Comprehensive Organic Synthesis 1992, Vol 5, Ch 7.2 Ziegler, Accts. Chem. Res. 1977, 10, 227 (Claisen) Bennett, Synthesis 1977, 589 (Claisen) Blechert, Synthesis 1989, 71 (HeteroCope) R. K. Hill, Asymmetric Synthesis vol 3, Ch 8, p503 (chirality transfer) Ziegler, Chem Rev. 1989, 89, 1423 (Claisen)
Claisen
O R
SN2'
The Reaction:
O R
O R
H ~ 20 kcal mol-1
X R
2
There is good thermodynamic driving force for this reaction. Bonds Broken: C-C (65 kcal mol ) & C-O (85 kcal mol ) Bonds Made: C-O (85 kcal mol-1) and C-C (85 kcal mol-1) R
-1 -1
X O
1 O
X R
2
H (kcal mol-1) 16 31 30
(Benson estimates)
Control of stereocenter 2 evolves into a decision how to establish the hydroxyl-bearing stereocenter
X O
OH H 77%
H O
~ 30
O
OR ~ 20
O
180-200 oC
O
Cope
O H 91%
OH
~ 20 kcal/mol
~ 30 kcal/mol
OR
O
OH
E:Z = 6.7:1
Heteroatom substitution at the indicated position increases exothermicity as well as reaction rate
65%
D. A. Evans
Chem 206
AcOHg
O OEt
75%
Watanabe, Conlon, JACS 1957, 79, 2828 Bronsted acids can also serve as catalysts O CH2 Cp2Ti AlMe2 Cl Ph O 96% Ph CH2 O
p. p.
H Me3C H2C
R B H Me3C H2 C
Use of Tebbe's Reagent: Evans, Grubbs, J. Am. Chem. Soc. 1980, 102, 3272. (review) S. H. Pines, Organic Reactions 1993, 43, 1 H
A H R
Me3C H2C R
The Ireland approach to the bicyclic acid A: Exocyclic Olefins: House, JOC 1975, 40, 86
OEt O O heat CMe3 O Me3C H H heat CMe3 Me3C H OEt Me3C O OEt HO H Me Me Me X O Claisen
X=H
H Me O Me OH
HO Me Me H
HO Me Me
Me
ratio 52:48
O Me3C
Me O H H HO Me Me
OH Me
EtOCH=CH2 Hg(OAc)2
Me OH
HH
Me H
ratio 75:25
HO Me Me
53% overall
O H
for exoocyclic olefins, overlap between developing sigma and pi bonds is equally good from either olefin diastereoface. In this instance, steric effects dominate & this system shows a modest preference for "equatorial attack." A related case is provided below.
The new stereocenter () introduced via the rearrangement had the wrong configuration!
D. A. Evans
Chem 206
Faulkner suggests that the installation of other substituents on Claisen transition states will lead to enhanced reaction diastereoselection: H ke X
110 C
O X O X Et Me O X O Et X
Et Me
O Me ka H
e
Me
e
Et
(E)
H Me
(Z) a
a
Faulkner & Perrin (Tet. Lett. 2783 (1969) have made the correlation between G for rearrangement & G for the corrresponding cyclohexane# equilibria:
Me
p. p.
Me
H O H Me
#
Me H Me H O
(E):(Z) found
90:10 >99:1 >99:1 >98:2 Faulkner, Tet Let 1969, 3243 Faulkner, JACS 1973, 95, 553 Johnson, JACS 1970, 92, 741
G = +1.5 kcal/mol
G = +1.75 kcal/mol
They then suggest that there is a good correlation between cyclohexane "A-values" & G for the rearrangement process. Their case is fortified by the following expamples: CHO
110 C
O R2 R1
R2
CHO X
O OPMB Et Me
R2 R1 (E) R1 (Z)
R1
Me Me Et
R2
Et iPr Et
(E):(Z) found
90:10 93:07 90:10
(E):(Z) predicted
91:9 94:6 91:9 Faulkner, JACS 1973, 95, 553
procedure
Y = Ac, Ireland Y = H, Johnson Y = H, Eschenmoser
conditions
LDA, TMSCl HC(OMe)3, H+ MeC(OMe)2NMe2
X
TMSO MeO Me2N
T, C
-78+55 130 80
(E):(Z) ratio
97:3 94:6 97.5:2.5
D. A. Evans
Chem 206
Eschenmoser, A. Helv. Chem. Acta 1964, 47, 2425; Helv. Chim.Acta 1969, 52, 1030.
Xylene, 150oC
Me EtO
O OEt O O OEt
OH
Me Et2N
OMe OMe
O NEt2
O NEt2
H
OEt
NMe2 Et O Me
Faulkner and Peterson
NMe2 Me
CH3CH2CO2H (cat)
EtO2C
Et O
p. p.
OH
60% Hg(OAc)2, EVE
138oC
Xylene, 110oC
Me
Me
98oC
Me OHC
Me
CO2Me Me Me OH
CH2=C(OMe)(NEt2) Xylene, 140 C, 14h
o
Me2N
Me O 94% Me Me
O Me
EtO Me
OEt NMe2
BF4-
+ O Et
Et
Me
Reactions to ponder:
C 3H 5 R Me OLi N Me O Me OLi N Predict the major diastereomer Me Welch, JACS 1987, 109, 6716 CMe2(OBn) O Me diastereoselection 6:1 Predict the major diastereomer Stevenson, Tet. Let. 1991, 32, 4199 Me
Me Me
OH
Me
OEt
H3PO4 125oC
Me Me
Me 60% Me Me
Me Me
CHO
+N Me
OMe
Me
Me + N
OMe Et
CMe2(OBn)
D. A. Evans
Ireland-Enolate Claisen
Reviews
Chem 206
New Aspects of the Ireland and Re;ated Rearrangements, Tetrahedron 2002, 58, 29052928 (handout)
R1 R2 H
Me
R1 O
R2 Me
R1 O OTBS
Ireland, R. E.; Mueller, R. H.; Willard, A. K. J. Am. Chem. Soc. 1976, 98, 2868 OH
t1/2 (32oC) = 3.5 h
(E)
OTBS
O O Me
LDA Me3SiCl
OTMS O O
R2 Me O
R1
Et O
66%
R2 Me
R1 R2 Me H
R1 O
H
R2 Me O OTBS
R1
O OTBS (Z)
p. p.
CO
Ha C O Hb
O Li N H R R
OTBS
R Hc
base Ha+
R
Hc R
Hb O
OLi R Me
key study: Ireland, JOC 1991, 56, 650 and earlier cited papers
Me
O Me H Li R H N R
(E) Geometry
OLi R Me
OH
OH
Me O
O O
LDA, TMSCl Et3N
Me
1,2 syn aldol relation permuted into 1,5 syn relationship via Claisen rearrangement
(Z) Geometry
Me RO Me Me Me Me Me OR O O O 63% yield (diastereoselection 86%)
20-60 C
Me Me O
Me
Me
Me Me O OTBS
The Ireland Model (JACS 1976, 98, 2868); Narula, Tetrahedron Lett. 1981, 22, 4119; more recent study: Ireland, JOC 1991, 56, 650 For a recent study on the effect of amide base structure on (E)/(Z) selectivity in the cont3ext of the Ireland enolization model see: JOC 1997, 62, 7516.
OTBS
D. A. Evans
Chem 206
OTMS OMe
BnO
BnO
OMOM Me Me O O O LI PMB
(A)
O t-BuMe2SiO
(E)
Me O
(B)
(Z)
BnO O Me OSiR3 Me O Me O OTMS OMOM OPMB OMe BnO OMOM Me
(A)
O t-BuMe2SiO
H Et H
OTBS H O
Et
ratio 95:5
Et
OTBS O OSiR3
85% yield
OPMB
p. p.
(B)
H O Et R
A Problem to consider
OH R 2 LDA O O
OTBS
2 LDA, TMSCl Me
Li O
Li
O O Me
OTMS Me O
OTMS O H
R TMSO H Me
favored
Me TMSO H
OTMS Me O
OTMS O
OTMS Me O OMe OH
larger smaller
H R
OTMS O R TMSO H
disfavored Me
TMSO
TMSO
2 LN(TMS)2/TMSCl CH2N2
Me
A(1,3) strain orients stereocenter relative size of carbon & oxygen substituents dictate relative face selectivity
D. A. Evans
Chem 206
Observations: Molecule contains an obvious symmetry plane The trisubstituted C=C's are the issue
OHC CHO Me OH Li Me Me EtO2C CO2Et Me Me LiAlH4 CrO3-pyr Li MeC(OEt)3 EtCO2H 138 C Me Me OH MeC(OEt)3 EtCO2H 138 C
HO Me
Et
Et
Me CO2Me
OH HO Me
1O
Et
3
Et
Me CO2Me
6
Et
6
Me CO2Me
p. p.
Et
OR
Me
Me CO2Me
Me CO2Me H+ 110 C O Et
6
Me CO2Me
OMe Et Et Et Me
6
Me OHC
Me Me Me Me Et Et
3
CHO
Me Me Me Me Me
PPh3 HO Me Me
1O
OR
Me Me CO2Me
OH Me
Et
Et Me CO2Me
OR
Me
Me
Me
Me
HO NaBH4 Me
Et
Et
nonselective [H]
OH
TSCl/pyr MeONa
D. A. Evans
Chem 206
Chirality transfer via the Claisen rxn is an integral aspect of the general utility of process
R. K. Hill, Asymmetric Synthesis vol 3, Ch 8, p503 (chirality transfer)
OEt OH R2
OEt O R1 R2 R1
R1
MeC(OEt)3 H+
R2
H H
R1 O
R2
R1 CO2Et
MeC(OEt)3 H R1
+
O R2
OH Na/NH3 H2 Pd CaCO3 R2
OEt
R1
Such chirality permutation processes are only as stereoselective as the energy difference between diastereomeric chair transiltion states:
R2 R1 O
H H
OH
R2 O
R1
favored
R2
R1
MeC(OEt)3 H+
R1 O R2
H
R2
R1 CO2Et
R1
X X R2 R2 OH
OEt
p. p.
disfavored
R2
R1
H
Me
tocopherol (Vitamin E) Cohen JOC 1976, 41, 3497 JACS 1979, 101, 6710
Me O Me Me Me O H Me MgBr OH Me Me Me Me Me OH Me Me Me NaAlH2(OR)2 Me Me Me Me Me
Note that chirality transfer is coupled to olefin geometry in product. Prior arguments (Faulkner) imply that the X substituent will play significant role in promoting selectivity.
Me
Me Me MeC(OEt)3 H+ X Me O Me
O X CO2Me N Me OH Me Me
ee > 90% (E)-selection > 90% R. K. Hill JOC 1972, 37, 3737
OH
Me
Me
50%
50%
Me
Me
CO2Me MeC(OEt)3 H+ N Me
Me Me OH Me
H2 Pd/CaCO3 Me
Me
(Z):(E) = 98:2
R O EtO
(E):(Z) = >99:1
O Me Me Me Me
92%
OH
77%
Me
D. A. Evans
Chem 206
H
OR
Ireland, JACS 1991, 56, 3572 Factors controlling diastereoselection Enolate geometry Chair vs Boat transition states Bartlett, JOC 1981, 46, 3896 Ireland, JACS 1991, 56, 3572
H H Me O OR H H
OR
H Me
O OR
Me H
Boat (Z)-enolate
Chair (Z)-enolate
Me H
O O
LDA,TBSCl
O
A
O OR
O Me OR O
Chair (Z)-enolate
Me Me
conditions
O O
TS (E)-boat (Z)-boat
LDA,THF LDA,TBSCl
p. p.
Me
A
O OR
B
O OR
LDA,THF DMPU
Me
H O H
OR
H O H
TS (E)-chair (Z)-boat
Me
H H Me
Me H
O OR
H H
OR
A further example:
OTBS Me
Chair (E)-enolate
Boat (E)-enolate
H O Me Me H O OR
O O
OMe
Chair (E)-enolate
Boat (E)-enolate
Me
Me
In this case the boat geometry is preferred from either enol geometry
O O O
OMe Me O H H Me O OTBS
LDA,TBSCl
O
A
O OR
O Me OR O
?
H
Me
destabilizing
TBSO
TS (E)-boat (Z)-boat
Me
It appears that both of the indicated interactions contribute to the destabilization of chair geometry
D. A. Evans
Chem 206
In this case the chair geometry is preferred from either enol geometry
O O
LDA,TBSCl
Me Me
A
O OR
B
Me OR HO O O
TS (E)-chair (Z)-chair
O O O H Me H RO O H Me OR
O O O H RO
1O 3
O RO O H Me O H O
R2
O R2 R1 OTBS
TBSO O O Me H
R1
favored
disfavored
Chlorothricolide
OR
[3,3]
CO2H
OR
p. p.
Ireland, J. Org. Chem. 1986, 51, 635 Ireland, J. Org. Chem. 1981, 46, 4863
CO2H Me H O OR O O TBSO R1 R2 O O R2 R1 OTBS CO2H H Me H O O RO O H OR O OR
In this case the boat geometry is preferred from either enol geometry
O O Me O
Me
O O O H Me H
LDA,TBSCl
A
O OR
O O OR OH RO O
Me
Me
TS (E)-boat (Z)-boat
In the initial approaches to the synthesis, the Schlosser-Wittig was unsuccessfully attempted for the fragment coupling process.
OR Me OR Me
OR
Summary:
O O Me O O O O O O
disfavored
favored
O
X = OH
O MeO O H Me H O H
X = SePh
Me
Me
60-72%
OMOM
decarboxylation
OMOM
D. A. Evans
Chem 206
A
H O Et
A
Et H O O O
Claisen
A
RO Et H HO O
B
Me
OH Et Claisen construction Me
OO
B
Me
OR Et
OR Et Me
Me O HO CO2H Me H
aldol
O
Me
A
Me Et H O Et
B
Me
Me OR Et Me
A
BnO
H
CO2H
A
BnO Et H O Cl OH
O BnO Et H
A
O O O
Et O
B
OMOM Me
Me
p. p.
RO Et
A
H O O O
B
OMOM Me
Claisen
RO
Me
B
OMOM Me
A
Et H O HO
B
Me
OR Et
OO
B
Me
OR Et
Me OH
A
O
B
O Me H
C
O Et H
D
O O
E
HO
Me CH2OH
A
RO Et H O COOR O
B
Me
OR Et
MeCOOH JACS 1993, 115, 7152-65 JACS 1993, 115, 7166-72 (and previously cited papers) A
O Me
X Et
B
O
O O Me Me
B
Me
A
O
R Et
O RO
Me O
MeO
A
Et H O
R R Et Me
Claisen construction
C
O Et H
D
O O
E
HO
Me CH2OH
D. A. Evans
Chem 206
O COOH Me
O COOH Me
15
H COOH H OH Me
Aldol
Me O H H OH
MeO2C
HO
OH
OH
1O
Claisen retrons
O RO OR COOH Me H OH O OR H
Claisen retrons
H
Dieckmann
H
3
MeO
COOH Me
COOH Me O OH RO
1O 3 5 3
MeO2C COOH Me
H 5
OH
OR
p. p.
O O
Claisen
OR COOH Me OH O HO HO OH COOR Me HO HO O O O OR OR
HOOC COOH
COOR OH OH OR C4H9
OR
Me
O Me O Me
83%
Li(0)
via erythrose
(MeO)3C OH O O O (CH2)3CO2Me H+ 160 C, 1h MeO
O (CH2)3CO2Me
12
An Application PGA1: Ireland JOC 1976, 41, 986; Aldrichimica Acta 1988, 21, 59
MeO2C
H O O O
59%
D. A. Evans
Chem 206
The Indanomycin Synthesis, Burke, Tet. Lett. 1985, 26, 1163; ibid, 1986, 27, 6295
O O N H H N H H
X Me
O Et H Me Et H CO2H O
H O
Et
"Right wing"
Et
"Left wing"
Me Me
O R2
Claisen
O OR Me
p. p.
"Left wing"
O O H LDA/TMSCl Me H BnO
H CO2H
Examples:
Me MeO TBSO O
OTMS 110 C 4h
Me Me H BnO O OTMS
H H BnO
80% yield
MeO2C
-78 C
[4+2]
Claisen
H
O H Et
H H
Et
Et O
CH2X OTMS H
OTMS
135 C 4h H Et
TMSO2C
Me
Et
65% yield
Et
Chem 206
R R1 R3 O R O
MeO
Me
24 22 O
O R2
O R2 R2
Me N O H O O
17
OH
19
O Me
OH
O
14
Me OMe
FK 506
Claisen disconnection
R3SiO MeO
29
70%
OMe OR O
MeO
29
OR O MeO
81%
H
p. p.
O O TBSOTf Et3N MeO H
O O LDA/TMSCl CHMe2
TMSO O
OR O
89%
H
MeO
71%
Me2HC
and R1 &R2
R O R1 O R2 R3 R3 R O
83%
Me H Me
D. A. Evans
Chem 206
R1 R2 Me
R1
OR O R2
These rearrangements present many of the same issues which were encountered during our discussion of carbonyl addition with regrad to assymmetric induction.
Chelate Control: -Hydroxy ester enolates: Kurth, JOC 1985, 50, 1840
OH Me OH O O 2 LDA, TMSCl H Me H H Me O O R 2 LDA Me O O Li O Li R El(+) Me El OH Me Me H O OTMS Me Me2HC OH O O R N Me O
chelate control
Me O Li
R' Me Me
p. p.
Me
O O
diastereoselection 87:13
Me2HC N O Me2HC N H Me Me O
chair TS
diastereoselection 81:19
185 C
diastereoselection 94:6
57%
Me Me
57:43
81:19
BF3-HOAc: Bryusova, J. Gen. Chem. (USSR) 1941, 11, 722 BCl3: Gerrard, Proc. Chem. Soc. 1957, 19; Schmid, Helv. Chem. Acta 1973. 56, 14 Et2AlCl: Sonnenberg, J. Org. Chem. 1970, 35, 3166 TiCl4: Mukaiyama, Chem. Lett. 1975, 35, 1041 (RO)2AlMe: Yamamoto, JACS. 1988, 110, 7922 (RO)2AlMe: Yamamoto, Tet. Lett. 1989, 30, 1265 (RO)2AlMe: Yamamoto, JACS. 1990, 112, 316 LiClO4: Reetz, Tetrahedron. 1993, 49, 6025
D. A. Evans
Chem 206
Me
LA
Me OH Me Me Me
p. p.
Me
LA + O
+ LA
Me R O H
Me -78 C
B
Me Me O
+ LA
Me Claisen Cope Me
A:B = 3:4
Me R O H O H
Me O
43%
19:81
LA
40% 85%
07:93
94%
03:97
The hindered Lewis acid will alter the partitioning of the Claisen process to the two ortho positions
D. A. Evans
Chem 206
R2
R1
R2
X R2 R3
Y R2
[3, 3]
R1 X Y
R3
X = C, N, O, S
O Ph
SiMe3
O R
SiMe3
R Ph C6H11
% ee 88% 71%
pyr
OH Cl S OPh
Et
p. p.
R SiMe2Ph GeMe3
% ee 90% 93%
Ar =
CF3
(LA)
ether
S O
X = O; Y = N
Threo: erythro 99:1 >97% ee (75%)
R R 200 C O H R 200 C Ph O N ONa O Ph ONa N Ph R N O Ph H R N N Ph
O O
Roberts, JACS 1960 82, 1950 Hill, JOC 1968 33, 1111
R
O O
H N
H3O+ H
Ph
D. A. Evans
R2 R1 X Y R3 R2
Chem 206
[3, 3]
R1 X Y
X = C, N, O, S
OTBS Me HN O CF3
X = O; Y = N:
The Trichloroacetimidate Rearrangement, Overman, JACS 1974, 96, 597
R O Cl3C H 3O CN
+
steps
H RO OH
OH
O N H
HN CO2H O
NH2
79%
HN O CCl3
OH OH
p. p.
79%
HN O CCl3
MeO
For an excellent review see: Overman, Angew. Chem. Int. Ed. 1984, 23, 579
NHBoc Me HN O CCl3 Me O heat BnO HN O CCl3 BnO Me O PdCl2(MeCN)2 THF, 25 C, 3h Me HN O CCl3 R NHBoc
+ NEt3
O
OM
OLi Me R N N O OLi Me
Me O
Me O
R'HN
moderate yields
D. A. Evans
Chem 206
http://www.courses.fas.harvard.edu/~chem206/
"Diels-Alder Reactions". Evans, D. A.; Johnson J. S. In Comprehensive Asymmetric Catalysis, Jacobsen, E. N.; Pfaltz, A.; and Yamamoto, H. Editors; Springer Verlag: Heidelberg, 1999; Vol III, 1178-1235 (electronic handout)
The Diels-Alder Reaction in Total Synthesis, K. C. Nicolaou, Angew Chem. Int. Ed. 2002, 41, 1668-1698 (electronic handout) Catalytic Enantioselective DielsAlder Reactions: Methods, Mechanistic Fundamentals, Pathways, and Applications, E. J. Corey, Angew Chem. Int. Ed. 2002, 41, 1650-1667 (electronic handout) Chemistry and Biology of Biosynthetic DielsAlder Reactions Emily M. Stocking and Robert M. Williams, Angew Chem. Int. Ed. 2003, 42, 3078-3115 (electronic handout)
Lecture Number 16
Cycloaddition Reactions-1
Cycloadditions: Introduction Ketene Cycloadditions The Diels-Alder Reaction
Reading Assignment for week: Carey & Sundberg: Part A; Chapter 11 Concerted Pericyclic Reactions Carey & Sundberg: Part B; Chapter 6 Cycloadditions, Unimolecular Rearrangements Thermal Eliminations Fleming: Chapter 4 Thermal Pericyclic Reactions
Wednesday, October 22, 2003
X CHO
N H Me
D. A. Evans
+
R
5% catalyst MeOH-H2O
CHO R
D. A. Evans
Cycloaddition Reactions-1
Consider [2 + 2] cycloaddition: Photochemical activation
new HOMO LUMO
Chem 206
[ 2s
Why does maleic anhydride react easily with 1,3-butadiene, but not with ethylene? So what are the "rules"?
O O O O O
+ 2s]
*
light
C C
bonding
X
[2+2]
O O
[4+2]
O O
bonding
light
C C C
+
C
concerted
HOMO
heat
X
X X
C C
C C
C C
C C
+ energy
We also know that the photochemical variant is concerted p. . The frontier orbitals of the reacting species must have the proper symmetries Nomenclature suprafacial
C C
2s
antarafacial
C
2a
[2s + 2s]
+ 2s cycloaddition + 2s]
Me bonding Me Me
Me Me Me h Me Me Me
Me
[2s + 2s]
Me Me
2s
bonding
C
antibonding
2s
C C C C
Dewarbenzene-Derivative
Prismane-Der.
2a
[2s + 2a]
2s
[ 2s
bonding
+ 2s] "forbidden"
[ 2s
+ 2a] "allowed"
must be antarafical for indicated stereochem
D. A. Evans
Summary of Ketene Cycloadditions
R R' R O R R' O
Carbonyl Alkene
Cycloaddition Reactions-2
O O O O O Ph R' R R' O
550 C _
Chem 206
O O O Br Zn _ ZnBr Ph2C C O
2
O
or
R R' R
C O H
R'
Ph Br
O R1 O R3 R O N R H R N2 O -CH2CH2 R O R'
h or
2
H 2C C O R1 O R3 R2 R C O R' R C O H
O C
1,3-Dipole
R'
p. .
Imine
h or
O R R'
X Y Z X
R = -CH=CH2
R'
Y O X Y O R R' R'
R C O R'
Staudinger Reaction (very general)
HOMO
[2s2a]
O
H
H 2C C O O
_ +
(CH3CO)2O
_ RCH2CO2Ar
AcOH -ArO
_
H
R C O
O LUMO
OH
_H O 2
OAr
D. A. Evans
[2+2]: Stepwise Versus Concerted
Cycloaddition Reactions-3
Ketene-Alkene [2+2]
O Me
+
Chem 206
H H C R' H C
R O R
H H R' H
R C R O
O
Fast
R'
O Me
C Me O C
Me
Me
Me Me Me Me O
Me
+
Me
+
Me Me Me
Me Me Me
Stepwise
Very large polar effects E olefins yield a mixture of cis and trans products Solvent effects observed, but it could merely be a ground state effect KIE seen for many reactions support stepwise mechanism Calculations (Wang and Houk) show a highly asynchronus transition state in the gas phase reaction All stereochemical outcomes can be rationalized assuming a stepwise mechanism
Concerted
Ketenes add stereoselectively to Z alkenes Z olefins are much more reactive than E
Me
Me
Me
B 1:2 H C
Me
+ Me
H Me Me C
Me
Me Me
Me
O_ C Me + H
O_ C H + Me
Me Me
p. .
C O
Me
O
+
ab initio Calulations
O H H
O H H
Me C O X
X Cl Cl Cl Cl Solvent hexane Et3N CHCl3 CH3CN endo / exo 4.3 / 1 2.2 / 1 1.6 / 1 0.59 / 1
X
endo X Br Br Br
Me
exo Solvent hexane Et3N CH3CN endo / exo 0.71 / 1 0.28 / 1 0.14 / 1 +
O C H O H H H
path A
38 kcal/mol
O O
32 kcal/mol path B
O O H H H H
Solvent effects implicate a zwitterionic intermediate Brady,et. al, JACS 1970, 92, 146-148.
Mechanism and Origin of Stereoselectivity in Lewis Acid Catalyzed [2 2] Cycloadditions of Ketenes with Aldehydes, Singleton, Angew. Chem. Int. Ed. 2002, 41, 1572
D. A. Evans
Transformations of -Lactones
R2 R1 O O O O R2 R1
+S _
Cycloaddition Reactions-4
The Staudinger Reaction
Chem 206
or BF3 -CO2
Me2S
O O
In this process, the illustrated ketene, generated in situ from an acid chloride, undergoes reaction with the indicated substrates to form -lactams in a stereoselective process. When the azo-methine (RN=CHR) geometry in the reactant is (Z) the product stereochemistry is trans (eq 1). In a complementary fashion, the (E) imine affords the cis-substituted product (eq 2). While this transformatlion could be viewed as a [2s+2a] cycloaddition, it is felt that this reaction is stepwise. H H H R S S R Et3N O Cl R C O H R N N O R R R H H R
(2)
N O
(1)
O R2N O
p. .
R2 O O OH
base or acid
R1
R1
H N
H H conrotatory R S closure N O
(1)
enantiomers
R
MeO
Application in Natural Product Synthesis: Ginkolide B, E. J. CoreyJACS 1988, 110, 649. O O CMe3
1. (COCl)2, PhH, 2. NBu3, toluene,
Ther are two contortaory modes. If you control the conrotatory mode, you control the absolute stereochemistry of the reaction: O CMe3 O N Bn Ph O Cl H N Ar
conrotatory R closure O
H H S N
O Et3N O N Ph O H H N O Ar + Bn Ph
O N O H H N Ar Bn
H O H
CO2H
H CH2COCl
NEt3 O C H O
JOC 1982, 47, 3470.
"[2+2] photocycloaddition/fragmentation strategies for the synthesis of natural and unnatural products.", Winkler, J. D.; Bowen, C. M.; Liotta, F. Chem. Rev. 1995, 95, 2003. "Stereoselective intermolecular [2+2]-photocycloaddition reactions and their application in synthesis.", Bach, T. Synthesis 1998, 683.
D. A. Evans
Cycloaddition Reactions-4
Me
1)
Chem 206
Me O N
+ _
O Br H
R3N
O
catalyst (10 mol%)
O R O C + Me3Si H H O
Me
R O C
i-Pr2NEt
[RCHO cat.]
N OTf Cu Me3C H2O OH2 CMe3 OTf PhMe2Si OEt 1 mol%, THF, 3 MS
-78 C, 24 h
O O
R3NHBr
CH2
EtO2C
77% yield, 93% ee
i-Pr N F3CO2S
Bn N Al R N
i-Pr SO2CF3
cat. = 5a: R = Me 5b: R = Cl
PhMe2Si O EtO2C
% ee 3 (configuration)
p. .
entry a b Aldehyde 2 (R)
3: >99% yield, 92% ee catalyst [time (h), temp (C)] 5b (8, -40) 5a (16, -50) 5a (72, -78) 5b (16, -50) 5a (24, -50) 5b (16, -40) 5b (16, -40) 5a (16, -50) 5a (16, -50) 5b (24, -40) % yield 91 93 89 91 80 90 74 86 91 56
2+
Me BnOCH2 PhCH2CH2
PhCH2CH2 c d e f g h i CH2CH(CH2)8 Me2CHCH2 BnOCH2CH2 TBDPSOCH2 92 (R) 92 (S) 95 (S) 91 (S) 93 (S) 91 (S) 89 (R)
O H N N Cu O R RO OR2 R O H C C Me3Si
1
Me
Me3Si
observed product
2
O O O
R1 R O
Me Me
93 (R) 85 (R) 54 (R)
2+
BnOCH2 Me3C
C6H11
O N Cu Me3C H2 O N
OH2
CMe3
X-ray
D. A. Evans
Chem 206
Representative natural products displaying the Diels-Alder retron: These natural products could well have incorporated the DA rxn into the biosynthesis
HO O O O H O H H H H Me NMe2 H Et O O Me R H H O
The Diels-Alder Reaction in Total Synthesis, K. C. Nicolaou, Angew Chem. Int. Ed. 2002, 41, 1668-1698 (handout)
Catalytic Enantioselective DielsAlder Reactions: Methods, Mechanistic Fundamentals, Pathways, and Applications, E. J. Corey, Angew Chem. Int. Ed. 2002, 41, 1650-1667 (handout)
O Et O
Hetero Diels-Alder Methodology in Organic Synthesis Boger, D.L. and Weinreb, S.N., Academic Press, 1987
Me
p. .
Natural Products Synthesis Through Pericyclic Reactions Desimoni, Tacconi, Barco, Polini, ACS Monograph 180, 1983, Chapter 5,
Compactin: R = H Mevinolin: R = Me
Me
Asymmetric Diels-Alder Reactions with Chiral Enoates as Dienophiles Modern Synthetic Methods 1986, Scheffold, Ed. Springer-Verlag,
Intramolecular Diels-Alder and Alder Ene Rxns, D. F. Taber, Springer-Verlag, 1984 Synthetic Aspects of D-A Cycloadditions with Heterodienophiles Weinreb, Tetrahedron, 1982, 38, 3087-3128 The Intramolecular DA Rxn: recent advances and synthetic applications Fallis, Can. J. Chem., 1984, 62, 183-234 Intramolecular [4 +2] & [3 + 2] Cycloadditions in Organic Synthesis Oppolzer, Angew. Chem. Int. Ed., 1977, 16, 10-23 Preparation & DA Reactions of Heterosubstituted 1, 3-Dienes Petrzilka, Synthesis, 1981, 753-786 DA Reactions of Azadienes Boger, Tetrahedron, 1983, 39, 2869-2939 Silyloxydienes in Organic Synthesis Danishefsky, Acct. Chem. Res., 1981, 14, 400-406 DA Reactions Part I: New Preparative Aspects Sauer, Angew. Chem. Int. Ed., 1966, 5, 211-230 DA Reactions Part II: The Reaction Mechanism Sauer, Angew. Chem. Int. Ed., 1967, 6, 16-33 Mechanistic Aspects of Diels-Alder Reactions: A Critical Survey Sauer, Angew. Chem. Int. Ed., 1980, 19, 779-807
Me O COOH H Me
Lepicidin
(Biosynthesis) JACS 1985, 107, 3694 Clive, JACS 1988, 110, 6914 Kozikowski, JOC 1987, 52, 3541 O H Keck, JOC 1986, 51, 2487 H Me O Grieco, JACS 1986, 108, 5908 H OMe H Heathcock, JACS 1985, 107, 3731 MeO H OMe Girotra, Tet. Let. 1983, 24, 3687 Hirama, JACS 1982, 104, 4251
HN O H H HO2C H
H H H Ph
Et H Ph Et
H H H H
Endiandric Acid C
X-14547A
Roush JOC 1984, 49, 3429 Nicolaou JOC 1985, 50, 1440 Ley Chem. Commun. 1983, 630
CO2H
H
Endiandric Acid B
(Syntheses) Nicolaou, JACS 1982, 104, 5555-5562
D. A. Evans
The Alder Endo Rule
Chem 206
H + H H
disfavored favored
"Exo product"
"Endo product"
C C C
HOMO-2
C C C
LUMO-3
Observation: The endo Diels-Alder adduct is formed faster even though the exo product is more stable. There is thus some special stabilization in the transition state leading to the endo product which is lacking the exo transition state. Exo TS Endo TS
C C
C C
LUMO-3
C C
C C
HOMO-2
p. .
Energy Primary orbital overlap leads directly to the formation of new chemical bonds.
2
H
Of the two possible transition states, the one having the "greatest accumulation of interacting double bonds will be preferred" (the Alder Endo Rule). Secondary orbital overlap is noted below.
Note that the termini only match at one end for the HOMO-LUMO pairing. Hence we say that the symmetry C requirements for the reaction in question are not met. This does not mean that the reaction will not occur, only that the reaction will not be concerted. Such reactions are called "symmetry-forbidden".
C C
C HOMO-2
C C C
C LUMO-3
Exo TS
Endo TS
Additional Reading: Lowry & Richardson, Chapter 10, theory of Pericyclic Rxns pp 839-900
D. A. Evans
Chem 206
Yates & Eaton, JACS 1960, 82, 4436
LUMO1
LUMO2
The lengths of the forming CC bonds are Ca. 1.5 times the normal bond distance. This factor comes out of the ab initio work of Jorgensen & Houk leading references:
Jorgensen, JACS 1993, 115, 2936-2942 Houk, Jorgensen, JACS 1989, 111, 9172
energy
Transition Structures of Hydrocarbon Pericyclic Reactions Houk Angew. chem. Int. Ed. 1992, 31, 682-708
Diene
The closer the two orbitals are in energy, the better they interact As E decreases for the relevant ground state FMOs, rxn rates increase
O H H
2.193
2.193
2.091
2.325
LUMO2 LUMO1
exptl
E
HOMO1 HOMO2
LUMO3
HOMO3
Rate Acceleration
log k = 4.96
Lewis acid catalysis not only dramatically increases rates by ca 10+6 it also improves reaction regiochemistry & endo diastereoselectivity
D. A. Evans
Orientation of Reacting Partners
CO2H CO2H CO2H
Chem 206
favored
Ni(Raney)
AcO
COMe
p. .
59 : 41 96 : 04
By employing a removable substituent, it is possible to access the normally disfavored product diastereomer
O2N RO CO2Me RO NO2 CO2Me
In general, 1-substituted dienes are more regioselective than their 2-substituted counterparts: Sauer, Angew. Chem. Int. Ed., 1967, 6, 16-33 Lewis acid catalysis improves endo diastereoselection
Danishefsky, JACS 1978, 100, 2918: The NO2 FG completely dominates directivity It then can be removed by elimination NO2 RO CO2Me NO2 RO CO2Me O
83% base NO2
RO
H CO2Me H disfavored 80 : 20 95 : 05
CO2Me
R3SnH RO O
R3SnH 86%
CO2Me
DA Reactions Part II: The Reaction Mechanism, Sauer, Angew. Chem. Int. Ed., 1967, 6, 16-33
NO2
Me
O2N
Me
Me
D. A. Evans
Chem 206
H H Cl CN CN CH2OMe Cl
MeO O
MeO O
Ratio: 90 : 10
Ratio 50 : 50 80 : 20 <5 : 95 X
O NPh O
25-50 C
Me
O PhN O
Me Me
O PhN
p. .
selection 80 : 20
H X X= OH Ratio
H X
36 : 64 83 : 17 >97 : 3 Me O OR O NPh Me O
selection >95 :5
Me OMe
Me
OR
Similar results provided by Stoodley Chem. Comm. 1982, 929 Kelly Tet. Let. 1978, 4311 OMe
BF3OEt2
O NPh
25-50 C
Me
OR
NPh Me O
O RO
OMe
Me
O RO Me
selection >95 :5
Me OH O O
0.4 equiv
Franck, Tet. Lett. 1985, 26, 3187 Franck, JACS 1988,110, 3257
Me OH O OMe
MgI2 0.5 equiv
Comments on the Transition State Me Avoid Eclipsing allylic substituents better donor (Me) anti to forming bond avoid gauche OR interaction Me PhN O
RO
selection >95 :5
OH O OMe
D. A. Evans
Chem 206
http://www.courses.fas.harvard.edu/~chem206/
"Diels-Alder Reactions". Evans, D. A.; Johnson J. S. In Comprehensive Asymmetric Catalysis, Jacobsen, E. N.; Pfaltz, A.; and Yamamoto, H. Editors; Springer Verlag: Heidelberg, 1999; Vol III, 1178-1235 (pdf) "Chiral Bis(oxazoline) Copper (II) Complexes: Versatile Catalysts for Enantioselective Cycloaddition, Adol, Michael and Carbonyl Ene Reactions". Johnson, J. S.; Evans, D. A. Acc. Chem. Res. 2000, 33, 325-335. (pdf) "New Strategies for Organic Catalysis: The first Highly Selective Organocatalytic Diels-alder Reaction", MacMillan, JACS, 2000, 122, 4243. (pdf) "New Strategies for Organic Catalysis: The first Enantioselective Organocatalytic 1,3-Dipolar Cycloaddition", MacMillan, JACS, 2000, 122, 9874. (pdf)
Lecture Number 17
Cycloaddition Reactions-2
The Diels-Alder Reaction
Reading Assignment for week: Carey & Sundberg: Part A; Chapter 11 Concerted Pericyclic Reactions Carey & Sundberg: Part B; Chapter 6 Cycloadditions, Unimolecular Rearrangements Thermal Eliminations Fleming: Chapter 4 Thermal Pericyclic Reactions
97% yield
D. A. Evans
17-00-Cover Page 10/23/03 3:34 PM
D. A. Evans
Chem 206
S-trans geometry
AlCl3 89%
Ph O
rxn from this face Lewis Acid-Ester Complex Conformation Dictates Diastereoselection
LA O O R H RS RL R O O H O R O H RL RS
LA
RL RS
p. .
Chem 3D model
R LA O H O RL RS R RL RS
front Face
H
AlCl3
O O
front Face
Me O Me O Cl Ti Cl Cl Cl Cl O Cl Cl Ti Cl
Chem 3D model
diene approach
Me O Me
X-ray
D. A. Evans
Chem 206
Cl Cl O O
Ti
Cl Cl O OEt Me
p. . X-ray structure
R O Ph
O Ph Ph O O N Ti
O O
Ph
Cl Cl O Me O
Ti
Cl Cl O Me
Narasaka JACS, 1989, 111, 5340 A. Jorgensen, JACS, 1995, 117, 4435
X-ray structure
D. A. Evans
Chem 206
Evans JACS, 1984, 106, 4261. Evans JACS, 1988, 110, 1238.
H O C H XV O H C
Me H XV
Exo-1 + Exo-2
Me EtO O O
R H H Me
Entry A B O O AlEtCl2
Temp 63 C 63 C
Endo-2 Endo-1 Endo-1 Temp. Endo-2 Endo / Exo 25 78 78 78 78 78 2.7 3.1 2.6 1.5 15.7 4.4 92 : 8 93 : 7 91 : 9 80 : 20 >99 : 1 92 : 8
p. .
EtO O Cl2EtAl
OR*
Helmchen Tetrahedron Lett. 1984, 25, 2191. ACIEE 1985, 24, 112. Tetrahedron Lett. 1985, 26, 3095.
+
N
1 Point Binding
C 5H 6
Cl Cl O O
Ti
Cl Cl O OEt Me
O O Me Al
O R N R
O O
Me Me2AlCl2
2 Point Binding
C 5H 6 O
O + O R N R
X-ray structure Why Imide Dienophiles?? They are ~ 100-1000X more reactive
D. A. Evans
Chem 206
Compare the alkylation rxn which is dominated by steric effects with the DA rxn which may be controlled by both steric and electronic effects Et O Me N R O Et N R O O LDA Et O O Et2AlCl Me O Al N R O Li O N R O MeI 30 Et * Me R Et O O N R O N O O O O
Me
Model
Al O + O N O
Al
30 Me
CH3
PhCH2
~3A
A Complex Application
OTIPS Et O O Me OTES H O O N Bn O Me2AlCl, 0 C 71% Et O O H H Me H O H H N Bn OTBS O O OTIPS OTES
p. .
G = 2.3 RT Log P1/P2 PLOT G FOR EACH RXN AS A FUNCTION OF THE SUBST., R.
20
CH2c-C6H11
CH2Ph
15
A1 10 A2
Et i-C3H7 Me
diastereoselection 10:1
Alkylation,
The control experiment with no chiral auxiliary: OTIPS Et Me O OTES H O O N O Me2AlCl, 0 C 74% O H Et O Me H H O H N O O OTIPS OTES
Ph
0 0 5 10 15
Diels-Alder,
Conclusions:
20 D1
D2
25
30
Steric effects correlate well for the two reactions Added electronic effects from Bn group enhance facial bias
17-04-Aux-control/DA-3 10/23/03 4:36 PM
diastereoselection 6:1
OTBS
H OTBS
D. A. Evans
Type I intramolecular Diels-Alder Reaction:
Chem 206
Me
O t-Bu
HO O
OR
Me H
Me H
H OR
Me H SiR3 OR
OH
(-)- Chlorothricolide
A Type II Intramolecular Diels-Alder:
O O O O O H CO2H O O H O Me Me O O O O H H O O Me C 5H 9 R3SiO
C8H15
OR
()-CP-263,114
Me
toluene, 120 C
Me O O N O O O
Me O C5 H 9
RO2C SiR3 OR
EtS Bn MeO2C
C8H15
CO2Me
Some Intramolecular Diels-Alder Reviews: Shea Angew. Chem. Int. Ed. 2001, 40, 820. Fallis Acc. Chem. Res. 1999, 32, 464-474.
Fukuyama et al JACS 2000, 122, 7825-7826. The concept: Evans, et al Angew. Chem. Int. Engl. 1997, 36, 2119-2121.
D. A. Evans
Chem 206
"Diels-Alder Reactions". Evans, D. A.; Johnson J. S. In Comprehensive Asymmetric Catalysis, Jacobsen, E. N.; Pfaltz, A.; and Yamamoto, H. Editors; Springer Verlag: Heidelberg, 1999; Vol III, 1178-1235. Review: Kagan, H. B.; Riant, O. Chem. Rev. 1992, 92, 1007-1019 Comprehensive Organic Synthesis, Vol. 5, Trost, Ed. 1991
re-face
re-face
X L
4.1 Intermolecular Diels-Alder Reactions, W. Oppolzer 4.2 Heterodienophile Additions to Dienes, S. M. Weinreb 4.3 Heterodiene Additions, D. L. Boger 4.4 Intramolecular Diels-Alder Reactions, W. R. Roush 4.5 Retrogade Diels-Alder Reactions, R. W. Sweger, A. W. Czarnik
Catalytic Asymmetric Synthesis, I. Ojima, Ed. 1993
(E) s-cis
M O X M L
M M X O
si-face
si-face
(Z) s-cis
p. .
Chiral Lewis Acids in Catalytic Asymmetric Reactions Narasaka, Synthesis, 1991, 1-11 (Carbonyl-Lewis Acid Complexes) Schreiber, Angew. Chem. Int. Ed., 1990, 29, 256-272 Rotational barriers in Aldehydes & Ketones Coordinated to Neutral Lewis Acids Wiberg, JACS, 1988, 110, 6642 Theoretical Studies on Conformations of Acrolein, Acrylic Acid, Methyl Acrylate & their Lewis Acid Complexes Houk, JACS, 1987, 109, 14-23 C2 Symmetry and Asymmetric Induction, Whitesell, Chem. Rev., 1989, 89, 1581-1590
Theoretical Studies on Conformations of Acrolein & Methyl Acrylate & their Lewis Acid Complexes Houk, JACS, 1987, 109, 14-23
However, there is no evidence for this orienting effect in this X-ray structure reported by Reetz, JACS, 1986, 108, 2405 F
F 3B
O+
However pi-bonding to coordinated C=O-Al complexes has been reported Barron, JACS, 1990, 112, 3446, JACS, 1990, 112, 2950 Theory predicts a small rotational barrier about BO bond: Wiberg JACS, 1988, 110, 6642
D. A. Evans
Chem 206
p. .
re-face R CO2Me
R O Ph R si-face CO2Me Ph O O Ph N Ti
R O Ph O O O Ph
X-ray
Chem 3D Models A. Jorgensen, JACS, 1995, 117, 4435
D. A. Evans
Chem 206
O N
N N Mg I I -78 C
Stereochemical Model:
X-ray structure
PM3 model
Mg
p. .
O N
O O
5 mol% cat. 25 C
R H H X
PM3 model
Re-face
R O R = Me R = Ph R = Cl
time 8h 8h 8h
O O
Cu(2+)-Based Catalysts:
Evans, Miller, Lectka JACS 1993, 115, 6460. Angew. Chem. Int. Engl. 1995, 34, 798-800. JACS 1999, 121, 7559-7573. JACS 1999, 121, 7582-7594
2+
temp 25 C -20 C 0 C
Me Me O O R + N O O Me3C N Cu H2 O OH2 N O
R = Ph R = OAc
0 C
D. A. Evans
Chem 206
Me O N Cu Me3C R O N
Me O N O O
2+
O
Me
Me O
2+ 2 X
CMe3 O O
Me
Me O
2+ 2 X
CMe3 Ph OMe O N N Cu O H N OBn Ph O
2+
2X
CMe3
N Cu Me3C RO2C N N O N
N O
N Cu Me3C MeO R O
N O
2 X
Michael Reactions
Aldol Reactions
p. .
Me O N Cu Me3C O O OR' R R CMe3 N Me O
2+ 2 X
O
Me
Me O
2+
O
Me
Me O
2+ 2 X
CMe3 Bn O N X N Cu O N Bn O
2+
N Cu Me3C O
N O P
2X
CMe3 OR'
N Cu Me3C O R
N O OR'
2 X
OR'
Diels-Alder Reactions
D. A. Evans
Chem 206
Me O
Me
Me
Me O
2+
2X
a: X = OTf b: X = SbF6
O N Cu Me3C H O 2 N
(A)
2 X
cat. 1b
N O
H O N O
OH2 CMe3
2
OTMS
100
(D) (B)
Me cat. 1b
O O N O O Pyr Me CO2Et O N O O
98
EtO2C
(E)
96
p. .
(B)
(A)
O MeO O
94
(C)
(C)
Me
OTMS StBu
Me MeO O
OH O StBu
92
(A)
O
Ph OEt O OEt
90
(B) (C)
(D)
Ph
88
(D) (E)
86
N
OTMS
(E)
cat. 2a
O O N O N
O Pyr
Troc N N H
O N
O O
CF3CH2OH
temperature (C)
Troc
"Chiral Bis(oxazoline) Copper (II) Complexes: Versatile Catalysts for Enantioselective Cycloaddition, Adol, Michael and Carbonyl Ene Reactions". Johnson, Evans, Acc. Chem. Res. 2000, 33, 325-335. (electronic pdf)
Chem 206
O H H RO O
X
+
OR
OR
LUMO
LUMO
LUMO
E
HOMO1 HOMO2 HOMO3
E
HOMO
LUMO
HOMO HOMO
HOMO
Rate Acceleration
CO2R XOC O OR RO
+
LA O
O X X O
+
OR
XOC
OR
LUMO
LUMO
E
HOMO
LUMO
LUMO
E
HOMO HOMO HOMO HOMO
LUMO
D. A. Evans
Chem 206
Me
Me O N
2+ 2 X
+
O O
A: X = OTf B: X = SbF6
O N
CMe3
Cu Me3C H O OH CMe3 2 2
O EtO2C N
O O
10 mol% 2B OSiR3 Ph Me
Ph
OSiR3 O
OMe N O O OSiR3 Me OMe H O 10 mol% 1A O OEt Endo T.S. N O O OMe >99:1 Endo:Exo 96% yield 99% ee O Me O CO2Et R3SiO Me O CO2Et
p. .
Me CO2Et
O Ph Me
CO2EtO N
O O
(CF3)2CHOH
Ph Me
OSiR3 O
CO2Et Evans, Scheidt, Johnston, Willis J. Am. Chem. Soc. 2001, 123, 4480.
CF3CO2H
R3SiO Me
O CO2Et
Me
Jorgensen J. Am. Chem. Soc. 1998, 120, 8599. 24:1 Endo:Exo 87% yield 97% ee
O Me
OEt
C4H10OTBS O O N O 5 mol% 1B H H
C4H10OTBS N O O O
CH2Cl2
81% yield 96% ee, 99:1 dr Evans, Johnson J. Org. Chem. 1997, 62, 786-787.
D. A. Evans
Chem 206
Me OH O
AcO H HO2C
11
Me OH O OH H Me
TBSO TBSO Me O
CO2Et Me OTBS
Ph2Se2O3 R3N, RT 63%
TBSO TBSO Me O
CO2Et
18
Me OTBS
H H Me
H
2
Oxidation at C11
H H Me
H H O O
17
19
O O
17
Me
Br
Br Me
50 C
Me Diels-Alder cycloaddn
()-FR182877
Sato, B. J. Antibiot. 2000, 123, 204, 615. Corrected Structure: J. Antibiot. 2002, C-1.
Hexacyclinic Acid
Hofs, R., et al. Angew. Chem. Int. Ed. 2000, 39, 3258.
TBSO H Br H H
TBSO
Me MeO H
p. .
O Me
C18 & C19 stereocenters exert complete control over the first cycloaddition (Evans)
HO H X
11
Me RO Me H Br H
-120
OR H H H Me
11
CO2R
kcal/mol (PM3)
OR Me H
MeO MeO
8
6
2
CO2Me
18
Me
O
19
Me OMe
endo-I
endo-II
Br Evans & Starr, JACS, 2003, 125, ASAP Sorensen et al, JACS, 2003, 125, 5393
Me
(natural configuration)
E = 59 kcal/mol @ 2.1
17-13-FR DA Rxns 10/22/03 4:01 PM
Me
toluene,
97% yield
(+)-Longifolene
O H Me O Me OMe OMe
1,5-H shift
H Me Me O Me
Me
1,5-H shift
Me H
Me
O Me
OMe
Me
Me
Me
OMe O O
Me Me O OMe O Me H
Me Me O MeO
H O Me
[4+2]
Me
Exo T.S.
Me
Me
Me Me O OMe
O Me
OMe O O
Me Me
OMe O O
Me
97% yield
D. A. Evans
Dipolar Cycloadditions
Dipolar Cycloaddition Reactions
Chem 206
http://www.courses.fas.harvard.edu/~chem206/
General References Carruthers, W. Cycloaddition Reactions in Organic Synthesis.; Pergamon: Elmsford, NY, 1990. Padwa, A. 1,3-Dipolar Cycloaddition Chemistry, John Wiley, 1984, Volumes 1 & 2, Jorgensen, Asymmetric 1,3-Dipolar cycloadditions, Chem Rev. 1998, 98, 863-909 Padwa, A. Generation and utilization of carbonyl ylides via the tandem cyclization-cycloaddition method." Acc. Chem. Res. 1991, 24, 22. (handout) Confalone, P. N.; Huie, E. M. The [3+2] Nitrone-Olefin Cycloaddition Reaction Org. React. (N.Y.) 1988, 36, 1. S. Kanemasa, Metal Assisted 1,3-Dipolar Cycloaddition Reactions, SynLett 2002, 1371-1387 (handout)
Lecture Number 17
Reading Assignment for week: Carey & Sundberg: Part A; Chapter 11, p 647-648 Concerted Pericyclic Reactions
Carruthers, W. Cycloaddition Reactions in Organic Synthesis.; Pergamon: Elmsford, NY, 1990.pp 294-331 (Handout) D. Ripin, W. Use of Isoxazoles as 1,3-Dicarbonyl equivalents in Organic synthesis; Evans Group Seminar 1997 (ElectronicHandout) Problem of the Day
Provide a plausible mechanism for this transformation in the space below. In attacking this question, it is important that you are aware of the transformation that transpires when terminal acetylenes are treated with Cu(I) or Ag(I) in the presence of an amine base. O Ph H Ar N H R
13% CuX R3N, RT
Ph N O
R
major
Ar
D. A. Evans
In 1995 Miura and co-workers reported the remarkable reaction illlustrated below (J. Org. Chem. 1995, 60, 4999). Recently, Fu has reported an enantioselective variant of this transformation (J. Am. Chem. Soc. 2002, 124, 4572). In most instances, the cis adduct is formed in large excess (>90%). There is really no thoughtful mechanism in the literature for this transformation. You will be graded on "reasonability"
D. A. Evans
Chem 206
B A C A D
B C E
[4S + 2S]
B A
LUMO B A
E LUMO D HOMO D
p. .
The specific set of reaction partners, will define the dominant frontier orbitals
H MeO2C
H CO2Me
N O
nitrone
MeO2C
CO2Me
D. A. Evans
Reaction Stereospecificity: Dipolariphile continued
Bn H N CO2Me Bn 100 N CO2Me RO O
Chem 206
Ratio 98:02
Me
heat in toluene
Me O Me N H Me H H H
70%
DeShong, JOC 1985, 50, 2309; Tet. Lett. 1986, 27, 3979
We will return to the other stereochemical element of this reaction shortly Reaction Regiochemistry (Padwa, Vol 1, pp 135)
HO Ph Ph N N N CO2Me N N N
MeI LiAlH4
p. .
LUMO
N Ph N N N C4H9 N N
Me CO2Me N H Me H O C4 H 9 H
Here is an elegant example of regiochemical control. While the authors offer no explanation for the outcome, it appears that the reaction is being governed by transition state steric strain factors. Oppolzer, JACS 1978, 98, 6722
Ph
HOMO
The specific set of reaction partners, will define the dominant frontier orbitals Steric Effects will frequently alter regioselectivity (Padwa, Vol 1, pp 144)
H C H Me Me C Me N N Me Me H CO2Me N N N H H Me Me N N N CO2Me Me Me CO2Me
Reaction Diastereoselectivity
H Ar N CO2Me H
CO2Me
100
MeO2C
CO2Me
MeO2C
CO2Me
MeO2C
CO2Me
100:0
conrotation
MeO2C Ar
Me
Ar N
100
MeO2C
N CO2Me
96:4
CO2Me CO2Me
MeO2C
CO2Me
D. A. Evans
Relative Orientation of Reaction Partners
Chem 206
DeShong, JOC 1985, 50, 2309; Tet. Lett. 1986, 27, 3979
H O
HH
MeO2C H R H O
The preceding trend appears to be reinforced by cis disubstitution I. Washita et al, Chem lett 1979, 1337
H H MeO2C H H O
Ratio 98:02
Bn N
Me O
p. .
The above analysis is clouded by the fact that the geometry of the 1, 3-dipole is not fixed.
MeO2C H H N Ph H H H CO2Me N Ph H
Orientation probably driven by ring strain as in Oppolzer case (previous page) Intramolecular Reaction Variants
"highly diastereoselective"
HNTMS2
O H O Bn N H
Ph 78%
Me
CO2Me
100% 82%
highly stereoselective
O CO2 Ar H R CH2 N Bn Ar H H H CH2 N Bn
H R R H N H O
22%
0%
18%
Ar
R N H Bn
Diastereoselection appears to be dictated by steric effects Tufariello, Accounts. Chem. Res. 1979, 12, 396-1403
D. A. Evans
Chem 206
Carruthers, W. Cycloaddition Reactions in Organic Synthesis.; Pergamon: Elmsford, NY, 1990.Chapter 6, pp2 69298 Me OH Me Et3N 0 C CO2Et Me CO2Et Me Me O O N
Isoxazoles
+
Me
Cl
Isoxazolines
+
Me Me
O N
Methods of Generation
N R OH NCS H R N
H O Et3N
Me
Method A
Oxazoline Cleavage
p. .
Cl Me O N Me H O Me Me Me H2 Raney Ni Me OH O Me Me OH O Me Me Me O R O R
Method B
R
Et3N PhN=C=O
NHPh
Stability
Nitrile oxides are usually prepared in the presence of the olefin or acetylene acceptor. These intermediates are generall unstable and will dimerize if not given an alternative reaction course
N R O N O R N O N O R
O N
H2 Raney Ni
Me
R R
C C
O R
H2 Raney Ni
Regioselectivity Nitrile oxide cycloadditions with olefins and acetylenes are usually quite regioselective and in the direction as illustrated above. DeShong, JOC 1985, 50, 2309; Tet. Lett. 1986, 27, 3979
Preferred method for reducing oxazoles and oxazolines: Nittta et al, Chem. Comm. 1982, 877-878: Mo(CO)6 MeCN
D. A. Evans
Miyakolide Synthesis:
Me Me
Chem 206
Me
O O Me
17 13 19
O O Me OH O O O
19 17
OH O
O 2N Me Me O O Me OR O Xp OH CO2Me O Me Me O Me
OMe
Me
OH
Me
OH
CO2Me
H O
OMe
Me
OPMB
CO2Me
Me
O
13
Me OH
11
OPMB
CO2Me
p. .
Me O
O M O H Me H
H 11
R OH
Me Me Me O O O Me OH O
R N
19 17
Me Me Me OR O 2N Me O Me OTES O
19
Transannular Aldol
O O O Me OMe
Me
3-ClPhNCO i-Pr2NEt 90 C 68 % Me Me
Me
OH
CO2Me Me OPMB O O Me Me N
19
Competing olefin chlorination eliminated this approach to the nitrile oxide precursor
Me Me HO N O OTES Me HO Me
Xp
OMe
O O Me
1
O
13
Me OTES
OMe
X
Cl
O OTES Me Xp
Me
OPMB
OMe
D. A. Evans
Chem 206
A
base
Ph
Et OH
Et3N
Me Ph Ph C N O N O R' Me Ph R' N O Me
67:33 95:5
60% 75%
Me
EtMgBr
O Me OBn
69:3174:26
conditions; no cat, ZnI2, Ti(OiPr)4
OH
N Me
O Me OH Ph
O Me OH
A
base
Ph
p. .
While lewis acid activation is known, no change in regiochemistry was noted under above connditions Magnesium alkoxides found to effect regiochemical control
N Ph R Me OH OH + Et3N OMgBr (2 equiv) O CH2OH Ph N O R CH2OH OH Me nBu
Et3N EtMgBr
N O
61:39 96:4
N nBu Ph
60% 75%
O Me nBu OH
Ph R OH
A
base
Me
Ph OH
46:54 >99:1
82% 66%
N Ph
Me
Cl
Me Pr
OMgBr (2 equiv)
>99:1
68%
Ph H H
X M
OMgBr (2 equiv) N Ph OH O
98:2
73%
H O R
syn product
Anti product
H O R H
A
OH base
Rate acceleratons
Me OH Me OH OH Me OH
OH
Et3N EtMgBr
6900
490
16,000
D. A. Evans
Chem 206
TBSO
O Me
Me
TBSO
O Me
S Me
82%
Me OH
87%
Me OH TBSO H N OH Me OH
Me
Me
OH TBSO
synsyn
N
antisyn
Me
Me TBSO N O Me Me Me OH
p. .
antianti
73%
Me Me
68%
synanti
Oxazoline Reduction
EtO TBSO N O Me Me Me OTES TBSO O OH Me EtO
O P Me
O P Me
O Me OH N Me S CHO
Raney Ni 90%
synanti
Me
Me
OTES
Lit Conditions: Curran, JACS 1983, 105, 5826; JOC 1984, 49, 3474 N TBSO N O Me Me Me OTES O
Raney Ni 94%
TBSO
OH Me
O Me Me
antisyn
Me S
Me
Me
OTES
D. A. Evans
The Basic Reactions
Chem 206
Padwa, A.; Hornbuckle, S. F. Chem. Rev. 1991, 91, 263-309. Reviews - Ylides Padwa, A.; Krumpe, K. E. Tetrahedron. 1992, 48, 5385-5483. Padwa, A. Acc. Chem. Res. 1991, 24, 22-28.
R1 A
O B
Rh2(OAc)4
F 3C F 3C
RCHO DMAD
R O R H
p. .
F 3C
CH3
O H
Arduengo, A. J., III; Janulis, E. P., Jr. J. Am. Chem. Soc. 1983, 105, 5929-5930
O N O
CH3
O 2N
O N N2
O Cu(acac)2 X
O 2N
CH3
PhH, 80 C
O N O
CH3
Intramolecular Variants
O
X = H, Br, OMe
O 2N C6H4NO2 CO2CH3 CH3 N Ph CO2CH3 CH3O2C CO2CH3 O X O CHN2 O H O
O O
Rh2(OAc)4
quantitative
Hamaguchi, M.; Ibata, T. Chem. Lett. 1975, 499-502.
D. A. Evans
Chem 206
Me
74%
H O Me Me N Bn N2 O O Me Rh2(OAc)4 PhCH3, 110 C Me Bn N O COMe O Me R O OH Br2, MeOH -45 C MeO O OMe OH R
O R
73%
O O Me O O N H H N O AcO O H DBN, CH2Cl2, RT O O
p. .
O N
O Me N2
75%
H O
"high yield"
O Me O N
AcO
pyrolysis
O N
52%
Sammes, P. G.; Street, L. J. J. Chem. Soc., Chem. Commun. 1982, 1056-1057 Hertzog, D. L.; Austin, D. J.; Nadler, W. R.; Padwa, A. Tetrahedron Lett. 1992, 33, 4731-4734.
D. A. Evans
Chem 206
O OH
H O A B A
OH O H B Me
Phorbol
O OH O O N
OAc O
O N
O H t-BuMe2Si O
p. .
Me
Me TBSO O O OTBS
55%
O OH O O Me N Me OAc
PhCH3, 200 C
Me H O
1) CH3CN,reflux, 60 h
O
O O
OTBS
2) acetylation
N
42%
O OH O
71%
Me O
1) heat
( )n Z Z Z O
OAc O ( )n Z O O H O Me
Me H O TBSO OTBS
2) acetylation
Z = CO2Me
OTBS
n = 1 : 70% n = 2 : 65%
Garst, M. E.; McBride, B. J.; Douglass, J. G. III. Tetrahedron Lett. 1983, 24, 1675-1678. Wender, P. A.; McDonald, F. E. J. Am. Chem. Soc. 1990, 112, 4956-4958
D. A. Evans
Chem 206
Problem 53. Williams recently reported an approach to the synthesis of quinocarcinamide (1) (J. Org. Chem. 1995, 60, 6791). The pivotal process that establishes the tetracyclic nucleus is the two-step transformation shown below (eq 1). CO2H CO2Me H Me Me Me N N N H N (1) N two steps N OMe
CH2OH O
OMe
CH2OH O
OMe
CH2OH O
Devise a strategy for transforming A into B and clearly illustrate your answer in the space below. Full credit will be awarded to concise answers. Problem 55. The following transformation was recently reported by Heathcock during studies directed toward the synthesis of sarain A (Tetrahedron Lett. 1995, 6, 2381). From your knowledge of the functionality present in the starting material, deduce the structure (including stereochemistry) of the reaction product which has the same molecular weight as the starting material. Hint. the 1H NMR spectrum of the product reveals that the olefinic resonances have disappeared. O
p. .
MeO
N Ts
N CO2Et
Ph
110 C 45-55%
product structure
Problem 65. The following stereoselective nitrile oxide cycloaddition has been reported by Kozikowski (Tetrahedron Lett. 1982, 23, 2081; J. Org. Chem. 1984, 49, 2762). Provide the stereostructure of the major product and rationalize the stereochemical outcome as indicated in the directions. Me O 2N Me
PhNCO, Et3N
Problem 87. The illustrated transformation has been utilized by Coldham (Chem. Commun. 1999, 1757) to construct the core ring system of the manzamines. N H S S BocN CHO CH2 O OEt
i
H S N N S Me N
N H
BocN
OH
NHMeHCl
D. A. Evans
Chem 206
Problem 90. Padwa and co-workers recently disclosed the illustrated multistep polycyclisation as a possible route to the strychnine core (Org. Lett. 2001, ASAP)
N2 O O O
Ph N
H Rh2(pfb)4 145 C O N O
Ph
In the space below, provide a mechanism for the indicated transformation. Hint: The management suggests that a carefull bidirectional analysis might help you to arrive at a sollution of this question. Problem 136. A recent paper by Harwood and Park highlights the rapidity which whch one may assemble complex architecture in a single chemical operation (Tetrahedron Lett. 1999, 40, 2907 and earlier cited references). The transformation in question is illustrated below. You are asked to address two aspects of this transformation. Ph H N O O H
benzene, heat
H Ph N H O O
p. .
Part A. Provide a concise mechanism for the indicated transformation. For now, ignore the stereochemical aspects of the reaction. Part B. Predict the stereochemical outcome of the reaction at the three new stereocenters, and provide a three-dimensional drawing of the transition state wherein these centers are produced.
Problem 171. A recent paper by Dolle (Tetrahedron Lett. 1999, 40, 2907) highlights the rapidity which whch one may assemmble complex architecture in a single chemical operation. The transformation in question is illustrated below. CO2Me O 1. BocNHNH2 CO2Me 2. EtOH, reflux N NBoc 75% yield, one diastereomer
Provide a concise mechanism for the indicated transformation. In that step where the complex stereochemical relationships are established, a carefully rendered three dimensional illustration is requested.
Problem 189. This question is taken from recent work reported by Jack Baldwin (Org. Lett., 1999, 1933 and 1937). Provide a mechanism for the conversion of I to II. O O O N2 O Rh2(OAc)4; H3O+ quench O O
I
O
OH
II
D. A. Evans
Chem 206
http://www.courses.fas.harvard.edu/~chem206/
http://www.chem.wisc.edu/areas/reich/pkatable/index.htm
Reading Assignment for this Lecture: Carey & Sundberg: Part A; Chapter 7 Carbanions & Other Nucleophilic Carbon Species
"Equilibrium acidities in DMSO Solution", F. G. Bordwell. Acc. Chem. Res. 1988, 21, 456-463. (handout) Wednesday, October 29, 2003
The thermodynamic acidities of phenol and nitromethane are both ~10; however, using a common base, phenol is deprotonated 10+6 times as fast. Rationalize
pKa(H2O) ~10 Base H rel rate: 10+6
D. A. Evans
19-00-Cover Page 10/27/03 11:36 AM
pKa(H2O) ~10
O H 3C N O
O H2 C N O
Acidity Concepts-1
Definition of Ka
Chem 206
Let HX be any Bronsted acid. In water ionization takes place: HX + HOH H3O+ + X
Nucleophile
where
Keq =
(A)
Since [HOH] is, for all practical purposes, a constant value, the acid dissociation constant Ka is defined wilthout regard to this entity. e.g. HX Hence Ka = H+ + X [H+] [X] [HX] where H+ = H3O+ (B)
pKa , describes quantitatively a molecule's propensity to act as an acid, i.e. to release a proton. - Medium effects - Structural effects (influence of substituents R1)
Acid Activation p. .
R1 X R2 X = e.g. O, NR ... R2 acid (protic or lewis acid) R1 X acid
From the above definitions, Ka is related to Keq by the relation: Ka(HX) = 55.5 Keq(HX) (C)
Since pKa is defined in the following equation: pKa = log10 [Ka] The pKa of HOH is + 15.7 Keep in mind that the strongest base that can exist in water is HO.
Ca 10+6 Activation
O O SiMe3
Lets now calculate the acid dissociation constant for hydronium ion.
H3O+ + H 2O H3O+ Keq = 1 + H 2O
obviously:
D. A. Evans
The Gibbs Relationship G = RT ln K or
Chem 206
HOH pKa 15.7 31 279 (est)** Medium HOH DMSO Vacuum
G = 2.3 RT log10 K G298 = 1.4 log10 Keq G298 = 1.4 pKeq 1.4 pKa
Keq 1 10
pKeq 0 -1 -2
MeOH
A HA G
C6H5OH O2NCH3
p. .
100
Medium Effects
O Ph C CH3
H A
In the ionization of an acid in solution, the acid donates a proton to the medium. The more basic the medium, the larger the dissociation equilibrium. The ability of the medium to stabilize the conjugate base also plays an important role in the promotion of ionization. Let us consider two solvents, HOH and DMSO and the performance of these solvents in the ionization process.
The change in pKa in going from water to DMSO is increasingly diminished as the conjugate base becomes resonance stabilized (Internal solvation!). Substrate DMSO 18.1 HOH 16.0 pKa 2.1
O
O H A H No H-bonding Capacity
O OEt
16.4 13.3 3.1
Water
H O H Me
EtO O Me NC O
DMSO
HO S Me
Me CN
13.3 11.1
8.9 11.2
4.5 0
As shown above, although HOH can stabilize anions via H-bonding, DMSO cannot. Hence, a given acid will show a greater propensity to dissociate in HOH. As illustrated below the acidity constants of water in HOH, DMSO and in a vacuum dramatically reflect this trend.
D. A. Evans
Chem 206
Electrons in 2S states "see" a greater effective nuclear charge than electrons in 2P states.
This becomes apparent when the radial probability functions for S and P-states are examined: The radial probability functions for the hydrogen atom S & P states are shown below.
H H C H C
O H O H
H C H C
O CH2H R
(H2O)
pKA = 4.8
pKA 19 pKA 26.5 - S-character of carbon hybridization sp3-orbitals 25% s-character sp2-orbitals 33% s-character sp-orbitals 50% s-character
Radial Probability
Radial Probability
Carboxylate ion more stabile than enolate because R C O more O electronegative than C O
O C CH2
100 %
100 %
1 S Orbital
2 S Orbital
2 S Orbital 2 P Orbital
3 S Orbital
3 P Orbital
Carbon Acids
R R H R H H RR H R R RR
S-states have greater radial penetration due to the nodal properties of the wave function. Electrons in s states see a higher nuclear charge. The above observation correctly implies that the stability of nonbonding electron pairs is directly proportional to the % of S-character in the doubly occupied orbital. Carbanions
CSP3 Least stable CSP2 CSP Most stable CSP2 CSP Least stable
sp 180 23
sp2 120 44
sp2 120 39
sp3 109 60
Carbenium ions
The above trends indicate that the greater the % of S-character at a given atom, the greater the electronegativity of that atom.
D. A. Evans
Chem 206
Hybridization vs Electronegativity There is a linear relationship between %S character & Pauling electronegativity
5
Alkyl Substituents on Localized Carbanions are Destabilizilng: Steric hinderance of anion solvation
NSP
4.5
Compare:
pKA (DMSO) S S S S
Pauling Electronegativity
H H Me H
N
3.5
PhSO2-CHH H
C SP
SP2
29 31
31.1
NSP3
PhSO2-CHMe H
38.3
C
2.5
SP2
CSP3
p. .
2 20
% S-Character
30.7
27.9 19.4
Inductive Stabilization
CH (56)
55
4
50
45
C H (44)
6 6
Heteroatom-Substituents: - 2nd row elements of periodic table Strong carbanion stabilizing effect
pKA (DMSO) PhSO2-CH-H H PhSO2-CH-SPh H pKA (DMSO) PhSO2-CH-SO2Ph H PhSO2-CH-PPh2 H
40
35
PhCC-H (29)
30
29 20.5
12.2 20.5
25 20 25 30 35 40 45 50 55
% S-Character
D. A. Evans
Chem 206
O C N O O C C
H O CH3 H H H C C N
18.2 (DMSO)
Ph Ph P CH3 Ph
31
31
35
26.5
CH3
H H
22.5
C C N H
31.5
The accepted explanation for carbanion stabilization in 3rd row elements is delocalization into vicinal antibonding orbitals
For efficient conjugative stabilization, rehybridization of carbanion orbital from nsp3 to np is required for efficient overlap with low-lying *-orbital of stabilizing group. However, the cost of rehybridization must be considered.
p. .
Cn
SX*
X C S
SX* (empty) Stereoelectronic Requirement for Carbanion Overlap: Enolization of Carbonyl Compounds
Stereoelectronic Requirements: The -C-H bond must be able to overlap with CO
Cn (filled)
This argument suggests a specific orientation requirement. This has been noted:
Anti (or syn) periplanar orientation of Carbanion-orbital and * orbital mandatory for efficient orbital overlap. H H Me Me He S S Ha He R
CO
CH3 O
Ha
base
Hc R
Hb O
R Hc
O Hb
Ha+
S H
He : Ha = 30
Ha
47.7
H
D. A. Evans
Phenol Acidity:
FG OH
Chem 206
Is the benzene ring somehow special. i.e "larger resonance space." (1) Acetone enol:
acetone Me O Me Keq = 10
-8
G FG
This topic has a number of take-home lessons. Most importantly, is is a useful construct on which to discuss the role of FG's in influencing the acidity of this oxygen acid.
How does one analyze the impact of structure on pKa of a weak acid (pKa > 0) ? O The Approach:
For equilibria such as that presented above, analyze the effect of stabilizing (or destabilizing) interactions on the more energetic constituent which in this case is the conjugate base.
FG
The surprising facts is that the acetone enol has nearly the same pKa as phenol. Hence, the answer to the above question is no!
+ solvent(H+)
Energy
OH FG
This argument suggests that the acidity of acetone enol is largely due to inductive stabilization, not resonance.
H+ pKa (H2O) = 10
3.2
G
OH O
HOCl (7.5)
pKa (H2O) = 17
Electronegativity of X
2.8
Loudon (pg 730): "The enhanced acidity of phenol is due largely to stabilization of its conjugate base by resonance." O O O O
2.6
2.4
from previous discussion, G298 = 1.4 Log10 Keq = 1.4 pKeq G (stab) = 1.4(Pkaphenol pKacyclohenanol) = 1.4(-7) = 9.8 kcal/mol
19-06-Phenol acidity 10/27/03 12:58 PM
2.2
HOH (15.7)
2 6 8 10 12 14 16
pKa of XOH
D. A. Evans
Chem 206
Variables:
X = O (carboxylic acid) X = NH (amide) Energy X = CH2 (Ketone/ester) R = CR3 R = OR R = NR2 O R
O X
pKa = 4.8
+ solvent(H )
+
pKa ~ 19
Carboxylate ion
G
R XH O Me C CH2H O EtO C CH2H Me2N O C CH2H O
O C CH2H O C CH2H
The Question: How does one analyze the impact of structure on pKa ? The Approach: For equilibria such as that presented above, analyze the effect of stabilizing (or destabilizing) interactions on the more energetic constituent which in this case is the conjugate base. Case I: Carboxylic Acids: Inductive Effects
O H C C OH H H O C C OH Cl Cl Cl Cl Carboxylate ion O stabilized by increased C C electron-withdrawing O Cl CCl3 group.
pKa ~ 30
pKa ~ 34
In this series of compounds, there are two variables to consider: Inductive Effect: OEt > Me2N > H3C but (O?) Resonance Effect:
Cl
O C
pKa = 4.8
pKa = 0.6
The degree to which substituent X: CH2 CH2 "contributes" electron density into enolate represents a destabilizing interaction: Trend: O > Me2N > OEt
O C
Resonance donation dominates inductive electron withdrawal as indicated by the data. Substituents on the -carbon: Stabilization by either resonance, induction, or both is observed:
O Ph C CH2CH3 O Ph C CH2OCH3 O Ph C CH2Ph O Ph C CH2SPh
pKa = 4.9
pKa = 1.9
pKa = 24.4
19-07 Weak Acids/Gen anal 10/24/01 8:16 AM
pKa = 22.9
pKa = 17.7
pKa = 17.1
D. A. Evans
Chem 206
Let us now focus on the oxygen lone pair in the hybrid orbital lying in the sigma framework of the C=O plane. * CO
O R R O
(Z) Conformer
(E) Conformer
G = +2 kcal/mol
C R
In the (Z) conformation this lone pair is aligned to overlap with * CO.
The (E) conformation of both acids and esters is less stable by 2-3 kcal/mol. If this equilibrium were governed only by steric effects one would predict that the (E) conformation of formic acid would be more stable (H smaller than =O). Since this is not the case, there are electronic effects which must also be considered. These effects will be introduced shortly. Rotational Barriers: There is hindered rotation about the =COR bond. These resonance structures suggest hindered rotation about =COR bond. This is indeed observed:
O R O R' R O + O R'
Energy
(E) Conformer
R R O C O
In the (E) conformation this lone pair is aligned to overlap with * CR.
* CR
O
R O C
barrier ~ 10 kcal/mol
O R O R O R
G ~ 2-3 kcal/mol
Since * CO is a better acceptor than * CR (where R is a carbon substituent) it follows that the (Z) conformation is stabilized by this interaction.
O R
O R R O
Rotational barriers are ~ 10 kcal/mol This is a measure of the strength of the pi bond.
Lone Pair Conjugation: The oxygen lone pairs conjugate with the C=O.
pKa ~ 30
pKa = 25.2
pKa = 15.9
R
O
pKa = 7.3
C R
The filled oxygen p-orbital interacts with pi (and pi*) C=O to form a 3-centered 4-electron bonding system.
O Me N H O Et HN O O
SP2 Hybridization
O O R
Me
+
O O
Oxygen Hybridization: Note that the alkyl oxygen is Sp2. Rehybridization is driven by system to optimize pi-bonding.
pKa = 24.5
pKa = 20.6
E(rel) = 0
D. A. Evans
Chem 206
Kinetic Acidity: Rates of proton removal Consider enolization of the illustrated ketone under non-equilibrating conditions:
OLi HA O OLi Me
Kinetic & Equilibrium Ratios of Enolates Resulting from Enolization with LDA & Subsequent Equilibration
HB
Me
HB
LiNR2
HA
Me
HB
LiNR2
O
(99) (1) Me (10)
O
(90) Me (98)
O
(2) (34)
O
(66)
kB B
HB
kA K A
HB
Kinetic Ratios
B GB
Energy
Equilibrium Ratios
Kinetic Ratios
Equilibrium Ratios
GA
O
(13) H
O
(53)
(47) H
O C3H7
(16)
K B
LiNR2
(87)
p. .
(84)
(87)
(13)
Kinetic Ratios A
Reaction Coordinate Kinetic acidity refers to the rate of proton removal. e.g. kA vs kB. For example, in reading the above energy diagram you would say that HA has a lower kinetic acidity than HB. As such, the structure of the base (hindered vs unhindered) employed plays a role in determining the magnitude of kA and kB. For the case shown above, GA will increase more than GB as the base becomes more hindered since the proton HA resides in a more sterically hindered environment. The example shown below shows the high level of selectivity which may be achieved with the sterically hindered base lithium diisopropylamide (LDA). Me Me N Li Me Me H O OLi H THF 78 C H OLi Me
Equilibrium Ratios
O
Kinetic Ratios
Equilibrium Ratios
O Ph
(14)
(86)
CH3
Ph
(99)
(1)
CH3
Kinetic Ratios
Equilibrium Ratios
Note that alkyl substitution stabilizes the enolate (Why??). This effect
Me
Me H
Hence, enolization under "kinetic control with LDA allows you to produce the less-substituted enolate while subsequent equilibration by simply heating the enolate mixture allows equilibration to the more substituted enolate.
LDA
Evans, Annis
Kinetic Acidity
Chem 206
Kinetic Acidity vs. Leaving Group Ability: E1cb Elimination Reactions Stirling, Chem. Commun. 1975, 940
O Ph S O O base O Ph S O O Ph S O O rds O Ph S O O
Observation: The thermodynamic acidities of phenol and nitromethane are both approximately 10; however, using a common base, phenol is deprotonated 10+6 times as fast. pKa(H2O) ~10
O H
pKa(H2O) ~10
H3C N
O H2 C N O
OPh
Ph S O
+ PPh3
Ph S O
CN
krel = 1 pKa HX 10
krel = 10+4 0
Proton transfers from C-H Bonds are slow. Why??? p. . Most carbon acids are stabilized by resonance. Hence significant structural reorganization must accompany deprotonation.
The greater the structural reorganization of the leaving group during E1cb elimination, the slower the rate of elimination.
O H
Base
Kinetic product
OH
H H N H
O O
Base
H N H
O O
Kinetic product
electron density now resides here, and nuclei have moved to accomodate rehybridization.
Jack Hine: Least Motion Principle (Adv. Phys. Org. Chem. 1977, 15, 1) Lowry & Richardson, 3rd Edition, pp 205-206 Those elementary reactions that involve the least change in atomic posiitons will be favored
The greater the structural reorganization during deprotonation, the lower the kinetic acidity
D. A. Evans
Chem 206
http://www.courses.fas.harvard.edu/~chem206/
Woerpel etal. JACS 1999, 121, 12208 (Handout) Woerpel etal. JACS 2000, 122, 168 (Handout) Woerpel etal. JACS 2003, 125, ASAP (Handout) "From Crystal Statics to Chemical Dynamics", Accounts Chem. Research 1983, 16, 153. (Electronic Handout) "Theoretical Interpretation of 1,2-Asymmetric Induction. The Importance of Antiperiplanarity", N. T. Anh, O. Eisenstein Nouv. J. Chem. 1977, 1, 61-70. (Handout) "Around and Beyond Cram's Rule" A. Mengel & O. Reiser, Chem Rev. 1999, 99, 1191-1223 (Electronic Handout)
Relevant Dunitz Articles Reactivity Trends C=X Stereoelectronic Effects Carbonyl Addition: Theoretical Models The Felkin-Anh-Eisenstein Model for C=O Addition Diastereoselective Ketone Reduction "Geometrical Reaction Coordinates. II. Nucleophilic Addition to a Carbonyl Group", JACS 1973, 95, 5065. "Stereochemistry of Reaction Paths at Carbonyl Centers", Tetrahedron 1974, 30, 1563 "From Crystal Statics to Chemical Dynamics", Accounts Chem. Research 1983, 16, 153. (Electronic Handout) "Stereochemistry of Reaction Paths as Determined from Crystal Structure Data. A Relationship Between Structure and Energy.", Burgi, H.-B. Angew. Chem., Int. Ed. Engl. 1975, 14, 460.
Reading Assignment for this Week: Carey & Sundberg: Part A; Chapter 8 Reactions of Carbonyl Compounds Carey & Sundberg: Part B; Chapter 2 Reactions of Carbon Nucleophiles with Carbonyl Compounds Carey & Sundberg: Part B; Chapter 5 Reduction of Carbonyl & Other Functional Groups
Friday, October 31, 2003
D. A. Evans
20-00-Cover Page 10/30/03 11:44 AM
D. A. Evans
The Set of Functional Groups:
R C O R Aldehyde Ketone R C O R
Chem 206
R R R Aldimine Iminium ion Ketimine (Imine) These functional groups are among the most versatile sources of electrophilic carbon in both synthesis and biosynthesis. The ensuing discussion is aimed at providing a more advanced discussion of this topic.
R Oxocarbenium ion
R C R
LUMO
R
C=X Polarization
R C O R C O
Dunitz-Burgi trajectory HOMO (Nu) CO Nu NuC ~107 The forming bond
R
p. .
Partial Charge: As the familiar polar resonance structure above indicates, the carbonyl carbon supports a partial positive charge due to the polarization of the sigma and pi system by the more electronegative heteroatom. The partial charges for this family of functional groups derived from molecular orbital calclulations (ab initio, 3-21(G)*, HF) are illustrated below: R R R R R R R C R + 0.33 N R + 0.51 C O R + 0.54 C N R C O R + 0.61 (R = H) + 0.63 (R = Me)
R R
HA
R C O
A
R
C R
The electrophilic potential of the C=O FG may be greatly increased by either Lewis acid coordination of by protonation. The magnitide of this increase in reactivity is ~ 10+6. Among the weakest Bronsted acids that may be used for C=O actilvation (ketalization) is pyridinium ion (pKa = 5). Hence, the Keq below, while quite low, is still functional. R R H
+
N H R
O R
O N
Keq ~ 10-11
The LUMO coefficient on carbon for B will be considerably larger than for A. Does this mean that there is a lower constraint on the approach angle for the attacking nucleophile? There is no experimental proof for this question; however, it is worthy of consideration What was the basis for the Dunitz-Burgi analysis?
pka = +5
pka = 6
D. A. Evans
Relevant Dunitz Articles
Chem 206
"Geometrical Reaction Coordinates. II. Nucleophilic Addition to a Carbonyl Group", JACS 1973, 95, 5065. "Stereochemistry of Reaction Paths at Carbonyl Centers", Tetrahedron 1974, 30, 1563 "From Crystal Statics to Chemical Dynamics", Accounts Chem. Research 1983, 16, 153. "Stereochemistry of Reaction Paths as Determined from Crystal Structure Data. A Relationship Between Structure and Energy.", Burgi, H.-B. Angew. Chem., Int. Ed. Engl. 1975, 14, 460. Dunitz Method of Analysis A series of organic structures containing both C=O and Nu FG's disposed in a geometry for mutual interaction were designed. These structures positioned the interacting FGs an increasingly closer distances. The X-ray structures of these structures were determined to ascertain the direction of C=O distortion. The two families of structures that were evaluated are shown below.
1,8-Disubstituted Naphthalenes. Substituents located at these positions are strongly interacting as illustrated by the MM2 minimized di-methyl-naphthalene structure shown below. In this structure (A), at 2.56 the C=O is starting to pyramidalize Cyclic aminoketones. Medium-ring ketones of various ring sizes were analyzed for the interaction of amine an C=O FGs. One example is shown below. 2.56
p. .
Nu
O 2.29
Me N
Me
Me
Me2N
Me
MeO
Me
Analysis of distortion of C=O in this and related structures formed the basis of the 107 attack angle. This value should be taken as approximate.
A (shown)
D. A. Evans
Chem 206
Cyclic aminoketones. Medium-ring ketones of various ring sizes were analyzed for the interaction of amine an C=O FGs. Two examples are shown below.
Sekirkine Birnbaum JACS 1974, 96 6165
Should these crystallographic date be relevant to the addition to complexed C=O & Iminium Ions?
R C R N R R R C O R R C N R R R R C O R
+ 0.33
2.46
+ 0.51
+ 0.54
(antibonding)
C
p. .
Energy
R R
C O (bonding) C O
(antibonding)
C R
2.69
Energy
C O (bonding) C O
Nu
DB angel ~107
DB angel >107 ??
Nu R R C O
R R
20-03-Dunitz-Burgi-2 10/29/03 4:39 PM
D. A. Evans
Pivotal Articles
Chem 206
R. V. Stevens in "Strategies and Tactics in Organic Synthesis", Vol. 1. On the Stereochemistry of Nucleophilic Additions to Tetrahydropyridinium Salts: a Powerful Heuristic Principle for the Stereorationale Design of Alkaloid Synthesis.; Lindberg, T., Ed.; Academic Press, 1984; Eliel etal. , JACS 1969, 91, 536 Kishi etal. , JACS 1982, 104, 4976-8
H H O O H Me Me
H O O
Ph H
PhMgBr
Me Me
dioxolenium ion
Eliel was the first to attibute stereoelectronic factors to the addition of nucleophiles to cyclic oxo-carbenium ions.
p. .
Nu
stereoselection 10:1 (55%) Chair-aixal attack on oxo-carbenium ion occurs for both carbon and hydride nucleophiles
H H R R N Nu R
NaCNBH3
N Me C 4H 9 Me N C 4H 9 only one stereoisomer
It was proposed that chair-axial addition would be preferred as a consequence of the intervention of a transition state anomeric effect (Path A). Attack through Path B would necessitate the generation of the twist-boat kinetic product conformation thus destabilizing attack from the equatorial diastereoface. While Stevens espoused this concept for iminium ions in the late 70's, his untimely death at the age of 42 significantly delayed his cited publication.
n-PrMgBr
N C 4H9 N n-Pr C 4H 9
D. A. Evans
Chem 206
Allyl O H trans:cis 99:1 (69%) BnO H Allyl
Me
Me SiMe3
BnO H H C O SiMe3
BnO
BnO
stereoselection >95:5
These cases provide dramatic evidence for the importance of electrostatic effects in controlling face selecticity. OBn
BnO H
p. .
H cis:trans 83:17(84%)
These cases provide dramatic evidence for the importance of electrostatic effects in controlling face selecticity.
Are the preceding addition reactions somehow related to the apparently contrasteric reactions shown below??
O R3SiO EtO OSiR3 HgI2 EtO2C >94 : 6 O OSiR3 JOC 1991, 56, 387 OSiR3
This analysis presumes that only pseudo-chair transition states need be considered.
OSiR3 H H N
Woerpel's model states that axial attack from the most stable chair conformer predicts the major product.
N exclusive adduct
D. A. Evans
Chem 206
Phorboxazole B
Evans, Fitch, Smith, Cee, JACS 2000, 122, 10033 HO O N Br B HSi Me
H
20 13
RO2C O A H H H MeO O
4
H OTPS Me H 91%
H H H
C
9
N CH2 Me O
Me
O
Me
H O
HO
OH
N O
Me
H OTPS Me
p. .
MeO
N Me O
Me
A O OH H R
9
13
R H H
O R Et3SiH H 9 O BnOCH2 O Me O
OTMS Me H H O O
CH2
TMSOTf
TIPSO
13
O BnOCH2
>95:5 Diastereoselection
R H H
O H H O R
9
O Me
H
C
9
O O
89%
CH2
Diastereoselection 89:11
H O BnOCH2
D. A. Evans
Chem 206
O ZnR C R
4- vs 6-Membered Transition Structures for C=O Addition Consider carbonyl hydration: H2C=O
H O H C H H O H + HOH H O H H C O O H H
R Zn R
slow
R' H
n HOH
H2C(OH)2
(n-1) HOH
T1
T2
H R
+42.2
L Me R C R B O L R R
Me C OBL2
H2C=O + 2 HOH
6Centered
CH CH2 L
R2C=O
L L R R C OBL2
H H C O H H O H H H C O H L H O fast H O
B L
H 2C R R C O
favored 6Centered
R B L H R R
R2C=O
R C H R R C O CH2 B
L L R R
R H H 2C C R OBL2
Transiton structure T2 ~40 kcal/mol more stable than transition structure T1.
favored
D. A. Evans
Chem 206
R Mg R S Br
4Centered disfavored
L
R C R
Solution structure of RMgBr is in dynamic eqkuilibrium through Schlenck equilib The Bimetallic (Binuclear) Mechanism for C=O Addition
OAlL2 Recent theoretical study: Yamazaki & Yambe, J. Org. Chem. 2002, 67, 9346 Me Mg R C O R
+ Br Br
n
L
R Al Me R C O
Me Me
S fast R C Me R
Me Mg Br Br O S Mg
S slow R R Me C
S Mg Br O Mg
Br
6Centered favored
Mg S
Me
Me L Bicyclic TS Br Mg O Br R L Mg Me
S Me R Me
Me 6-Centered Boat
Yamazaki TS
R R2 fast R C O Mg S Br R2
+ solvent (S)
Grignard Reagents:
R
C O
+ R2 Mg
Br
R R
O MgBr C R2
Mg Br
R C O slow Br R C O S Br Mg R2
R R O MgBr C R2
The molecularity and transition structure for this reaction have not been carefully elucidated. The fact that the Grignard reagent is not a single species in solution greatly complicates the kinetic analysis.
R S
R2 Mg
D. A. Evans
Chem 206
Mengel, A. and O. Reiser, Around and Beyond Cram's Rule. Chem. Rev. 1999, 1191-1223
Fischer
Cram
Cornforth
Felkin
Anh/Eisenstein
Cieplak
Tomoda
D. A. Evans
Dauben, JACS 1956, 78, 2579 O Me3C H
0 10 20 30 40
Chem 206
Torsional strain considerations are dominant. Staggered TS conformations preferred The principal steric interactions are between Nu & R.
RL R C O predicted to be favored TS RM O H RL C R RM
destabilizing interaction
Nu:
Nu:
RL
RL H H C O RM
destabilizing interaction
Observation: Increasingly bulky hydride reagents prefer to attack from the equatorial C=O face. Assumption: Hindered reagents react through more highly developed transition states than unhindered reagents
O H
H RM
Nu:
Nu:
RM disfavored
Nu
~107
RL R
R
RL R C RM H OR M R H RL C O RM
C R
HOMO
Nu: CO
Nu:
H
C O
Nu:
Karabatsos JACS 1967, 89, 1367
Nu:
Felkin TL. 1968, 2199-2208
attack angle greater than 90 ; estimates place it in the 100110 range Burgi, Dunitz, Acc. Chem. Res. 1983, 16, 153-161
D. A. Evans
Chem 206
Houk:
H RM
predicted to be favored TS wrong prediction
"The tendency for the staggering of partially formed vicinal bonds is greater than for fully formed bonds" Lecture7
Nu:
Nu:
Anh & Eisenstein Noveau J. Chim. 1977, 1, 61-70 Anh Topics in Current Chemistry. 1980, No 88, 146-162 RL
RL H OH C H Nu RM
Nu: Felkin
H RL RM RL
H H
O RM
One explanation for the rotational barrier in ethane is that better overlap is achieved in the staggered conformation than in the eclipsed conformation.
Nu:
O
favored H
C
CH HOMO CH * CH LUMO
RL HO C H Nu RM H
C H
Nu: anti-Felkin
C
CH
O H
H RM
Y
C
Dunitz-Brgi C=ONu orientation applied to Felkin model. The antiperiplanar effect: Hyperconjugative interactions between C-RL which will lower *C=O will stablize the transition state. Theoretical Support for Staggered Transition states (Lecture 7)
(Read this) Houk, JACS 1982, 104, 7162-6 (Read this) Houk, Science 1986, 231, 1108-17
X
C
CH * CH LUMO
CH
Following this argument one might conclude that: The staggered conformer has a better orbital match between bonding and antibonding states. The staggered conformer can form more delocalized molecular orbitals.
D. A. Evans
Chem 206
The tendency for the staggering of partially formed vicinal bonds is greater than for fully formed bonds Ground State
C
The following trends are made on the basis of comparing the bonding and antibonding states for the molecule CH3-X where X = C, N, O, F, and H. -anti-bonding States: (CX)
CH3 H * CRL LUMO CH3 CH3 CH3 NH2 CH3 OH
RL C Nu C
RL C
Transition State
X
C CNu HOMO C
* CRL LUMO
Nu C CNu HOMO
X
C
Nu
Nu
CRL
Under debate
RL
The following are trends for the energy levels of nonbonding states of several common molecules. The trend was established by photoelectron spectroscopy. Nonbonding States
Nu
C Theoretical support:
Padden-Row, Chem. Commun. 1990, 456; ibid 1991, 327 Houk, J. Am. Chem. Soc. 1991, 113, 5018 Frenking & Reetz, Tetrahedron 1991, 47, 8091
RL
D. A. Evans
Addition of Enolate & Enol Nucleophiles
RL
Chem 206
H OH RL RM Nu H H
Cram
Nu O Me Me H H H
Reagent Ratio 1:1 5:1 + Anti-Felkin Isomer
Nu: Felkin
O RL RM H H C O RM
Me Me H
OH
Nu:
H RL
(Felkin) favored
ClMg C CEt Li Me Me
OH RL RM Nu
Nu: anti-Felkin
O H
H RM
H O Me
Nu: Trend-1:
disfavored
RTi (OiProp)3
OH R Me
R-Titanium R = Me R = n-Bu Ratio >90 : 10 >90 : 10 + Anti-Felkin Isomer
For Li enolates, increased steric hindrance at enolate carbon results in enhanced selectivity OLi H R O Me Me
Enolate (R) R = Me R = OtBu Ratio 3:1 4:1
M. Reetz & Co-workers, Angew Chemie Int. Ed.. 1982, 21, 135.
OH
O R
+ Anti-Felkin Isomer
Trend-2:
OH R1 Me
Ratio
O
+ Anti-Felkin Isomer
OLi Me H R Me
L. Flippin & Co-workers, Tetrahedron Lett.. 1985, 26, 973.
R1
R2
OMe R
Me O
OH
O OMe
+ Anti-Felkin Isomer
MeMe Me
Ketone (R) R = Ph R = c-C6H11 Ratio >200 : 1 9:1
10 : 1 24 : 1 15 : 1 36 : 1 16 : 1
4:1
D. A. Evans
Chem 206
O Me OH
Me H [H]
HO Me H
Me H
+ Anti-Felkin Isomer
Hydride Felkin
O RL RM R H C O RM
RL RM
H H
H
Cram Reagent Ratio TS
Nu:
R RL
(Felkin) favored
OH RL RM R
Hydride anti-Felkin
O H
R RM
54 : 1 5:1 3:1 1 : 10
Nu:
R H2 C Me O (CH2)2Ph
MH 78 C
disfavored
R H2C Me
OH
+ Anti-Felkin Isomer
(CH2)2Ph
R2BH
Reagent
+
OH RL RM R
R H
C H
O RM B R R RL
Ketone (R) G. Tsuchihashi & Co-workers, Tetrahedron Lett. 1984, 25, 2479.
Ratio
Felkin
O RL RM R
R=H R=H R = Me R = Me
96 : 4 47 : 53 >99 : 1 88 : 12 OH Me
(Felkin) disavored
OH RL RM R
O
MH
R2BH anti-Felkin
Me Me
M. M. Midland & Co-workers, J. Am. Chem. Soc. 1983, 105, 3725.
Me Me
Reagent Ratio
Me
TS
O H R B R
C H
R RM
favored
Li+HB(sec-Bu)3 HB(Sia)2
22 : 1 1:4
Felkin Anti-Felkin
Nonspherical nucleophiles are unreliable in the Felkin Analysis Exercise: Draw the analogous bis(R2BH)2 transition structures
D. A. Evans
Chem 206
Ph
H H Nu C O RM H H Nu
Cyclohexyl
C O RM
B
(Felkin-Anh Prediction)
C C
Cyclohexyl
Felkin-Anh analysis predicts the wrong product!
Ph
C
Cyclohexyl
C Case I:
O
Ph
O HO Me-Li Me Me OH NaBH4 CO2Me CO2Me CO2Me CO2Me HO NaBH4 H CO2Me CO2Me OH HO H H OH
CO2Me CO2Me M Nu
CO2Me CO2Me
CO2Me CO2Me
70: 30
H
Electronegative -CO2Me substituent will stabilize both CC bonding & antibonding states CO2Me CO2Me
Et Et Et
Et
Et
NaBH4 MeLi
39: 61 34: 66
Et
G. Mehta, Chem. Commun. 1992, 1711-2: "These results can be reconciled in terms of the Cieplak model."
D. A. Evans
The Felkin-Anh Eisenstein Model: A Breakdown Cieplak Model for C=O Addition
Chem 206
Case II: The Le Noble Examples Le Noble, JACS 1992, 114, 1916
O NaBH4 Me N i-PrOH, 25 C Me N Me N
Felkin-Anh Prediction
OH
HO
Point A: TS is stabilized by antiperiplanar allylic bond, but.... Point B: Nature of the stabilizing secondary orbital interactions differ: C
X R H Nu C O R
Ratio, 95:5
OH
X
C
Nu
C
+ Syn Isomer R (R) R=F R = CO2Me Anti:Syn Ratio 62:38 61:39 45:55 43:57
X
C
Nu
Cieplak
Felkin Anh C C
Nu
C
R = SiMe3 R = OH
Point C: CX Electron donating ability follows the order: CH > CC > CN > CO
H
(Houk disputes the ordering of CH, CC)
NaBH4 MeOH, 0 C
+ Syn Isomer OH (R) R = NO2 Anti:Syn Ratio 79:21 63:37 43:57 36:64
Point D:
"Structures are stabilized by stabilizing their highest energy filled states. This is one of the fundamendal assumptions in frontier molecular orbital theory." The Cieplak hypothesis is nonsense." "Just because a hypothesis correlates a set of observations doesn't make that hypothesis correct." The management
R = Cl R = OMe R = NH2
"Every generation of scientists starts where the previous generation left off, and the most advanced discoveries of one age constitute elementary axioms of the next." Aldous Huxley
It is a capital mistake to theorise before one has data. Insensibly one begins to twist facts to suit theories, instead of theories to suit facts. (Sherlock Holmes, A Scandal in Bohemia)
D. A. Evans
Chem 206
http://www.courses.fas.harvard.edu/~chem206/
1. "Theoretical Interpretation of 1,2-Asymmetric Induction. The Importance of Antiperiplanarity", N. T. Anh, O. Eisenstein Nouv. J. Chem. 1977, 1, 61-70. (pdf) 2. Structural, mechanistic, and theoretical aspects of chelation controlled carbonyl addition reactions.Reetz, Acc. Chem. Res. 1993 26: 462. (pdf) 3. "A Stereochemical Model for Merged 1,2- and 1,3-Asymmetric Induction in Diastereoselective Mukaiyama Aldol Addition Reactions and Related Processes." Evans, et. al. JACS 1996, 118, 4322-4343. (pdf) 4. The Exceptional Chelating Ability of Dimethylaluminum Chloride and Methylaluminum Dichloride. The Merged Stereochemical Impact of - and Stereocenters in Chelate-Controlled Carbonyl Addition Reactions with Enolsilane and Hydride Nucleophiles. Evans, Allison,Yang, Masse, 2001, 123, 10840-10852. (pdf)
R
Me Al N O O
1+ Me2 AlCl2
O R
(1)
s s s s
Breakdown in the Felkin-Anh Model Cyclohexanone Revisited Diastereoselective Additions to Cyclic Ketones Chelate Controlled Carbonyl Additions
Bn
s Reading Assignment for this Week: Carey & Sundberg: Part A; Chapter 8 Reactions of Carbonyl Compounds Carey & Sundberg: Part B; Chapter 2 Reactions of Carbon Nucleophiles with Carbonyl Compounds Carey & Sundberg: Part B; Chapter 5 Reduction of Carbonyl & Other Functional Groups
Monday, November 3, 2003
"Asymmetric Diels-Alder Cycloaddition Reactions with Chiral ,-Unsaturated-N Acyloxazolidinones". Evans, D. A.; Chapman, K. T.; Bisaha, J. J. Am. Chem. Soc. 1988, 110, 1238-1256.
Syn Diastereomer:
O H OP R R A O H R B OP R O H R Me2AlCl H R M O M
&
O P
Centers Reinforcing
Nu
OH Nu R
OP
(2)
Me2AlCl
P
Nu
OH Nu R
OP
(3)
D. A. Evans
21-00-Cover Page 11/3/03 9:33 AM
Anti Diastereomer:
&
Centers Opposing
D. A. Evans
Chem 206
Ph
H H Nu C O RM H H Nu
Cyclohexyl
C O RM
B
(Felkin-Anh Prediction)
C C
Cyclohexyl
Felkin-Anh analysis predicts the wrong product!
Ph
C
Cyclohexyl
C Case I:
O
Ph
O HO Me-Li Me Me OH NaBH4 CO2Me CO2Me CO2Me CO2Me HO NaBH4 H CO2Me CO2Me OH HO H H OH
CO2Me CO2Me M Nu
CO2Me CO2Me
CO2Me CO2Me
70: 30
H
Electronegative -CO2Me substituent will stabilize both CC bonding & antibonding states CO2Me CO2Me
Et Et Et
Et
Et
NaBH4 MeLi
39: 61 34: 66
Et
G. Mehta, Chem. Commun. 1992, 1711-2: "These results can be reconciled in terms of the Cieplak model."
D. A. Evans
The Felkin-Anh Eisenstein Model: A Breakdown Cieplak Model for C=O Addition
Chem 206
Case II: The Le Noble Examples Le Noble, JACS 1992, 114, 1916
O NaBH4 Me N i-PrOH, 25 C Me N Me N
Felkin-Anh Prediction
OH
HO
Point A: TS is stabilized by antiperiplanar allylic bond, but.... Point B: Nature of the stabilizing secondary orbital interactions differ: C
X R H Nu C O R
Ratio, 95:5
OH
X
C
Nu
C
+ Syn Isomer R (R) R=F R = CO2Me Anti:Syn Ratio 62:38 61:39 45:55 43:57
X
C
Nu
Cieplak
Felkin Anh C C
Nu
C
R = SiMe3 R = OH
Point C: CX Electron donating ability follows the order: CH > CC > CN > CO
H
(Houk disputes the ordering of CH, CC)
NaBH4 MeOH, 0 C
+ Syn Isomer OH (R) R = NO2 Anti:Syn Ratio 79:21 63:37 43:57 36:64
Point D:
"Structures are stabilized by stabilizing their highest energy filled states. This one of the fundamendal assumptions in frontier molecular orbital theory." The Cieplak hypothesis is nonsense." "Just because a hypothesis correlates a set of observations doesn't make that hypothesis correct." The management It is a capital mistake to theorise before one has data. Insensibly one begins to twist facts to suit theories, instead of theories to suit facts. (Sherlock Holmes, A Scandal in Bohemia)
R = Cl R = OMe R = NH2
D. A. Evans
Observation
H O MeMetal H H
Chem 206
6% 21% 42%
Felkin-Anh predicts opposite trend. Cieplak argument consistent with results. The Frenking Position: Cieplak stabilizing interaction is "dubious." Why not stabilize the forming sigma bond? Enhanced rate of axial Nu attack on cyclohexanone is caused by better electrostatic interactions of the ketone with the attacking reagent and not by torsional considerations. Nonequivalence of the *C=O LUMO with a greater extension on the axial face dictates stereoselection (Klein, 1973).
"If nucleophilic addition occurs anti to the better donor bond (Cieplak), the equatorial isomers should have considerably more axial attack than the parent while the axial isomers should have only a slight increase in axial attack." OH H O NaBH4 H OH MeOH, 25 C H H H R R R
(R) Substituent
"Exactly the opposite is observed."
R = OAc R = Cl
"Favored"
Nu
M O
Nu
H +
R
Frenking & Reetz, Angew. Chem. Int. Ed. 1991, 30, 1146
D. A. Evans
Chem 206
OH R X Nu
O R
Ratio 9 : 1
Nu Nucleophile
X O H C H R
favored
OH R X Nu
Ratio > 200 : 1 The molecular volume occupied by cyclohexyl acknowledged to be larger than that for phenyl. Because of shape phenyl "can get out of the way."
Nu
disfavored
OH R X Nu
Cyclohexyl
O RM R X
O H
O R
Nu Nucleophile
R O X C H H
favored
C C
Ph
Cyclohexyl
OH R X Nu
C C
Ph
Cyclohexyl
Nu
disfavored
D. A. Evans
Chem 206
OH C6H11 H C 5 3 OR
Chelate
Chelate organization also provides a powerful control element in carbonyl addition reactions
R R R R R O O M
NuM
OH H5C3
C6H11 OR
Felkin: RL=OR
R R R R O M
Nu O M
H
+
R R R R O
Nu OH
(OR) O Nu R
H+
Acid
Solv.
O R
NuM
OH Nu R
Reviews
Reetz, Accts. Chem. Res. 1993, 26, 462-468 (pdf) Reetz, Angew. Chem. Int. Ed. 1984, 23, 556-569
MgBr2 R = CH2OBn THF (0) MgBr2 CH2Cl2 (-20) R = CH2OBn TiCl4 CH2Cl2 (-78) R = CH2OBn R = SiMe2(t)Bu BF3-Et2O CH2Cl2 (-78)
Me
Me TBSO OH RL OR
Felkin: RL=OR
MgBr O OCH2OBn
Chelate Model
Me TBSO OH OCH2OBn
Me
path A
O R OR H
H H
O R
Nu Me TBSO
Me-MgBr
diastereoselection 50 : 1
Nu:
R
Me TBSO OH OCH2OBn
Me
O OCH2OBn
Chelate Model
path B
OH H H R OR Nu
O RO
diastereoselection >100 : 1
Chelation model
R
Nu:
MgBr
OH R OR
Chelate
H O H
path C
Me Et OBn
Me
THF
M O O R
H H
Nu
Me
H OH
Me Et OBn
Nu:
D. A. Evans
Chem 206
OH Me R
OH
diastereoselection 95 : 5 (Chelation)
OH OTBS
Chelation
O OTBS TiCl4
Ratio 30 : 70 2 : 98 95 : 5
R = CH2OBn R = CH2OBn
R = SiPh2(t)Bu THF
Degree of chelate organization may be regulated by choice of solvent and protecting group. Note that SiPh2(t)Bu group prevents chelation.
2 Me2AlCl
Me O Al
Me TBS O
diastereoselection 93 : 7 (Felkin)
1+ O Me3C OH OBn
Case Study
Nu:
Nu:
H Me Me2AlCl2
Me
Felkin Control O H OP
(M)
Me MO
OH Nu Me
OP
diastereoselection 97 : 3 (Chelation)
H H
Me2AlCl & MeAlCl2 only Lewis acids that will chelate strongly to OSiR3 Groups. Evans, Allison, Yang,Masse, JACS 2001, 123, 1084010852 O H OP
t
D
Lewis acid (M) P O M
CH2OP
1,2-Syn (Felkin)
OTMS Bu
Lewis Acid
t
O Bu
OH
OP
t
OH
OP
Bu Me Felkin 10 12
2 P = TBS 11 : 12 (%) 09 : 91 07 : 93 07 : 93 97 : 03 77 : 23 (55) (41) (55) (62)c (55)
Me
H
Me OH Nu Me 1,2-Anti (Chelation)
entry A B C D E
(M)
C
Nu:
OP
1 2
CH2Cl2 P = Bn P = TBS
Lewis acidb BF3OEt2 SnCl4 TiCl4 Me2AlCl MeAlCl2
Me Chelation 9 11
1 P = Bn 9 : 10 (%) 26 : 74 50 : 50 97 : 03 90 : 10 78 : 22 (76) (87) (74) (45) (70)
M O P O
Me H H
Nu:
D. A. Evans
Chem 206
Since
R R Substrates which can participate in C=O chelation will be more reactive since the effective concentration of chelated intermediate will be higher. R
Me TBSO OH OCH2OBn
Me
Ketone +
RM
O M R + RM
OMgX OR Me OMgX
product
diastereoselection 50 : 1
Me
H O
Me BnO
R OH
O Me O Me Bu OR
+ isomer
Me2Mg k2 Me
R
Me Bn CMe3 SiMe3 Si-i-Pr3
rel rate
213 174 9 7 1
BnO
M. T. Reetz & Co-workers J. Am. Chem. Soc.. 1983, 105, 4833. Other nucleophiles reported
Ratio 40 : 60 90 : 10
Me2Mg k1 Me Me
Bu
reference rxn
Me BnO O
SiMe3
Acid -78 C CH2Cl2
Me BnO OH
+ isomer
k1 = 2.5 k2
R R O
R O better than R
O R
Note that beta chelation can be developed as a control element by varying solvent & Nu. Note BF3 gives "apparent" chelate control
D. A. Evans
Chem 206
OP
(8)
iPr
Hb OM H
Nu:
1 P = PMB 2 P = TBS
1,3-Anti
(M)
Ha H PO
C C R
entry A B C
R t-Bu i-Pr Me
3:4 (P = PMB) 89 : 11 92 : 08 91 : 09
O H
OP R P (M) O M H
E
R C
Nu:
OH
OP R
Nu
F1
O H
Me Me Me
1,3-Anti (Chelation)
Me2CH
F2
P O M O
C
Nu: H
1,3-Anti Relationship is favored by either polar or chelate models H OTMS O H OBn Me Ph TiCl4 OTMS O H OPMB R
R = (CH2)2Ph
i
MLn
O Ph
OH
OBn Me
diastereoselection 92 : 8
Pr BF3OEt2
i
O Pr
OH
OPMB R
B C
diastereoselection 81 : 19
D. A. Evans
Chem 206
OP iPr
Me Anti-Felkin 16 18
15 : 16 (P = PMB) 99 : 01 98 : 02 97 : 03
The Syn Diastereomer Integration of 1,3- Polar Model & Felkin-Anh Model
Nu
H O R OH OPMB
OP iPr Me R
OTMS Nu
OH
OP iPr Nu
OH
OP iPr
O H
OPMB
R
Ha F3BO H
C C iPr
Hb H OP
BF3OEt2 solvent
iPr
OTMS R O H
RL
19 P = PMB 20 P = TBS entry R t-Bu t-Bu i-Pr i-Pr Me Me Solvent CH2Cl2 toluene CH2Cl2 toluene CH2Cl2 toluene
Me Felkin 21 23 21 : 22 (P = PMB) 96 : 04 88 : 12 56 : 44 32 : 68 17 : 83 06 : 94
Me Anti-Felkin 22 24 23 : 24 (P = TBS) 96 : 04 94 : 06 87 : 13 75 : 25 58 : 42 40 : 60
BF3OEt2
Nu
OH
RL
Me F3BO
C RL
H H
Me
Me
Nu
O H
If both models are correct, they should integrate when the two stereocenters are reinforcing
Me F3BO H
C C iPr
Hb H OP
OR
R
A B C D E F
Conclusions
A: Anti diastereomer is reinforcing. Both models integrate. B: Syn diastereomer transitions from Felkin control (Large Nu) to 1,3-control (Small Nu).
Me & reinnforcing?
D. A. Evans
Chem 206
OH
TBSO OTBS OH
Me
Diastereoselection 59 : 32 : 9a
a
R O H Me entry A B C Conditions BF3OEt2, toluene BF3OEt2, toluene Ph3CClO4, CH2Cl2 R Me H H OPMB iPr Bu3Sn R Me Felkin : anti-Felkin 20 : 80 13 : 87 62 : 38 OH OPMB iPr
LDA, THF
D. A. Evans
Chem 206
OTBS OH CHO O M O Me O XV
Metal M = MgCl M = ZnCl Ratio 70 : 30 97 : 3 + isomer
Me H BnOCH2O O
Me-M -78 C
Me
Chelate Model
Me2CH
D. A. Evans & E. Sjogren Tetrahedron Lett. 1986, 27, 4961.
Me O O O H
Me2CuLi -78 C Et2O
Me O O Me OH
+ isomer
Me TBSO
R = BOM (CH2OBn)
RO
O H
RO
OH
Me Me O Me
Chelate Model
Me O
Me Me O Me
Me
Metal M = [CuCN]1/2 M = Li
Me
Ratio 98 : 2 33 : 67
Chelate Model
Me
Me Me BnOCH2O O H
Me2CuLi -78 C Et2O
OTMS Me H Me Ph
TiCl4 -78 C CH2Cl2
Me Me BnO OH O Ph
+ isomer
Chelate Model
Chelate Model
Me BnOCH2O O
H Me2CuLi
-78 C Et2O
Me BnOCH2O
Me OH
diastereoselection >92 % OH
O diastereoselection 50 : 50 H H O CO2R H Me
TiCl4 Me2Zn
Me
chelate model
CO2R H Me
diastereoselection 96 : 4
D. A. Evans
Chem 206
Me
H H
O+ C O H
OAc B
OH OAc favored R1 R3 R2 OH
T. Oishi & Co-workers Chem. Pharm Bull. 1984, 32, 1411. Me Ph NH2 O
Chelate Model
diastereoselection 97 : 3
R1
Me4NBH(OAc)3
H R2 R1 H R3 C O
OAc B
OH OAc R1 R3 OH R2
J. Barluenga & Co-workers J. Org. Chem. 1985, 50, 4052. O O OEt C3H 5 G. R. Brown & Co-workers Chem. Commun. 1985, 455. M-H
Chelate Model
diastereoselection 88 : 12
H O H OH OH Me Me Me
OH
+ isomer
diastereoselection 96 : 4
OH Me Me Me Me O Me NaBH(OAc)3 HOAc, -20 C Me Me Me Me OH OH Me + isomer
O Me Me
O N
CH2MOM M-H Me Me
OH
O XC Me Me Me
OH
O XC Me
diastereoselection 98 : 2
OH Me O Me Me Me Me NaBH(OAc)3 HOAc, -20 C Me Me Me Me OH OH Me + isomer
Me MOMCH2
M. Yamaguchi & Co-workers Tetrahedron Lett. 1985, 26, 4643. T. Oishi & Co-workers Tetrahedron Lett. 1980, 21, 1641 (Zn(BH4)2 on esters. Bu OH Ph O Ph Ph O B Bu O Ph NaBH4 -100 C K. Narasaka & Co-workers Chem. Lett. 1980, 1415. Ph
diastereoselection 98 : 2
OH
OH Ph + isomer
Propose a mechanism for tihs highly diastereoselective transformation, Evans, Hoveyda JACS 112, 6447 (1990)
O OH Me O R2CHO R1 Me 15% SmX3 catalyst R2 Me Me O OH R1
diastereoselection 96 : 4
D. A. Evans
Me OH H Me Me OH
M-H
Chem 206
O O O O
Me OH
O OH Me O COOH
M-H
Me
Me
Me
Temp. & Solvent not specified in this study in first three cases
Reagent
Reagent NaBH2(OR)2 NaBH4 DIBAL (2.4 equiv) DIBAL (2.4 equiv) with ZnCl2
Ratio 50 : 50 70 : 30 95 : 5 99 : 1
Me Et O O
M-H
Me Et O OH + OMe Et
Me Me O OH Ph OMe
1:1 3:1 11 : 1 R. Frenette & Co-workers J. Org. Chem. 52, 304 (1987) M-H
Me Ph O Me O Ph O Me
Ratio 50 : 50 70 : 30
Me O
COOMe
OMe
Y. Kishi & Co-workers Tetrahedron Lett. 1978, 2741.
* di-2-(o-toluidinomethyl)pyrrolidine
OH O OH
MeM -78 C
OCH2OCH3 Me
M-H
Me
OCH2OCH3 +
OCH2OCH3 Me
t-BuPhMe2SiO
t-BuPhMe2SiO
Me OH
+ Isomer
67-87% yields
HO
Li-BH(R)3, LiAlH4
HO
73 : 27 76 : 24 G. Tsuchihashi & Co-workers Tetrahedron Lett. 1987,28, 6335.
Me
OCH2OCH3
M-H
OCH2OCH3 Me + HO
Li-BH(R)3, LiAlH4
Me
OCH2OCH3 OH
HO
28 : 72 72 : 28
O R
R = Me, Ph(CH2)2
MeTi(O-iProp)3 0 C
OH R
OH Me
+ Isomer
Ratio 4-5.5 : 1
OH
4
M O O R
R' H X RZ H
RZ
III
M O O R
R' RE X H H syn-pentane
RE
II
IV
PFA Model Prediction: The (Z) enolate substituent causes a destabilizing syn-pentane interaction (I), while the (E) enolate substituent experiences no such interaction (II). Therefore, (E) enolates are predicted to give superior 3,4-anti selectivity relative to (Z) enolates. Cornforth Model Prediction: The (E) enolate substituent causes a destabilizing syn-pentane interaction (IV) while the (Z) enolate substituent experiences no such interaction (III). Therefore, (Z) enolates are predicted to give superior 3,4-anti selectivity relative to (E) enolates. Due to this dichotomy, the experimentally determined relationship between enolate geometry and aldehyde diastereofacial selectivity should validate a single model for asymmetric induction. Angew. Chem. Int. Ed., 2003, 42, 1761-1765.
CornforthSupport 11/5/03 9:27 AM
D. A. Evans
Chem 206
http://www.courses.fas.harvard.edu/~chem206/
Database Problem 27: Chiral amino alcohol 1 efficiently mediates the addition of diethylzinc to aromatic aldehydes. While a number of other amino alcohols are also effective in controlling the absolute course of the addition process, this amino alcohol has been the focus of a recent computational investigation that addresses the preferred transition state geometry for this addition process (Pericas, et al. J. Org. Chem. 2000, 65, 7303 and references cited therein). It should be noted that, while 1 is not the actual catalyst, it is modified under the reaction conditions to the competent catalytic agent. Provide a detailed mechanism for the overall transformation. Use 3-dimensional representations to illustrate the absolute stereochemical aspects of the indicated transformation.
O N Ph Ph
(R) 1
OH H
0.06 equiv 1 Et2Zn, 0 C toluene
(S)
Et
97% ee
Ph OH
Cume Question, 2000: Corey's introduction of chiral oxazaborolidine catalysts 1 in the borane-mediated enantioselective reduction of ketones represents an important advance in asymmetric synthesis (Corey & Helal, Angew. Chem. Int. Ed. 1998, 37, 1986-2012). Provide a detailed mechanism for the overall transformation. Use 3-dimensional representations to illustrate the absolute stereochemical aspects of the indicated transformation.
Ph Ph H N B
1
O Me
0.1 equiv 1
OH
(R)
Me
97% ee
Me
1 equiv BH3THF
Database Problem 151: The following stereoselective transformation has been reported by Fujisawa (Chem.Lett. 1991, 1555). Given the structure of the product, rationalize the stereochemical outcome of the process.
Ph N R H OMe
R"-Li
D. A. Evans
22-00-Cover Page 11/5/03 8:51 AM
D. A. Evans
Chem 206
Me N Me Zn O O Et H C
H C O R Noyori & co-workers, J. Am. Chem. Soc. 1986, 108, 6072. J. Am. Chem. Soc. 1989, 111, 4028. Review: Noyori Angew. Chem. Int. Ed. 1991, 30, 49 Review: L. Pu, Chem. Reviews 2001, 101, 757-824
the catalyst
Me
ZnEt O H Et
Me
90-98% ee
Et2Zn
Me2Zn PhCHO
Zn Zn Me Me Me Et Me
p. p.
Zn
Me
Me N Me Zn O O Et
Me N Me Zn O O Et Et H C
RDS
H C Me H Et H
Me
Zn
Zn
Et
98% e.e. 91% e.e. 93% e.e. 93% e.e. 96% e.e. 90% e.e. 61% e.e.
Zn
Zn R
The method is catalytic in aminoalcohol. Two zinc species per aldehyde are involved in the alkylation step.
22-01-Et2Zn-1 11/5/03 8:46 AM
D. A. Evans
Chem 206
N Me
(S,S) dimer
(R,R) dimer
Bu N Et Zn O
Bu Me Me2 N Zn Me O Me2 N Zn Me O
N Li
Ph
p. p.
Problem: Rationalize the stereochemical course of each of the catalysts Non-linear effects observed with the Noyori Catalyst (DAIB-Zn)
100
(S) catalyst
(R) catalyst
(S,R) dimer
Product (%ee)
Me2 Me N Zn O O Zn N Me Me 2
Observations (S,S) dimer dissociates upon addition of RCHO & effects catalysis
Ph
Me
(S,R) dimer is overwhelmingly more stable than (S,S) homodimer (S,R) dimer is ineffective as a catalyst
100
%ee of catalyst
D. A. Evans
Chem 206
(S) catalyst
O H OH
Et
98% ee
OH
RCHO
Et2Zn
O H
O Me
O H
Me
O H
91% ee
OH
n-Bu
88% ee
H
78% ee
95% ee
93% ee
(S) catalyst
p. p.
O
Et2Zn
96% ee
OH
(S) catalyst
Bu3Sn H
(n-Pen)2Zn
Bu3Sn
Bu N Me Et 21
85% ee
OH
the catalyst
O
Me H
3
(S) catalyst
H
Et2Zn
H H
90% ee
OH
OR
(S) catalyst
n-Bu H
n-Bu
Et
21
OTIPS
15 OTES
H 21
OTIPS
15 OTES
Et2Zn
60% ee
OH MeO
Me H
3
Et2Zn,
0 C, hexane
O MeO O
Me H
3
11
SnBu3
D. A. Evans
Chem 206
O B X
BH3
OBH2 C RS RL Y + N RS H 2B H
O C RS
2 equiv BH3 30 C, 10 hr
OH H R Ph
H Y N O B X O
B + O
( HBXC )
H 2B
O H
RS C RL
C RL
p. p.
Itsuno, J. Org. Chem. 1984, 49, 555 Itsuno, J. Chem. Soc. Perkin Trans I. 1985, 2615
Ph
B
Ph
BH3
N+ O B H 3B R
+ X O N B Ph B H Me H O+ H Ph
00000 00 00 00 00 00 00 00 00 000
R=H R = Me
O R Me
OH R H Me
Corey, JACS 1987, 109, 5551 Corey, JACS 1987, 109, 7925 Corey, JOC 1988, 53, 2861
97 % ee 97 % ee 91 % ee
N
H Ph Ph O B Me
Mathre, JOC 1993, 58, 2880 catalyst prep: Mathre, JOC 1993, 58, 799 Mathre, JOC 1991, 56, 751 (Review) Martens, Tertrahedron Asymmetry 1992, 3, 1475
Improved version
Chem 206
B
00000 00000 000 000 000 000 000 000 000 000 000 000 000 00000 000 00000 0000 0000 0000 000 0000 0000 0000 000 0000 0000 000 0000
Ph + X O N B Ph B H Me H O+
B
00000000 0000 00000000 0000 000 0000 000 000 000 000 000 000 00000 000
p. p.
D. A. Evans
Ph
D. A. Evans
H Ph Ph O The catalyst B Me
Chem 206
Me Me Me F Me
N O O
1.5 equiv
O BH O
HO Me
92% ee
ArCOO O
OH
ArCOO
91 : 9
(R)-cat, as above
O n-C5H11
OH Cl
Ph
94% ee (>99%)
NaI MeNH2 OH
p. p.
O B Me
OH
90 : 10
O OH O
NaH
NHMe CF3
86% ee Prozac
NHMe
Cl
O Br
OH
Br
R
OH R CCl3
91% ee
OH R CCl3 N3
0.1 equiv
n-Bu N3 R COOH
Corey, JACS 1992, 114, 1906 Tet. Let 1992, 33, 3435 Tet. Let 1992, 33, 3431
HO
rm temp
D. A. Evans
Chem 206
Me B Cl OH RL RS
Ph
Me B H Al OEt O O
THF 50 - 90%
Ketone
acetophenone butyrophenone 2,2-dimethylpropiophenone 3,3-dimethyl-2-butanone 2,2-dimethylcyclohexanone
Reaction Conditions
25 C 25 C 25 C 25C, 12 days 25C, 2 days
% ee
98% 98% 79% 95% 91%
Li
Reviews: Midland, Asymmetric Synthesis, Vol 2, p 45Granbois, Asymmetric Synthesis, Vol 2, p 71Brown, Accts. Chem. Res. 1992, 25, 16-24 Singh, Synthesis 1992, 605-617
p. p.
Brown's Model
Reagent
Alpine-Borane
72 - 92% e.e.
59 - 89% e.e.
78% e.e. R=Me 90% e.e. R=CO2Me 95 - 100% e.e. (71% ee, R=i-Pr) 15 - 75% e.e.
Me B H Favored TS RL
R Cl
BINAL-H
>95% e.e.
Small ligand (Rs) Less hindered aliphatic ketones are not reduced with useful levels of enantioselectivity
RS
Darvon-LiAlH4
25% e.e.
----
Brown, J. Org. Chem. 1985, 50, 5446 Brown, J. Org. Chem. 1986, 51, 3394 Brown, J. Org. Chem. 1988, 53, 2916
D. A. Evans
Chem 206
"Structure and Reactivity of Lithium Enolates. From Pinacolone to Selective C-Alkylations of Peptides. Difficulties and Opportunities Afforded by Complex Structures". D. Seebach Angew. Chem. Int. Ed. Engl., 27, 1624 (1983). "Stereoselective Alkylation Reactions of Chiral Metal Enolates". D. A. Evans Asymmetric Synthesis, 3, 1 (1984). "Generation of Simple Enols in Solution". B. Capon, B.-Z. Guo, F. C. Kwok, A. K. Siddhanta, and C. Zucco Acc. Chem. Res. 21, 121 (1988). "pKa and Keto-Enol Equilibrium Constant of Acetone in Aqueous Solution". Y. Chiang, A. J. Kresge, and Y. S. Tang J. Am. Chem. Soc. 106, 460 (1984).
Tautomers: Structural isomers generated as a consequence of the 1,3-shift of a proton adjacent to a X=Y bond. for example:
H Z X Y Z X
H Y
O R H H
+H+
OH R H H
base catalysis:
R O
CH3
Enols & Enolates are the most important nucleophiles in organic & biological chemistry.
H+ O Ra Rb base Ra O Rb El(+) Ra OH Rb
acid catalysis:
+H+
O R
H CH3
H+
OH R H H
CH3
El(+) O Ra El H 3C OH H 3C H El(+) H H 3C H O CH3 H3 C H Kresge, JACS 1984, 106, 460 On the origin of the acidity of enols: Wiberg, JACS 1996, 118, 8291-8299 H
+H+
Rb
OH H
pK = 8.22 (measured)
R Ra
N Rb El H3C
pK = 19.16 (calculated)
metalloenamine
D. A. Evans
Chem 206
OLi
+
Me
R (Z)
Me
R-Substituent -OMe, O-t-Bu -S-t-Bu -Et -CHMe2 -CMe3 -C6H5 -NEt2 -NEt2
MeNH2
H2O
Keq > 10
The enamine content in an analogous imine is invariably higher than its carbonyl counterpart. In the case above, ring conjugation now stabilizes the enamine tautomer as the major tautomer in solution.
R Me
R R
OLi
Solvent
Ratio, (E):(Z) 95 : 5 16 : 84
O Me H Li R H N R
Base Structure
O R
(Z) Geometry
OLi
The Ireland Model (J. Am. Chem. Soc. 1976, 98, 2868) Narula, Tetrahedron Lett. 1981, 22, 4119 more recent study: Ireland, JOC 1991, 56, 650 For the latest word on this subject see: Xie, JOC 1997, 62, 7516-9 Stereoelectronic Requirements: The -C-H bond must be able to overlap with CO
Me
(Z) Geometry
Ha
CO
R Hc
O Hb
base Ha+
Hc R
Hb O
D. A. Evans
Base Structure
O Et Me
Chem 206
OLi OLi Me Me
Regioselective Enolization
O Me Mbase
OLi
Et
Me
A
Base LiN(i-Pr)2 Me LiN(SiMe3)2 Ph3CLi Ph3CLi NaH KH temp 78 78 78 heat heat heat control kinetic kinetic kinetic thermo thermo thermo
(Z) Geometry Me
N Me Li Me (LOBA) 98 : 2
Collum (J. Am. Chem. Soc. 1991, 113, 9572) Collum (J. Am. Chem. Soc. 1991, 113, 9575) Collum (J. Am. Chem. Soc. 1991, 113, 5053)
A: Alkyl groups stabilize metal enolate A: As MO bond becomes more ionic A is attenuated Kinetic Selection sensitive to structure
O OLi Ph Mbase Ph OLi Ph
For the latest in the series of Column papers see: JACS 2000, 122, 2452-2458 O Et Me LiNR2 THF, -78 C Et Me Ratio, (E):(Z) LiTMP LiTMP, 10% LiBr 86 : 14 98 : 2 OLi OLi
Et
Me
A
O
+
ratio: 99:1
(25)
(18) Ph
Unsaturated Ketones
1-Bu3N 1 KO Me Me KOtBu t-BuOH O LiN(i-Pr)2 LiO Me
R 3N krel
n-Bu3N 3000
thermodynamic enolate
kinetic enolate
see kinetic acidity handout for an extensive compilation of cases.
D. A. Evans
Chem 206
Me
O LDA
Me
OLi
only enolate
O
O Me LDA O O LDA Me
Me
only enolate
LiO OLi
only enolate
Me
OLi MeO
only enolate
Me
OLi
OLi
Me O LDA Me Me
OLi
only enolate
Me Me Me
Me
"There is no likelihood man can ever tap the power of the atom. The glib supposition of utilizing atomic energy when our coal has run out is a completely unscientific Utopian dream, a childish bug-a-boo. Nature has introduced a few foolproof devices into the great majority of elements that constitute the bulk of the world, and they have no energy to give up in the process of disintegration."
D. A. Evans
Chem 206
http://www.courses.fas.harvard.edu/~chem206/
"Structure and Reactivity of Lithium Enolates. From Pinacolone to Selective C-Alkylations of Peptides. Difficulties and Opportunities Afforded by Complex Structures". D. Seebach Angew. Chem. Int. Ed. Engl., 27, 1624 (1983). (handout) "Stereoselective Alkylation Reactions of Chiral Metal Enolates". D. A. Evans Asymmetric Synthesis, 3, 1 (1984). (handout)
"Generation of Simple Enols in Solution". Capon, Guo, Kwok, Siddhanta, and Zucco Acc. Chem. Res. 21, 121 (1988). "Keto-Enol Equilibrium Constants of Simple Monofunctional Aldehydes and Ketones in Aqueous Solution". Keeffe, Kresge, and Schepp JACS, 112, 4862 (1990). "pKa and Keto-Enol Equilibrium Constant of Acetone in Aqueous Solution". Chiang, Kresge, and Tang JACS 106, 460 (1984).
Tautomerism in C=O and C=NR Systems C=O Enolization with Metal Amide Bases C=O Enolization: Kinetic Acidities Mild Methods for Enolate Generation Enolate Structure: A Survey of X-ray Structures Metallo-Enamine X-ray Structures
Reading Assignment for this Week: Carey & Sundberg: Part A; Chapter 7 Carbanions & Other Nucleophilic Carbon Species Carey & Sundberg: Part B; Chapter 2 Reactions of Carbon Nucleophiles with Carbonyl Compounds
D. A. Evans
23-00-Cover Page 11/7/03 8:28 AM
CO2Et N Boc
Bn Me2CH
98 (S) 94 (S)
D. A. Evans
Chem 206
"Structure and Reactivity of Lithium Enolates. From Pinacolone to Selective C-Alkylations of Peptides. Difficulties and Opportunities Afforded by Complex Structures". D. Seebach Angew. Chem. Int. Ed. Engl., 27, 1624 (1983). "Stereoselective Alkylation Reactions of Chiral Metal Enolates". D. A. Evans Asymmetric Synthesis, 3, 1 (1984). "Generation of Simple Enols in Solution". B. Capon, B.-Z. Guo, F. C. Kwok, A. K. Siddhanta, and C. Zucco Acc. Chem. Res. 21, 121 (1988). "pKa and Keto-Enol Equilibrium Constant of Acetone in Aqueous Solution". Y. Chiang, A. J. Kresge, and Y. S. Tang J. Am. Chem. Soc. 106, 460 (1984).
Tautomers: Structural isomers generated as a consequence of the 1,3-shift of a proton adjacent to a X=Y bond. for example:
H Z X Y Z X
H Y
O R H H
+H+
OH R H H
base catalysis:
R O
CH3
Enols & Enolates are the most important nucleophiles in organic & biological chemistry.
acid catalysis:
+H+
O R
H CH3
H+
OH R H H
CH3
H+
O Ra Rb Ra
OH Rb
El(+) O Ra Rb El H 3C OH H 3C H El(+) H H 3C H O CH3 H3 C H Kresge, JACS 1984, 106, 460 On the origin of the acidity of enols: Wiberg, JACS 1996, 118, 8291-8299 H
+H+
base
Ra
O Rb
El(+)
OH H
pK = 8.22 (measured)
H+
R Ra N Rb
R Ra
H Rb M
R Ra El(+)
N Rb El H3C
pK = 19.16 (calculated)
base
R Ra
Rb
metalloenamine
D. A. Evans
Chem 206
OLi
+
Me
R (Z)
Me
R-Substituent -OMe, O-t-Bu -S-t-Bu -Et -CHMe2 -CMe3 -C6H5 -NEt2 -NEt2
MeNH2
H2O
Keq > 10
The enamine content in an analogous imine is invariably higher than its carbonyl counterpart. In the case above, ring conjugation now stabilizes the enamine tautomer as the major tautomer in solution.
R Me
R R
OLi
Solvent
Ratio, (E):(Z) 95 : 5 16 : 84
O Me H Li R H N R
Base Structure
O R
(Z) Geometry
OLi
The Ireland Model (J. Am. Chem. Soc. 1976, 98, 2868) Narula, Tetrahedron Lett. 1981, 22, 4119 more recent study: Ireland, JOC 1991, 56, 650 For the latest word on this subject see: Xie, JOC 1997, 62, 7516-9 Stereoelectronic Requirements: The -C-H bond must be able to overlap with CO
Me
(Z) Geometry
Ha
CO
R Hc
O Hb
base Ha+
Hc R
Hb O
D. A. Evans
Base Structure
O Et Me
Chem 206
Regioselective Enolization
O OLi Me Mbase Me OLi Me
OLi
Et
Me
A
Base LiN(i-Pr)2 Me LiN(SiMe3)2 Ph3CLi Ph3CLi NaH KH temp 78 78 78 heat heat heat control kinetic kinetic kinetic thermo thermo thermo
(Z) Geometry Me
N Me Li Me (LOBA) 98 : 2
Collum (J. Am. Chem. Soc. 1991, 113, 9572) Collum (J. Am. Chem. Soc. 1991, 113, 9575) Collum (J. Am. Chem. Soc. 1991, 113, 5053)
A: Alkyl groups stabilize metal enolate A: As MO bond becomes more ionic A is attenuated Kinetic Selection sensitive to structure
O OLi Ph Mbase Ph OLi Ph
For the latest in the series of Column papers see: JACS 2000, 122, 2452-2458 O Et Me LiNR2 THF, -78 C Et Me Ratio, (E):(Z) LiTMP LiTMP, 10% LiBr 86 : 14 98 : 2 OLi OLi
Et
Me
A
O
+
ratio: 99:1
(25)
(18) Ph
Unsaturated Ketones
1-Bu3N 1 KO Me Me KOtBu t-BuOH O LiN(i-Pr)2 LiO Me
R 3N krel
n-Bu3N 3000
thermodynamic enolate
kinetic enolate
see kinetic acidity handout for an extensive compilation of cases.
D. A. Evans
Chem 206
Me
O LDA
Me
OLi
only enolate
O
O Me LDA O O LDA Me
Me
only enolate
LiO OLi
only enolate
Me
OLi MeO
only enolate
Me
OLi
OLi
Me O LDA Me Me
OLi
only enolate
Me Me Me
Me
D. A. Evans
M R
Chem 206
M=H M = Li 0.19 0.22
Metal Tautomerism
For alkali metal enolates (M = Li, Na, K etc.) the O-metal tautomer is strongly favored. This generalization holds for most alkaline earth enolates (Mg+2) as well. These are the generally useful enolate nucleophiles For certain metal enolates from heavy metals such as M = Hg+2 the C-metal tautomer is sometimes favored. M R R
O Me
CMe3
O
O
M
O R
O R R
Me2 N O Li N Me2
Li N Li
Resonance Structures
O resonance structure
resonance structure
Since enolates usually function as carbon nucleophiles, it is therefore of some interest to assess the relative importance of the illustrated contributing polar resonance structures. Within the last decade good X-ray crystal structures of a number of metal enolates have been obtained.
One would predict that as the relative importance of the C structure increases, the CO bond would shorten and the CC bond would lengthen. Me The prediction stated above does hold, but the net change in 1.36 the CC bond length is < 2 % ! R 1.32 O 1.35 H R H 1.34 H H O Li
Mg Mg Br
H Me CMe3 Br O Mg OEt2
In solution and in the solid state metal enolates have a strong tendency to aggregate into dimers and tetramers to satisfy metal solvation requirements.
M R O + M O R R O
M O R M
M RO M O M O R
OR M
D. A. Evans
Chem 206
Li Enolates
Si
Me CMe3
Williard, P. G.; Hintze, M. J. J. Am. Chem. Soc. 1987, 109, 5539-5541. Li Li O OLi Li O Li O Li O N Li Li O O
O Li O Li N
Si
O N Li Li O Li
Si
Li Li
Li
Li O Li O O Li Li O O Li O Li
Li Li Li
D. A. Evans
Chem 206
Zn Enolates
O
Me3C
Br
Br Zn O Me3C O
O CMe3
Me3C
ZnBr
O Zn Br
Br Zn Zn C O C Zn 2.0 Br Dekker, J.; Boersma, J.; van der Kerk, G. J. M. J. Chem. Soc. Chem. Commun. 1983, 553. Dekker, J.; Budzelaar, J.; Boersma, J.; van der Kerk, G. J. M. Organometallics 1984, 3, 1403.
23-07 Zn Enolate structure 11/7/03 8:14 AM
Br
O Zn 2.0
Br O
D. A. Evans
Chem 206
Review: Comprehensive Organic Synthesis, 1991; Vol 2, Chapter 1.8, pp 277-299 Frstner, A. "Recent Advances in the Reformatsky Reaction." Synthesis 1989, 571. CHO Zn, Et2AlCl
-20 C
O O
O O
OH
R O O Br CHO
SmI2/0 C
R O O OH
R = H: 85% yield R = Me: 82% yield aldol diastereoselection 70:30 no config assignment
Br
48% yield
R = H: 76% yield
Me O
CHO Br
OH
Zn, Et2AlCl
Me O O
Based on the Nozaki recipe JACS 1977, 99, 7705
O C6H13
diastereoselection 10:1 55% yield
Br CHO R
SmI2/0 C
O O
SmI2/0 C
C6H13 O
O O
Br
CHO
O O OH
82% yield
O Ph Me
PhCHO
Br
Zn in HOH 25 C
O Ph Me
OH Ph Ph
OH
Good entry into prior literature
Ph Me Br
O O R Me O Br O R Me Me
G. A. Molander & Co-workers, J. Am. Chem. Soc. 1987, 109, 6556.
O O Me
2 SmI2/THF -20 C
diastereoselection 60:40 87% yield Rxns carried out in water with either activated Zn or Sn. 19 cases reported.
O R Me O Et OH
Br
Br
O Me
2 SmI2/THF -78 C
O R Me Et OH
O Bn N Br
O
Zn/THF
O Bn N
OZnBr
25 C
O Bn N
Me
Me
O
Proposed Transition structure
R(H) Et O O Sm
78% yield C. H. Heathcock & Co-workers, J. Org. Chem. 1987, 52, 5745.
R (R)H H
D.A. Evans
Chem 206
Cl4
TiCl4 (1.0 equiv) Et3N (1.0 equiv)
Ti
O Me
Et3N
O O
Ti N
+366 +17
+316 7
+9
BF3 complexation generates a "superacid" comparable to the acidity of H2SO4 Ren et al, JACS 1999, 121, 2633-2634 (pdf)
O Me
Et3N
O O
Ti N
O Me 2
Some qualitative observations (Evans Group, Unpublished)) Xn O O N Bn Lewis Acid (MXn) TiCl4 TiCl3(Oi-Pr) TiCl4(THF)2 TiCl2(Oi-Pr)2 AlCl3 MgBr2OEt2* TiCl(Oi-Pr)3 SnCl4, Et2AlCl, ZrCl4 O Me
Lewis Acid (1.0 equiv) Et3N (1.0 equiv)
pKa 9 (DMSO) Bn Et3NH Cl4 Ti N Bn estimated pKa (DMSO) ~ +7 Hence TiCl4 complexation lowers acidity by ~20 pka units. this number is the same mgnitude as the BF3acetaldehyde case just discussed O Me O O Cl4 Ti N Bn O Me
H
O O
M N
CH2Cl2 O
pKa ~ +7
In these experiments, the Lewis acid was added first followed by the amine.
D.A. Evans
Chem 206
Choose Lewis Acid (LA) which can reversibly associate with amine base (B:).
() (+)
LA
B:
LA
O OEt
+
R CH3
+O LA
R
LA CH2H R
LA CH2
Me Base = DBU, 5 min, 99%, >50:1 E:Z i-PrCHO, 1 equiv = DIPEA, 7 h, 97%, >50:1 E:Z OEt Base MeCN Me rt
+ BH
(+)
pKa 19.2 (DMSO), K+ counterion pKa 12.2 (Diglyme), Li+ counterion Roush & Masamune, Tet. Lett. 1984, 25, 2183-2186
+ B:
() (+)
LA
B
Complexation Reversible Reversible Reversible (Et3N, EtNi-Pr2) Reversible (Et3N, EtNi-Pr2) Reversible (Et3N, EtNi-Pr2) Reversible (Et3N, EtNi-Pr2) Irreversible (Et3N, EtNi-Pr2) Reversible (Et3N, EtNi-Pr2) Reversible (Et3N, EtNi-Pr2) Reversible (Et3N, EtNi-Pr2)
O (EtO)2P
1 equiv
Useful Lewis Acid Pairs MgBr2 + NEt3 LiX + NR3 Sn(OTf)2 + NR3 R2B-OTf + NR3 R2BCl + NR3 PhBCl2 + NR3 TiCl4 + NR3 i-PrOTiCl3 + NR3 (i-PrO)2TiCl2 + NR3 (i-PrO)3TiCl + NR3
O R CH3 RS O CH3
OTf = OSO2CF3
NHCbz CHO Me
NHCbz
O OEt
Me
85% + 10% recovered aldehyde
Me
Me
Conventional methods of deprotonation (NaH) resulted in epimerization (Overman JACS 1978, 5179).
Magnesium Enolates
O OEt
MgBr2, 1.2 equiv Et3N, 1.1 equiv RCHO, 1 equiv THF, rt
All of the above systems will enolize simple ketones to some extent.
O PhO CH3 EtO O CH3 R2N O CH3
O R OEt
D.A. Evans
Chem 206
Titanium Enolates
The Early Literature Lehnert, W. Tetrahedron Lett. 1970, 4723-4724.
Diethylmalonate acylations
O EtO O OEt Me O Cl
MgCl2, 1 equiv Et3N, 2 equiv MeCN, rt
O EtO
O OEt EtO
O OEt Et
O Et
O EtO Et
O OEt Et
Ketone Carboxylation
O
O Me 85% yield
MgCl2, 2 equiv NaI, 2 equiv Et3N, 4 equiv CO2, MeCN rt
75% yield
O Ph
OH Ph Me
Mg
O
MVK
O O
EtOH -CO2
O Me 75% yield
Ketone and aldehyde combined followed by sequential addn of TiCl4 and then amine
O Ph
TiCl4 Me
+
O Ph H Ph
O Me
O Ph
TiCl4 H
Michael reaction
O O N Bn O Et3NH O O Me
MgBr2OEt2
O CO2Me Brn
Mg
Et3N CH2Cl2, 0 C
O N Me Bn CO2Me Brocchini, Eberle, Lawton J. Am. Chem. Soc. 1988, 110, 5211-5212. O S
TiCl4 OH DIPEA THF -40 C
O CHO S OH NO2
10-15:1 Z/E
O NO2
Chem 206
O Xp O O OMe
BOMCl PhSCH2Cl
O O N
O Me 1
TiCl4
Bn
Enolization process not responsive to tertiary amine structure DIPEA, Et3N, N-Ethylpiperidine all suitable bases. DBU and tetramethylguanidine do not provide enolate. CH2Cl2 is the only suitable solvent for these enolizations.
Cln
Et
N-Propionyloxazolidone (1)
Lewis Acid TiCl4 i-PrOTiCl3 TiCl42THF (i-PrO)2TiCl2 (i-PrO)3TiCl % Enolization 100 100 80 70 ~10
Ethylisopropylketone
Lewis Acid TiCl4 i-PrOTiCl3 (i-PrO)2TiCl2 % Enolization 100 80 50
O Xp Me 88%, >99:1
HC(OMe)3
O O
Ti N
O Me
ClCH2NHCOPh
O Xp Me 89%, 97:3
MeOCH2NHCbz
(CH2)2COEt
CH2NHCOPh
Bn
O Me Me Me
Irreversible Complexation
Order of addition of reagents is not important for i-PrOTiCl3 or (i-PrO)2TiCl2. R 3N + i-PrOTiCl3 + R3N-TiCl3(OiPr) Reversible Complexation
Enolizable substrates:
J. Am. Chem. Soc. 1990, 112, 8215-8216.; J. Org. Chem. 1991, 56, 5750-5752.
O R Me t-Bu
O Me i-Pr
O Me O MeO
O OMe PhS O R Me
O Me O O N Me Bn O O Me
1. TiCl4 DIPEA 2. i-PrCHO
O O N
OH Me
O MeO Me
Me Bn
Me
Me
86% yield, >99:1 Evans, Clark, Metternich, Novack, Sheppard J. Am. Chem. Soc. 1990, 112, 866.
D.A. Evans
Chem 206
O BR2
Di-n-butylboron triflate
Mukaiyama, Inoue Chem. Lett. 1976, 559-562. Bull. Chem. Soc. Jpn. 1980, 53, 174-178. Enolizes ketones with 2,6-lutidine or DIPEA in ethereal solvents.
Mr
Borane and lutidine or DIPEA form 1:1 complex with L2B-OTf. Complexation reversible as enolization will occur upon addition of ketone. Less hindered nitrogen bases - pyridine, Dabco, DBU, irreversibly complex with L2B-OTf.
R B R O Me -X
R B O R
R B O Me charged R
R -X +X Me OBL2 R
R O B
R X syn Me
anti
+X
Me
Enolate Stereochemistry
Evans, Nelson, Vogel, Taber J. Am. Chem. Soc. 1981, 103, 3099-3111. Goodman, Tetrahedron Lett. 1992, 33, 7219. Enolization Model: Paterson, Tetrahedron Lett. 1992, 33, 7223. O Me Me 9-BBN-OTf, Et3N Cy2B-Cl, Et3N Me R2B-X, R3N Me Me ratio ~ 88: 12 ratio ~ 3: 97 O BR2 Me Me Me Mr O BR2 anti H R H
R Me syn H
NR'3
O Me
BL2OTf
R Me
BL2X
Cy2BCl-ketone complex may deprotonate through syn complex R2BOTf-ketone complex may deprotonate through charged complex with (Z) preference
D. A. Evans
Chem 206
Question: Why do we generally show enolates reacting with electrophiles at carbon as opposed to oxygen ?? Let's begin the the discussion with an observation: "As electrophile reactivity increases, the percentage of reaction at the enolate oxygen increases." For example, consider the reactions of cyclohexanone enolate with the two electrophiles, methyl iodide and the much more reactive acetyl chloride:
O OEl
The Hammond Postulate is also relevant to this issue and is broadly used to make qualitative statements about transition state structure. Hammond, JACS 1955, 77, 334 (handout) In attempting to grasp the Hammond Postulate, let's consider two extreme reactions, one which is strongly endothermic and one which is strongly exothermic. T
1
El(+)
El(+)
O
B
Energy
Me C Cl O O Me I
El
A
Rxn Coordinate
The very reactive acid chloride gives almost exclusively the O-acylation product while the less reactive methyl iodide affords the alternate C-alkylation product. These results may be understood in the context of qualitative statements made by Hammond (The Hammond Postulate) and Hine (The Principle of Least Motion) The Principle of Least Motion: "As reactions become more exothermic, the favored reaction becomes that path which results in the least structural (electronic) reorganization."
Hammond Postulate "For strongly exothermic reactions, the transition state T looks like reactant(s) e.g. B." As applied to the enolate-electrophile reaction, for very exothermic reactions, e.g. the reaction with acetyl chloride, the transition state for the process will involve little enolate structural reorganization. Hence in this instance the electrophile heads for the site of highest electron density
Carey & Sundberg: Part A; Chapter 4, pp217-220 for discussion of Hammond's Postulate
See Hine in Advances in Phys. Org. Chem. 1977, 15, 1-61 Since the X-ray data clearly support the picture that resonance structure 1 best represents the enolate structure, highly reactive electrophiles will favor O-attack according to Hine's generalization.
23-14 C vs O Enolate React 11/6/03 5:29 PM
Based upon the above discussion draw a detailed mechanism for the protonation of cyclohexanone enolate.
O
H+
D. A. Evans
Metalloenamines:
Chem 206
Imines may be transformed into their conjugate bases (enolate counterparts) with strong bases: R pKa~ 29-33 N Li-NR2 Metal R N R-MgX R N
NR C C C C
O C C
NR2 C C
OMe
Electrophile
Br2, O3 H3O+
O R C Cl O R C H O R C R
+ + + + + + + + +
+ + + + + + +
+ + + +
+ +
The usual bases employed are either lithium amides (LDA) or Grignard reagents. Note that Grignard reagents do not add to the C=N pi-bond due to the reduced dipole. With this functional group, deprotonation is observed to be the preferred reaction.
Decreasing Electrophilicity
X
no reaction
However:
Metal R N I
Me Me N
good yield
Me
Me Me
O R C OR O H 2C CH2 I
Metalloenamines are reactive enough to open epoxides in good yield. Ketone enolates are only marginally reactive enough for this family of electrophiles. O
Li-NR2
Me2CH
R N Li CH2 N R OH
Me
O R C NR2
Nature uses enamines, "stabilized" enolates, and enol derivatives in CC bond constructions extensively.
Today's astrological forecast, Boston Globe, Monday, November 10, 2003 Capricorn (Dec 22Jan 19th)
"Be prepared for someone to try to steal your ideas or take credit for your work. You're on to something tangible and you need to act fast."
D. A. Evans
Chem 206
http://www.courses.fas.harvard.edu/~chem206/
"Structure and Reactivity of Lithium Enolates. From Pinacolone to Selective C-Alkylations of Peptides. Difficulties and Opportunities Afforded by Complex Structures". D. Seebach Angew. Chem. Int. Ed. Engl., 27, 1624 (1983). (handout) "Stereoselective Alkylation Reactions of Chiral Metal Enolates". D. A. Evans Asymmetric Synthesis, 3, 1 (1984). (handout)
Introduction and General Trends Enolate Alkylation: Electronic & Steric Control Elements Enolate Alkylation: Unusual Cases Chiral Amide Enolates Chiral Ester Enolates Chiral Imide Enolates Chiral Metalloenamines
Reading Assignment for this Week: Carey & Sundberg: Part A; Chapter 7 Carbanions & Other Nucleophilic Carbon Species Carey & Sundberg: Part B; Chapter 2 Reactions of Carbon Nucleophiles with Carbonyl Compounds
D. A. Evans
24-00-Cover Page 11/9/03 11:46 AM
D. A. Evans
Metalloenamines:
Chem 206
Imines may be transformed into their conjugate bases (enolate counterparts) with strong bases: R pKa~ 29-33 N Li-NR2 Metal R N R-MgX R N
NR
C C C C
O C C
NR2 C C
OMe
Electrophile
Br2, O3 H3O+
O R C Cl O R C H O R C R
+ + + + + + + + +
+ + + + + + +
+ + + +
+ +
The usual bases employed are either lithium amides (LDA) or Grignard reagents. Note that Grignard reagents do not add to the C=N pi-bond due to the reduced dipole. With this functional group, deprotonation is observed to be the preferred reaction.
Decreasing Electrophilicity
X
no reaction
However:
Metal R N I
Me Me N
good yield
Me
Me Me
O R C OR O H 2C CH2 I
Metalloenamines are reactive enough to open epoxides in good yield. Ketone enolates are only marginally reactive enough for this family of electrophiles. O
Li-NR2
Me2CH
R N Li CH2 N R OH
Me
O R C NR2
Nature uses enamines, "stabilized" enolates, and enol derivatives in CC bond constructions extensively.
D. A. Evans
Chem 206
Question: Why do we generally show enolates reacting with electrophiles at carbon as opposed to oxygen ?? Let's begin the the discussion with an observation: "As electrophile reactivity increases, the percentage of reaction at the enolate oxygen increases." For example, consider the reactions of cyclohexanone enolate with the two electrophiles, methyl iodide and the much more reactive acetyl chloride:
O OEl
O 78 C NC 1 OMe fast R1
Li
O OMe 2 CN
R2
slow
El(+)
O
Intermediate 2 breaks down to product more slowly than the acylation step Under these conditions, proton transfer from product to enolate does not occur. See accompanying "Acylation Handout"
O R1 R2 O OMe
+ LiCN
Me C Cl O O Me I
El
Kinetic Acidities nicely illustrate LNM Principle: *Lecture 18" pKa(H2O) ~10
O H O H 3C N O
The very reactive acid chloride gives almost exclusively the O-acylation product while the less reactive methyl iodide affords the alternate C-alkylation product. These results may be understood in the context of qualitative statements made by Hammond (The Hammond Postulate) and Hine (The Principle of Least Motion) The Principle of Least Nuclear Motion: "As reactions become more exothermic, the favored reaction becomes that path which results in the least structural (electronic) reorganization." Hine in Advances in Phys. Org. Chem. 1977, 15, 1-61 (handout) Since the X-ray data clearly support the picture that resonance structure 1 best represents the enolate structure, highly reactive electrophiles will favor O-attack according to Hine's generalization. See reinforcing examples on the accompanying page.
24-02 C vs O Enolate React 11/9/03 12:16 PM
pKa(H2O) ~10
O H 2C N O
Proton kinetically controlled transfers from C-H Bonds are slow due to the extensive reorganization required in conjugate base. Leaving Group Ability: Stirling, Chem. Commun. 1975, 940
O Ph S O base O Ph S O rds O Ph S O O Ph S O
X
O
Ph S The greater the structural OPh O reorganization of the leaving group during E1cb elimination, the slower krel = 1 the rate of elimination. pKa = 10
CN
D. A. Evans
Chem 206
The Hammond Postulate is also relevant to this issue and is broadly used to make qualitative statements about transition state structure. Hammond, JACS 1955, 77, 334 In attempting to grasp the Hammond Postulate, let's consider two extreme reactions, one which is strongly endothermic and one which is strongly exothermic. T B
Energy
SN1 reactions are typical examples of strongly endothermic processes Hammond: "The transition state will look like products."
Energy
Rxn Coordinate
G A
Rxn Coordinate GA GE H Me3C H OTs
Hammond Postulate "For strongly exothermic reactions, the transition state T looks like reactant(s) e.g. B." As applied to the enolate-electrophile reaction, for very exothermic reactions, e.g. the reaction with acetyl chloride, the transition state for the process will involve little enolate structural reorganization. Hence in this instance the electrophile heads for the site of highest electron density
Does GE GA = G (E A)??
GA: 26.9 GA:27.6 OTs Me3C H H
Carey & Sundberg: Part A; Chapter 4, pp217-220 for discussion of Hammond's Postulate
Based upon the above discussion draw a detailed mechanism for the protonation of cyclohexanone enolate.
O H+ O Me3C
G= +0.7
E
Wnstein & Holness, JACS 1955, 55, 5562
D. A. Evans
Review
Chem 206
Evans, D. A. Stereoselective Alkylation Reactions of Chiral Metal Enolates.; Morrison, J. D., Ed.; AP: New York, 1984; Vol. 3, pp 1-110.
Stereoelectronic Issues
Enolization: Breaking CH bond must overlap with CO in TS Alkylation: Forming CEl bond must overlap with CO in TS H C C R H base R M O H C C R
El(+)
LDA O N Boc Me RX
R O N Boc Me
RX BnBr AllylBr
R M O
Me C H H N O H O R
El R M O H C C R
R M O
El C C R H
RO O
H N
H O H
LDA
H C Boc N LiO RO
RX
Cyclohexanone Enolate:
El(+)
a
H
Me3C R e
El Me O
H H
OH Li/NH3 R H LiO
H
Me
OH
El(+)
Me-I Me OH
R-substituent Me CO2Me
Chair vs boat geometries not stongly reflected in diastereomeric TS s. The transition states is early and enolate-like.
D. A. Evans
Steric Effects
El(+) a Me3C H El(+)
Chem 206
R + O Me
A
Ratio, E:A 84:16 87:13
Representative cases
CO2Me Me LDA MeI Me LDA MeI Me CO2Me Me Me CO2Me Me Ratio, 80 : 20
Li
The enolate R = Me (Chem 3D)
CO2Me
CO2Me
Me
CO2Me Ratio, 90 : 10
Me
Me
Me
However
Me
Me
D. A. Evans
Chem 206
Cases which do not appear to give the expected product based on the analysis of steric effects
CO2Me LDA R allyl-Br Me Me O H R C 3H 5 CO2Me
Me Me
O O
t-Bu
CO2Me
88 : 12
Seebach, Angew. Chem. Int. Ed 1981, 20, 1030 Ladner, Angew. Chem. Int. Ed 1982, 21, 449
Contrasteric relatives:
t-Bu O O OLi S-t-Bu MeOD >95%ds 60% ds BnBr acetone 95%ds t-Bu O O R COS-t-Bu
However:
Me Me O O CO2Me LDA
Me Me
acetone CO2Me
Li
ratio, 80 : 20
t-Bu O
Me CO2Me 70 : 30 Me
t-Bu Me O
Me CO2Me Me
Me O HO2C Me
>95 : 5
HO2C
LDA, conditions
Ladner, Chem. Ber. 1983, 116, 3413-3426. Me CO2R X R-Cl R-Br CO2R Ratio 80:20 02:98
Those factors defining olefin face selection are currently being defined: Would you have predicted the outcome of the following reaction? OSiR
O
3
HgI2 EtO2C
>94 : 6
OSiR3
OH CMe2
D. A. Evans
Chem 206
N Et
(E) Et H O
disfavored
O XC R
enolization
favored
OM XC
El(+)
s-BuLi (THF) R
O Me N
O
El(+)
CH2OH N
Me El
O RO El R
hydrolysis
XC El
diastereoselection Ca 95 %
Allylic Strain controls Enolate Geometry: Enolization selectivity: Ester-based chiral controllers XC limited by enolization selectivity (Lecture 23)
O RX Me Base LDA (THF) LDA (THF) OLi LMNR2 RX (E) OLi H strongly favored O Me C R N R H O H H C R N R Me strongly disfavored
+ RX
Me (Z) Ratio, (E):(Z) 95 : 5 95 : 5
Me
D. A. Evans
Chiral Amide Enolates
RX M O Li O M-NR2 Me HOH2C RX N N Me HOH2C N
Chem 206
Amide Hydrolysis
O N CH2OH
H
+
O R HO N Me
O O H2 N +
HCO3H2O, 5 min
HOH2C N
O O Me (minor) R R Me OH
H R O C H O O H N H
H 2O R
O O Me
HN
Br
96:4 (98%)
Br
98:2 (84%)
Chem 3D model
Li Li
Li
Me Me
17
Me H
Me Me OH O
OH OH Ca O
14 12
O N O
O
9
LDA RX The nature of enolate chelation is ambiguous. Nitrogen chelation is a real possibility. Me N OH Me O Me Ph
14
Me2HC O Me
14
Me O O 84% Ph
Me O
14
Me O N
Me
Me
Li
Me2HC O
12
PhCH=CHCH2Br
CH2OH N 83% Ph
14
O I Me
Me Me diastereoselection 97:3
Me
D. A. Evans
Alkali Metal enolates:
R LDA or NaNTMS2 O R2 R O M N Me2CH O M N Me O O Ph
Chem 206
O O N N3 Bn O
JACS 1987,109, 6881. JACS 1990,112, 4012-4030
Enolate Amination
XC M=K M N Bn M = Li
CHMe2 SO2N3
Trisyl-N3 HOAc O O
O R N R1
diastereoselection 91-99+ %
O XC
O BocN=NBoc R N
(Trisyl-N3) CHMe2
Enolate Hydroxylation
O R N Me Na enolate is required. Why? O O Ph Imide (R) PhCH2CH2=CHCH2MeO2CCH2CH2CH2PhMe3CPhHC O NSO2Ph R OH Me Ratio 94 : 6 95 : 5 96 : 4 90 : 10 >99 : 1 Ph Yield * 86 % 91 % 68 % 77 % 94 %
Na-N(TMS)2
Enolate Acylation
O Me N Me2CH O O
LiNR2
O N
O O
X-ray structure
24-08-Enolate alk-6 11/9/03 9:06 PM
For all indicated rxns, as the R on the enolate grp increases in size enolate-El face selectivity increases. Explain.
D. A. Evans
Chiral Ester Enolates
Chem 206
Li N Me Me
(LiCHIPA) THF
Me
Me
Me
SO2Ph N O R H O Me
Me
LiCHIPA THF, HMPA 4:1
RO Me2HC
LDA toluene
O N Li O
THF
SO2Ph N Me
Me
Me
Me
CO2t-Bu N El O OMe B
O Me
H
H LiO Me (E)-enolate
El(+)
O Me Me LiO Me (Z)-enolate
H
El(+)
Rationalize the effect of HMPA on the stereochemical outcome of reaction. El(+) MeI Koga, JACS 1984, 106, 2718-2719 MeI Bn-Br Bn-Br addend THF Yield 63% 57% 48% 77%
Me
Me
SO2Ph N Me X O O
Me
Me
Me
H
SO2Ph N El X O O
Me
H
Me
Helmchen, Angew. Chem. Int.Ed. 1984, 23, 60-61 Helmchen,Tet. Lett. 1983, 24, 1235-1238 Helmchen,Tet. Lett. 1983, 24, 3213-3216 Me Me SO2Ph N O O Me Me Me Br
KO-t-Bu
Me
SO2PhH
Me Me O N
Rationalize the stereochemical outcome of reaction.
Me
H
N X O Me
H
H Me
D. A. Evans
O EtO n-C4H9 H O EtO n-C4H9 H
LiNR2 MeI
Chem 206
Ph
NH4Cl
Ph
OM OMe R
R-substituent R = Me diastereoselection 87:13 80:20 40:60
O OMe R
Me3Si
R = Et R = CHMe2
I. Fleming & Co-workers, Chem. Commun. 1985, 318. Y. Yamamoto & Co-workers, Chem. Commun. 1984, 904.
Ph
LiNR2
OBn
MeO
p. p.
RO2C H CO2Me
MeO
LiNR2
RO2C H H CO2Me
Me
OH
Br
95% yield
Me Bn N Boc R
O N OH
S S diastereoselection >95%
TBSOCH2
Me CH2
LiNR2 MeI
"one isomer" Me
H CO2Me
Me
Me
R PhMe2Si
OM OEt
R
MeI
O OEt Me
R = Me: diastereoselection 99:1 R = Ph: diastereoselection 97:3
PhMe2Si
I CO2Et R
OLi O-t-Bu
CO2Et
R = H: one isomer
KOt-Bu THF -78 C I. Fleming & Co-workers, Chem. Commun. 1984, 28.
D. A. Evans
Seminal Paper: Stork & Dowd, JACS, 1963, 85, 2178-2180 Reviews:
Metalloenamines-1
Representative Reactions:
Me Me
EtMgCl H3O+
Chem 206
Me
Martin in Comprehensive Organic Synthesis, 1991; Vol 2, Chapter 1.16, pp 475-502 Whitesell Synthesis, 1983, 517-535 Bregbreiter in Asymmetric Synthesis, 1983; Vol 2, Chapter 9, pp 243-273 Enders in Asymmetric Synthesis, 1984; Vol 3, Chapter 4, pp 275-339
N
conditions: base + R-X in refluxing THF
Me2CHI
Me Me
N
60% overall
O Me
Me Me 83% overall O Me H
R
El(+)
EtMgCl MeI
H3O+
H3O+
Me Me
60% overall
M
El(+)
N El anti product
Acidity Measurements: (Streitwiser, JOC 1991, 56, 1989; Fraser, ibid. 1985, 50, 3234):
Kinetic product geometry strongly favors the syn isomer (>99%) (Fraser)
N Me
MeI
O Bu
Geometry Rationalization:
Me
BnBr
Me
+ 1 equiv HMPA
D. A. Evans
Stereoelectronic Issues:
N Bn LDA Li N Bn H MeI Me3C H CMe3 CMe3 X Ratio, 97:3 Me Me3C Me H
Metalloenamines-2
Chiral Metalloenamines:
early papers: H full papers: X R2 O M N Me H Ratio 94:06 60:40 N H LDA Me3C MeI Me Me3C NC NNMe2 Ratio, 96:04 Me NNMe2 Meyers, J. Am. Chem. Soc 1981, 103, 3081 RX MeI EtI n-PrI H CN Bn
LDA El(+) H3O+
Chem 206
Meyers, J. Am. Chem. Soc 1976, 98, 3032 Whitesell, J. Org. Chem. 1978, 42, 377-378 Meyers, J. Org. Chem 1978, 43, 892 Meyers, J. Am. Chem. Soc 1981, 103, 3081 Meyers, J. Am. Chem. Soc 1981, 103, 3088 R2 O
Fraser, JACS 1978, 100, 7999 (handout) Tendency for axial-chair alkylation is significantly greater that for ketones H Me3C H X Me H Me3C H X X Me Me H Me3C X H Me H
R1
base
R1
El(+)
R El
LDA MeI
Major Product
O El
ee 87 94 99
CMe3
H Me
H Me NNMe2
N R CH2OMe
D. A. Evans, K. Scheidt
Chem 206
LI
LI
Me Li N N Me H Li N H
LI
LI
LI
D. A. Evans
Chiral Metallated Hydrazones
Me N N CH2OMe
LDA
Chem 206
O Li N N
RX
MeO N N R
THF deleted
Li
H N N Li O Me R
A (Enders)
Which of the reactive chelate conformations are we to begin our analysis from?
Li
For a review of this methodology see Enders, D. in Asymmetric Synthesis.; Morrison, J. D., Ed.; AP: New York, 1984; Vol. 3, p 275-339.
Enolate Acylation
D. A. Evans
H24-00-Cover page 11/10/03 8:03 AM
D. A. Evans
The Reaction:
Acylation R1 R2 OM Carboalkoxylation R1 R2
+
Chem 206
O X O X OR3 R1 R3 R1
O R3 R2
Deacylation: When an acyl residue is employed in the one of the illustrated bond constructions, it may then be removed by nucleophilic deacylation: Several examples are provided. Deformylation:
O Me CHO O
Me Me HCO3
O Me Me Me
O OR3 R2
Me Me
Situations where the reaction is employed: Acyl moiety is a constituent of the target structure:
O OH R1 R2 R1 R2 OR3 R1 O OR3 R1 O R2 O O OR3 R1 O
() +
competitive ring cleavage not a problem due to more electrophilic formyl C=O
Decarboxylation:
O X (+) OR3 O X
+
O CO2-t-Bu
RBr
O R CO2-t-Bu H
CF3CO2H
R2 O
OR3 R2
O O
CO2
Acyl moiety employed in assisting bond construction but not part of the target structure:
O R O R O H O
()
O H
+ RX (+)
Decarboxylation in this system is a sigmatropic rearrangement involving C=O participation representative procedure: Henderson, Synthesis 1983, 996
Me
Me
R CO2
H3O+ CO2
O R
Me
Me
Me
Me
CO2Me O
O O OR
O C O
HO
leading references JOC. 1991, 56, 5301-7 Tet Let. 1990, 31, 1401-4
Acylketene intermediate
D. A. Evans
Chem 206
O
RO
O OR
OR H O+ 3 R
CO2Me O
Keq ~ 10+4
CO2Me O
A
+ MeOH
Keq ~ 10-2
+ MeO
Strictly speaking, the Claisen and Dieckmann condensations are defined as condensations between ester enolates & ester electrophiles. In this discussion, we choose to liberalize the classifcation to include ketone enolates as well.
Me2CO3
B
CO2Me
O OR R R
+4
O OR + RO
2 R
Critical issue: Product enolate A is significantly destabilized by peri-interaction with aromatic ring disrupting the required planarity of the delocalized enolate. Hence, the greater stability of B dictates the product. MeO O H O O Keq >> 1
A
O OR R
+
CO2Me
O OR R pKa 12 R
CO2Et
HCO2Et KOtBu
CO2Et OH Me Me O
Meyers, JOC 1976, 41, 1976
Contrary to popular belief, final enolization step does not render the process irreversible
Reaction Control Elements: These reactions can be manipulated to give either kinetic or thermodynamic control:
CO2Me
LDA
Me
Me
HCO2Et
OH Me O Me Me O OH
JACS 1965, 87, 5728 Piers, Tet. Let 1968, 583
O NC
-78 C
O kinetic product
Me
O Me
MeO benzene
OMe
HCO2Et MeO benzene
NaH
O MeO
0 C
OMe
Thermodynamic product
Me
CO2Me
D. A. Evans
Chem 206
O R1 R2
O OMe
+ LiCN
R2
OMe CN 2
Enolate acylation with 1 is fast Intermediate 2 breaks down to product more slowly than the acylation step Under these conditions, proton transfer from product to enolate does not occur.
R1 O
slow
Consider this process in the broader context of elimination reactions of the E1cb classification where: O OMe R2 O CO2Me 84% O
+ LiCN
Y might be either C or some heteroatom X might be various leaving groups such as CN, OR etc. R X R Y H Data is available for the case where X = CN, OR & Y = carbanion: Stirling, Chem. Commun. 1975, 940-941 FG H
base base
R X
R Y
slow
R R Y
+ X
Examples: O
LDA
1 O Me O Me Me OTMS Me
Me-Li LDA
Me
Me O Me
CO2Me
65%
FG
slow +
FG
X
LDA
CO2Me
Mander Tet. Lett. 1983, 24, 5425
log
1 CMe3 O
R2Cu(CN)2Li2
Me3C H
O Me CO2Me 75%
+ isomer
7%
O 1 CO2Me
Above data makes the point that CN is a poor LG but it also leads one to the faulty conclusion that 2 should partition to acyl cyanide rather than methyl ester! O O CN R2
+ LiOMe
O R1
Li
O OMe CN 2 R1
O OMe R2
OTBS 82%
Hashimoto, Chem. Lett. 1989, 1063
R1
R2
LiCN
J. L. Leighton, D. A. Evans
Chem 206
OR MeO2C O O P(OMe)2
Acylating agents can be desiged where the tetrahedral intermediate exhibits exceptional stability:
O R N Me
Nu(-)
O R Nu
Li O Me N Me
H3O+
MeO2C O R
P(OMe)2
OMe O R' N Me
BrMg
OEt CbzHN Bn
O OEt
R'
OMe
OMe
O Me N N Me
R1M H3O+
O R1 N Me
R2M H3O+
O R1 R2
Nucleophiles: Acceptable
RLi, RMgX OLi RO DIBAL R LiN R LiAlH4 Li Ar Li(MgX) O
S
Unacceptable
RZnX & other colalent metal alkyls OLi CH2Li R other colalent metal enolates Weak hydride reagents: NaBH4
MeO
OMe
OMe
W. Wipple, H. Reich J. Org. Chem. 1991, 56, 2911-2.
O t-Bu
O O t-Bu 83%
O LiB(R)3H
THF, -78 C
O Me 47%
OMe An excellent review on all aspects of Weinreb amide chemistry: M. Sibi, Organic Preparations and Procedures Int., 1993, 25 (1), 15-40.
OMe
TBSO
O N OMe
DIBAl-H THF, -78 C
O Me
OMe Me
Me
Me
Me
95%
OMe OMe
OMe
TBSO
O H
Me OMe
OMe Me
Me
Me
J. L. Leighton, D. A. Evans
Chem 206
Me
OR O
7
OR
11
O Me
16
O
D
27
29
H O
F
35
17
21
O OR
Me
26 32
97%
OH
Me
Me
Me
Me
O Me OMe Me
Me OH
Me
C1-C16 Subunit
C17-C37 Subunit
Me
Et
Me TESO
20
Me
O N Me Me OMe
LDA
O
D
Me H O Me OMOP O
28
O
29
H O
F
PMBO Et
23
80%
Me Me O NMe2
X Me Me
21
OBn Me
Et
TESO
20
O
32
O
23 26
O
D
21
PMBO HF MeCN-H2O
Me H Me
5
MeHO
28 30
Me
F
35
80%
Me HO
H H
20 32
Et
Me Me O Me 33
H H H H
Me Me OH O
8
1
Me
OH
O Me
Me OH
O
H
Et
Me O
O
O O 25 Me
OH
Me Me O
The Solution:
OH
Me H
Me Li Me CH2 Me Me Me O MeN H Me Li O Me
Me H O Me OMOP N
29
PMBO Et
Et2O, -78 C
Me
Me
26
several steps
Et
Me Me
C20C21
MeO
NMe2
Me
20
HO
12
Me
MOP =
C OMe Me
H O Me N CH2 OMOP
Me OH O
7 12
Me
C
Me
21
Me
D
27
29
LDA, 0 C
H O
F
35
15
OH
Me
OH
OH OH
O O Me OH Me
83% C C 28 29
Me OH Me
30
Et OH
7
Me H
Me
Me O
OH
11
O
15
OH
O
D
21 27
MeHO
O
1
Me
Me
Me
Me
OH
O Me
Me O
35
Me OH
Et
D. H. Ripin, D. A. Evans
Chem 206
H N
O
()
The Problem:
H H N
O
()
H N
R 3P
R3P=S
H N
H N
N H
The Solution:
O O Me N H Me (CH2)2CO2Me
(+)
N S
O O Me H N O Me Me (CH2)2CO2Me N Me (CH2)2CO2Me N N H S X H N
O
()
??
H N O
Me Me (CH2)2CO2Me
R3 R N R R
O O Me H N O (+) Me Me (CH2)2CO2Me N Me R
N R
Key papers:
A. Eschenmoser Helv. Chim. Acta. 54, 710 (1971) A. Eschenmoser Angew. Chem., Int. Ed. Engl. 6, 866 (1967) A. Eschenmoser Angew. Chem., Int. Ed. Engl. 8, 343 (1969) Review: Trost Comp. Org. Synth. Vol. 2, Ch. 3.7 (1991)
S N R R Reagents R N R R
??
JOC 46, 3558 (1981), Synthesis 149 (1973) Bull. Chim. Soc. Belg. 87, 229 & 293 (1978) Indian J. Chem., Sect. B 14, 999, (1976) JACS 102, 2392 (1980) Chem. Ind. (London) 803 (1974) Thioamide ThioamideAngew. Chem. 79, 865 (1967)
Chem 206
ONa
CO2Et CO2Et
NaH/C6H6
CO2Et
Kinetic Control?
CO2Et
A
O CO2RCO2R
( )n ( )n
EtO2C
B1
CH2CO2Et
CO2Et CO2Et
Thermodynamic Control?
ONa
O CO2R
O CO2R
O CO2R
O CO2R
NaOEt/EtOH EtO2C
Not observed
CO2Et
Explanation:
excellent acceptable situation dependent high dilution required
B2
Enolization at (A) preferred on basis of inductive effects. Hence, Path A preferred in kinetically controlled situation Enolates (B1) and (B2) both more stable than enolate (A) Under equilibrating conditions (B1) appears to be preferred over (B2)
O OEt O EtO
O OEt
+ base-H
A variety of bases may be considered for the enolization step. Either alkoxide or a non-nucleophilic base such as NaH are commonly used. Choice of base can be important (Vide infra).
KOtBu / PhH
MeO
N CO2Et CO2Et
NaOEt / EtOH
CO2Et OH
Ring Closure:
O EtO
O CO2Et
MeO
N OH CO2Et
NaOEt EtOH
EtO
Statements claiming that the final enolization step renders the process irreversible are simply incorrect.
H24-07-Dieckmann-1 11/5/00 5:29 PM
Chem 206
t-BuO2C
N Bn CO2Bn
Me O O
Bn
N
2
H. Rapoport J. Org. Chem. 46, 3230 (1981) A. Eschenmoser Helv. Chim. Acta. 54, 710 (1971)
OMe Me
NaH CuBr
N H Me (CH2)2CO2Me N
This center readily epimerizes to a 2:1 mix of diaster. in favor of the shown.
N H
Br CO2Me
99%
Br
CO2Me
H O
Me
84% O
Me (CH2)2CO2Me O O O NH N Br S O Me R N
N2
S HN
N2
NaOH
S
ii
O N CO2t-Bu N CO2t-Bu
Ra-Ni, 68%
O CO2t-Bu
Rh(OAc)2
Me Me R3 N MeO2CCH2 Me MeO2CCH2
+ S
S. Danishefsky Tet. Lett. 30, 3625 (1989)
Me R2 Me R2 Me
O N CO2t-Bu
S N CO2t-Bu
H N
64%
R R S+ R R S-Ylids
Chem 206
CO2Et SEt
Me
8:1 mixture
CO2Et Me
TsHN J.L. Adams, J.Org.Chem. 1985, 50, 2730. X X Me CO2Et tBuOK / PhH Me
N O
O O CO2Et CO2Et Peterset, Recl.Trav.Chim.Pays-Bas 1977, 96, 219. X Me O O Me Me (TMS)2NLi THF, -78oC HO
O O Me Me
When X = NR2, this is a good reaction, but when X = OR, it is a poor reaction.
Cl
LDA -78 C
Chem 206
CO2Me
Me
R Li-TMP
Me
R NMe2 OH JACS, 1979, 101, 5060 Woodward, JACS, 1962, 84, 3222 O OH O OH OH CONH2 O
CO2Me
60-70%
CO2Me H
6-demethyl-6-deoxy-tetracycline
O CO2Bn
MeO2C O MeO2C
CO2Me
PhOCH2CONH
N O
N O
OH CO2tBu
Hatanaka, Tet. Let, 1983, 24, 4837 O CO2Me H HO C C OCOMe H Li-NTMS2 3 equiv H LiO C C C O H OLi HO O CO2Me OMe HO O
CO2Me
CO2Me
78%
HO
OH
D. A. Evans
Chem 206
Me O O
D
27
OR
7
OR
11
O Me
16
29
H
F
35
Li Me
26
NMe2
O
32
NMe2
O OH Me
17
21
O OR
Me
Me
Me
Me
O Me OMe Me O
C1-C16 Subunit
C17-C37 Subunit
Me H O
F
Et
Me OH
Me
TESO PMBO
20 23
O N Me OMe
LDA
O
D
Me H O Me O OMOP
28
O
29
Et
Me H NMe2
80% Me Me
X Me Me
21
OBn Me
Et
TESO
HF MeCN-H2O
O
32
O O O
D
21
PMBO 80% HO
H H
20
20 23 26
Me H Me
5
Me HO
28 30
Me O
35
Et Me
32
Me Me O Me
33
Me Me OH O
8
1
Me
OH
O Me O
Me OH
H H
O
H H
Et
Me
OH
O O
H
25
Me Me O
The Solution:
OH Me Me
Me H
O Me N MeO H O Me OMOP N
Me
29
PMBO
Me
Et
Me
26
several steps Et
C20C21
Me Me O Li MeN O Me H O Me N CH2 OMOP
NMe2
Me
20
HO
12
Me
Me
MOP =
C OMe Me
NMe2 O Me H O Et H OBn Me
Me
A
Me
C
Me
21
Me
D
27
OH
7
29
12
LDA, 0 C H
F
35
15
O OH
H Me
OH
OH OH
O Me OH MeO
83% C C 28 29 Me OH Me
30
Et
A
Me H
Me
Me H O Me O Me NH O OMOP NMe2
OH
7
OH
11
O
15
OH
O
D
21
Me HO
27
O OH
Me
Me
Me
Me
OH
O Me O
Me O
35
Me OH
CH2
OBn Me
Et
D. A. Evans
Chem 206
Me Me O Li O Et2NLi MeN
THF
Me Et OH O MeO Me Me
B C
O Li MeN O Me
Me
B
17
Me Me
B
O OH H Me Me
Me
Et
O Me OH Et
Et
Me N
Me Me
B
18
NMe2
Me
Et
18
Me N NMe2 Li
Ferensimycin B
N Me
11
Me O HO
Me
A
O H Me
O H O O Me OH Et Et OH
Et
Me N
Et NMe2 Me O
B
11 21
Et
Me
O OH H Me Me
18
O Mg Br
Et
Me
Et
21 Et O Me NH Et OH NMe2
Me
18
Me O Et
11
NaHSO4 H 2O
Me
B
18
Et Et OH OH Me O
B
11
Me
Et
O Me OH Et
OH
Me
Et
Me O
Me
Me
18
Me O
21
Me
B
18
Et
O Me OH Et
Et Me
11
OH
Et
O Me OH Et
21
Et
OH
Me The C-11 ketone must be protected during the C-18C-19 bond construction Me O
B
11
Me
18
Et Et O OH Me O
B PPTS MeOH
Et
()
Me
PPTS MeOH
Me
Me O Et Et Me Et H
B
Me
18
Me Me
18
N Me
RM
11
Et
O Li MeN O R
Me Me
B
17
Me
Et
Me O
Me O
Et Et
epi-C18 6
Me N
NMe2
Et
Me N
NMe2
carbonyl-protected intermediate
"Nature, it seems, is an organic chemist having some predilection for the aldol and related condensations."
"That Outpost of Empire, Australia Produces some Curious Mammalia The Kangaroo Rat The Blood-sucking Bat and Aurthur J. Birch, inter alia."
D. A. Evans
Chem 206
http://www.courses.fas.harvard.edu/~chem206/
Stereoselective Aldol Reactionsw in the Synthesis of Polyketide natural Products, I. Paterson et al. in Modern Carbonyl Chemistry, pp 249-297, J. Otera, Ed. Wiley VCH, 2000 (handout) Ager, D. J., I. Prakash, et al. (1997). Chiral oxazolidinones in asymmetric synthesis. Aldrichimica Acta 30(1): 3-12
Polyketide Biosynthesis Historical Perspective on the Aldol Reaction Aldol Diastereoselectivity Enolate Diastereoface Selectivity Absolute Control in the Aldol Process
Reading Assignment for this Week: Carey & Sundberg: Part A; Chapter 7 Carbanions & Other Nucleophilic Carbon Species Carey & Sundberg: Part B; Chapter 2 Reactions of Carbon Nucleophiles with Carbonyl Compounds
D. A. Evans
25-00-Cover Page 11/12/03 8:56 AM
Teruaki Mukaiyama
Chem Lett. 1973, 1011
BM
O X R1
BM
O X
BM(H+)
OH R2 R1 X R1 O TMS O H
R2
X R1
R2
M
O H R2 X
M
O O TMS
R2 R1
Clayton Heathcock
30-aldol Variants 11/12/03 9:34 AM
Satoru Masamune
D. A. Evans
Chem 206
"Nature, it seems, is an organic chemist having some predilection for the aldol and related condensations." J. W. Cornforth O
Me Me Et O Me Me MeO OH H R OH Me Me OH Me O O O Me R O H NMe2 OH Me
O Acylation CO2 R Me
O SR Reduction R
OH
O SR
Me
Erythromycin A, R = OH Erythromycin B, R = H
HO
O SR
OH Acylation CO2 R
O Reduction SR R
OH
OH
O SR
Retro-biosynthesis: Erythromycin A
O Me HO Me Et O Me Me MeO OH OH OH O OH OH O OH Me Me Me Me Me Me Me Et O Me O H O OH Me Me OH Me O O O Me Me Me H OH Me O H NMe2 OH Me erythronolide aglycon O Me HO Me Et O Me O Me H Me Me OH OH H O O OH Me Me OH Me OH OH Me
Me OH OH O OH
Me OH
Me O OH
Me
Me
Me
Me
Me
Me
Me
Me
O SR
Recent overview: Staunton, "Polyketide biosynthesis: a millennium review." Nat. Prod. Rep. 2001, 18, 380-416.
HO
D. A. Evans
Chem 206
OMe Me
OMe Me
OHMe O Me
Erythrolide B
Me
O Acylation SR O SR CO2 R Me
O SR Reduction R
OH
O SR HO2C Me
OMe OH
OH
OMe O
OMe
OMe O Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
O SR
OH
Bn N
OH R
CO2
Me
Me
Me
Me
Me
Me O
Me
Aldol
XC
Bn N O O
O N
O O
O Me
O Me
Me
See Lecture 23; page 23-08: with M. Ennis JACS 1984, 106, 1154.
D. A. Evans
General Reviews of the Aldol Literature:
Chem 206
DuBois 1965-67: Rough correlation between enolate stucture & product stereochemistry for alkali and alkaline earth enolates
O X Me (E) Enolate O X M Me H O R X Me O M H O R X Me O OH R X Me O OH R
Mukaiyama in Organic Reactions, 1982; Vol 28, pp 203-331 Evans in Topics in Stereochemistry, 1982; Vol 13, pp 1-115 Heathcock in Asymmetric Synthesis, 1984; Vol 3, pp 111-212 Comprehensive Organic Synthesis, 1991; Vol 2 Group I & II metal enolates: Heathcock; Chapter 1.6, pp 181 Group III metal enolates: Masamune; Chapter 1.7, pp 239 Transition metal enolates: Paterson; Chapter 1.9, pp 301
anti diastereomers OH R X O OH R
Control relative stereochemical relationships Zimmerman 1957: Proposed chair-like geometry for the Ivanov Reaction
OMgX H O H Ph
i-PrMgBr
(Z) Enolate
Me syn diastereomers
L X
OMgBr OMgBr Ph
MgBr O Ph
PhCHO H3O
+
Ph
OMgX Ph O H H O
MgBr O X
OH R2 Me
R2CHO
syn diastereomer
L X
OH R2
O Ph OH Ph
OH
O OH Ph
OH
O OH
R2CHO
Ph
ratio, 75:25
Ph
Zimmerman recognized that diastereoselection should be a function of the relative sizes of the substituents on the carbonyl component. He also speculated on the role that the metal center might play in controlling the process. The only flaw in the study was that he failed to determine whether the aldol adducts were stable to the reaction conditions.
Zimmerman, J. Am. Chem. Soc 1956, 79, 1920 (handout)
D. A. Evans
Why Boron?
To tighten up the transition state. Design TS where control can come exclusively from metal center X
R2CHO
Chem 206
BO MC 1.4-1.5 2.0-2.2
BC 1.5-1.6
Now that there are good methods for preparing (E) enolates, it appears that both enolate geometries are nearly equivalent. JACS. 1989, 111, 3441-3442.
Chx2BCl Et3N Et2O
OH R2 OBChx2
O
PhCHO
OH Ph
O X
BL2 Me H
Ph Me 95% anti O
PhCHO
X R2 O C Me H L B O
R2CHO
OH Ph
Ph Me 98% syn
disfavored syn:anti X = CMe3 M = Li M = MgBr M = BBu2 X = C 6H 5 X = Et M = Li M = BBu2 M = Li M = BBu2 M = Li M = AlEt2 M = BBu2 M = BBu2 M = BCy(thex) > 98 : 2 > 95 : 5 > 97 : 3 80 : 20 > 97 : 3 80 : 20 > 97 : 3 48 : 52 50 : 50
It appears that there is not a great difference in aldol diastereoselectivity Dissection of the Aldol Problem: Select for one product diastereomer
O X M O X Me M Me O H R X Me O X Me OH R X Me O X O X H O X El Me M Me Relevant stereochemical information could be included in either X or M El Me O O OH R X Me OH R O OH R
syn diastereomers
anti diastereomers
O (t)BuS
Evans et al. JACS 1979, 101, 6120-6123; JACS 1981, 103, 3099-3111 Masamune, Tet. Lett 1979, 1665, 2225, 2229, 3937
El(+)
D. A. Evans
Chem 206
R N O O
+ O
R O O N O
R R N O O O B
R H O Me O R R N O Me O N Me R O OH R O L O B L O
D. A. Evans
Imide Hydrolysis
Chem 206
Imides may suffer attack at either of the two C=O functions (eq 1, eq 2)
O R * El O O R * El N H Bn N O Bn R'O
OMe
Ti(OBn)4
O R * El OR' HN
N3 O
exocyclic
N O
O O
pKa 20
endocyclic
Product distribution a function of attacking nucleophile (Tet. Lett. 1987, 28, 6141)
Trans-thioesterification:
MeO Me OMe O N O O OTIPS Et Me O O H H O H H N O O OTBS
(Lepicidin Synthesis) J. Am. Chem. Soc 1993, 115, 4497-4513
Substrate
Me O N Me O O Bn
Substrate
Me O N Bn
Me Ph
Bn-SLi THF, 0 C
MeO Me
OMe O SBn
90-94%
PhH2C O OMe
OTIPS Et O
LiSEt THF, 25 C
OTES Bn
Me H O H H H
OBn NH
N3 O OH
BocHN O NH2
O 89% yield H
97%
RCOSR O MeO Me Bn
M. Bilodeau, unpublished results
O N
O O
LiO2H HOH/THF
O MeO Me
O OH HN Bn
O O
OH O
Me3Al
O N OMe O-Protect
Rmetal
OP R Me
O R
R Me
Me
for recent examples see, J. Am. Chem. Soc 1992, 114, 9434-9453
D. A. Evans
Chem 206
M = B, Ti
RL
OH R
Et BnOCH2CH2 Me2CH
RL RM Me
O RL
Examples:
OH R Me Me TBSO Me Me Me TBSO Me Me Me Me Me TBSO Me O Me TiCl4 EtNiPr2 Me2CHCHO Evans, JACS 1991, 113, 1047. O Me TiCl4 EtNiPr2 Me2CHCHO O Me TBSO Evans, JACS 1991, 113, 1047. TiCl4 EtNiPr2 Me2CHCHO O OH
BuMe2Si
Me
BuMe2Si
Diastereoselection = 96-98%
TBSO Me Me TBSO Me Me Me
OH Me Me Me OH Me
Me
Me
Me
D. A. Evans
M
Chem 206
Diastereoselection major : others Me 94:6 (90%)
Examples:
O Me R-CHO RL RM Me O R-CHO RL RM Me OH R Me Me Me OH R Me Me TBSO Me O Me TBSO O TBSO (Chx)2BCl Me Et3N iPrCHO O OH
RL RM O M
Me Me Me Me syn-anti diastereomer
Me
96:4 (75%)
L M L
O O
R C H RM R O C H RL
H O Me H RL H O Me H RM RL RM Me OH R RL RM Me OH
favored
O RL RM
M
RCHO
L M L
Me
disfavored
An analogous case:
O BnO (Chx)2BCl Et3N BnO RCHO O OH R Me Me BnO Me Me O OH R
OH R
Me
Me
disfavored ?
O RL Me Me RL Me
O M H
RL Me Me
diastereoselection 95:5 I. Patterson, J. M. Goodman, M. Isaka Tetrahedron Lett. 1989, 30, 7121-71 O O N Me Bn Me O O BnO Me Me O
C H
Me
favored ?
syn-anti diastereomer
D. A. Evans
Chem 206
Masamune, Sato, Kim, Wollmann J. Am. Chem. Soc. 1986, 108, 8279-8281.
Me R S O O B Me
HO
O SCEt3 Me
disfavored
HR Me H BR*2 R Me H S
O O Me R B
Me
HO
O SCEt3 Me
favored
Me
O SCEt3
Me
HO R
O SCEt3
Me Me B
+ RCHO
favored
D. A. Evans, D. H. Ripin
Masamune-Reetz Analogy:
R H O B R SCEt3 Me RCHO Me S R H O O B
Chem 206
R R
References:
CF3 (Corey) JACS. 1989,111, 5494 (Corey) JACS. 1990,112, 4977 (Corey) TL. 1991,32, 2857 (Corey) TL. 1993,34, 1737.
Phchex-
F3C
S O O
S O O Br
1
Does this reagent perform in accord with the Masamune-Reetz analogy? Note: The sulfonamide nitrogens are pseudo-tetrahedral
Enolization:
Either enolate geometry possible with proper choice of base, solvent, and substrate. O
t
(R) PhMe2CHMeCH2-
% ee Yield 97 95 >98 86 % 91 % 68 %
B * R2
BuO
Me B * R2 Me
O PhS Me
A mechanistic proposal for enolization control is presented in paper (Corey) JACS. 1989,111, 5494
% ee Yield 91 83 84 % 82 %
D. A. Evans
M Me RO O M Me RO
Chem 206
OH R Me OH R
Complimentary aldol reactions may be obtained by changing metal as well as enolate geometry
TiCl4 i-Pr2NEt RCHO O Xq Me Me O OH R
Reference Rxn
RL
syn-syn
OH R
Chelate-Organized RL Variant
O Xq Me
Me
Nonchelate Reaction
O Me
t
anti-syn
OH R
OH Me
O Xq Me
BuMe2SiO
BuMe2SiO
Me
Me
Me
anti-anti
Masamune, JACS 1981, 103, 1566 (boron enolate) Evans, JACS 1991, 113, 1047 (titanium enolate) O Me Me3SiO
LDA
Diastereoselection: 99:1
JACS, 1990, 112, 866; Tetrahedron, 1992, 48, 2127-2142. chiral reagent needed
LDA PhCHO
OH Ph
O BnO Me O BnO Me Me
OH R
Me3SiO
anti-syn
OH R
Diastereoselection: 90:10
Me O Li RL O R O H H Ph
Me O
syn-syn
OH R
BnO Me Me
Tetrahedron Lett. 1988, 29, 585-588 Tetrahedron Lett. 1989, 30, 7121-7124 Tetrahedron Lett. 1992, 33, 4233-4236
anti-anti
D. A. Evans
Chem 206
http://www.courses.fas.harvard.edu/~chem206/
Lithium Diisopropylamide-Mediated Lithiations of Imines: Insights into highly Structure -Dependent Rates and Selectivities. D. Colum, JACS 2003, 125, ASAP (handout) W. R. Roush, J. Org. Chem. 1991, 56, 4151-4157. (handout)
(E) & (Z) Enolates: Felkin Selectivity Double Stereodifferentiating Aldol Reactions The Mukaiyama Aldol Reaction Variant Allylmetal Nucleophiles as Enolate Synthons
Reading Assignment for this Week: Carey & Sundberg: Part A; Chapter 7 Carbanions & Other Nucleophilic Carbon Species Carey & Sundberg: Part B; Chapter 2 Reactions of Carbon Nucleophiles with Carbonyl Compounds
D. A. Evans
26-00-Cover Page 11/17/03 8:40 AM
D. A. Evans
Chem 206
The Non-Reinforcing syn- RCHO is the most Interesting Dependence of the Selectivity of Felkin-controlled Reactions on Nu Size
+ + H Me R Me Me O OH RL H O OP R
i
RL O C O
H
OH
OP
i
R + + R MLn
Pr
Pr R Me
Pr
Felkin
O OH RL Me Me
Me 19 P = PMB 6 P = TBS
21 anti-Felkin/1,3-anti
P = PMB R 20 : 21 96 : 04 56 : 44 17 : 83
P = TBS 20 : 21 94 : 06 75 : 25 40 : 60
Disfavored
Anti-Felkin
The illustrated syn-pentane interaction disfavors the anti-Felkin pathway. Evans, Nelson, Taber, Topics in Stereochemistry 1982, 13, 1-115. W. R. Roush, J. Org. Chem. 1991, 56, 4151-4157.
t-Bu i-Pr Me
OB(Chx)2 Me H Me Me
OH
OR Me
Ha H
C R
Nu:
Me OM
O R Me Nu Lewis acid Nu
OH R Me Felkin Selecton
Me
Me
Me
Me
Felkin
Ha H PO
C C R
Hb OM H
OB(Chx)2 H Me
O H
major : minors centers non-reinforcing R = TBS (79% yield) 94 : 6 R = PMB 74 : 26 (82% yield)
Me
Me Me
stereocenters reinforcing
non-reinforcing
Achiral (E) enolates preferentially add to the Felkin diastereoface High anti:syn diastereoselectivity ( 97 : 3) is observed in all cases
Evans etal. JACS 1995, 117, 9073
D. A. Evans
Chem 206
Disfavored L nM O R MLn Me H Me O RL
RL O C O
H
OH
OH
OTBS Me R
OH
OTBS Me
Me
Me
Felkin
O R MLn OH
H Me Me H
TMSO Me Me O PhS
Favored
Anti-Felkin
O R
O iPr
TiCln Me H
OPMB iPr Me
Felkin
(R")
O OCH2OBn Et Me O OCH2OBn CHMe2 Me
TiCln Me H
OPMB iPr Me
D. A. Evans
Chem 206
O H Me Me
OH
O Me Me Me
OH
Me
Me
Me
Me
Me
Me
Me
Product Stereochemistry
Me
The Issue:
Can one reliably take the diastereoselectivites of the individual reaction partners and use this information in the illustrated extrapolation:
OH
Me
G (rxn)
Me
Me
Me
Nu
Me O
G (aldehyde)
El
Me
G (enolate)
G (Rxn) ~ G (enolate) + G (RCHO) log [Product ratio] ~ log [enolate ratio] + log [aldehyde ratio] [Product ratio] ~ [enolate prod ratio] x [aldehyde prod ratio]
The extrapolation:
OM Me Me H Me O
OH
Hence, for the case at hand: [Product ratio] ~ [10] x [10] ~ 100
Mismatched reactant pair: Stereo-induction from partners nonreinforcing
OM Me O H
G (rxn) = ?
Me
Me
Me
OH
Me
Me
G (rxn)
Me
Me
Me
D. A. Evans
Chem 206
Me Me
diastereoselection 96 : 4
OPMB Me Me Me
diastereoselection 94 : 6
TBSO Me Me Me Me O (c-hex)2BCl, Et3N R-CHO Me TBSO O OH
M = TiCl4
diastereoselection: anti : others R = TBS: >99 : 1 (85% yield) R = PMB: >99 : 1 (84% yield) (E)-Boron Enolates: The mismatched cases
TBSO Me Me O H Me Me OR Me Me Me O BR2 TBSO R Me Me Me O OH OR R TBSO R Me Me Me H O OH OR R Me
R = TBS: 87 : 13 (76%)
diastereoselection 62 : 38 (87%)
"Double Stereodifferentiating Aldol Reactions. The Documentation of "Partially Matched" Aldol Bond Constructions". Evans, D. A.; Dart, M. J.; Duffy, J. L.; Rieger, D. L. JACS 1995, 117, 9073-9074.
D. A. Evans
Chem 206
Given a polyprpionate chain of alternating Me & OH substitutents, select a disconnection point sectioning the fragments into subunits of comparable complexity by adding C=O as illustrated. OR R Me Me Me Me Me Me T1A OH O OR OR R
RO R Me
OH
OH
Me
Me
Me
Me
Me
OMe
Me OMe Me OH OH
9 11
OR R Me T1B OR R Me Me OR Me
OR
OH ' Me aldol
OR ' Me R O
3
Me
Me
Me
Me
OMe OH
5 7
OH
9
O
11
O H HO
1
O
3
OMe OH
5 7
Focusing on the =O FG, there are 2 1st-order aldol disconnections highlighted. Let's proceed forward with T1B. Carry out the dissconnection to subunits 2K and 2A.
O H Me
Me R
Me
Me
Me
Me
Me
Me
Me
Me
Me
C1C11 Assemblage
O Me
7
O Sn(OTf)2 Et3N O H
9
O
7
OH
9
For substituted enolate and enolsilane-based processes, there are at least three identifiable stereochemical determinants that influence reaction diastereoselectivity (eq 1). Two of these determinants are associated with the local chirality of the individual reaction partners. For example, enolate (enolsilane) chirality influences the absolute stereochemistry of the forming methyl-bearing stereocenter, and in a similar fashion, aldehyde chirality controls the absolute stereochemical outcome of the incipient hydroxyl-bearing stereocenter. The third determinant, the pericyclic transition state, imposes a relative stereochemical relationship between the developing stereocenters. This important control element is present in the aldol reactions of metal enolates (M = BR2, TiX3, Li, etc.), but is absent in the Lewis acid catalyzed (Mukaiyama) enolsilanes aldol variants that proceed via open transition states. O R1 Me M Me H O
' R2
XP
Me Bn A
Me
Me
Me
(85%) Diastereoselection 95 : 5 Me
Me Me O
5
Me O
9
Me O
9
Me
Me
Me
Me
Me
Me
86% Me Me O
9
O R1 Me M = BR2
OH
' R2
(1) O
O N
O
1
O
3
Me
Me
Me
Me Sn(OTf)2 Et3N XP
O
1
OH
5
Stereochemical Determinants enolate facial bias aldehyde facial bias pericyclic transition state
M = SiR3
Me Bn A
Me
Me
Me
Me
Me
Anti-Felkin Adduct Diastereoselection >95 : 5 (86%) The Sn(OTf)2 aldol reaction of A: seethis lecture + JACS, 1990, 112, 866
D. A. Evans
Chem 206
OB(c-Hex)2 Et Me Me -78 C Et O OH TBSO O Me Me O
Me H O H
14
Me TBSO O O
Diastereoselection 97:3
OH Me
Background
OB(Chx)2 iPr Me O Me O TESO O H
TESO
OH
OR iPr
HO OH
Me OR
Evans, Trotter, Coleman, Ct, Dias, Rajapakse, Tetrahedron 1999, 55, 8671-8726. MeO O TrO O H Me H Me
BR2
OH
R = PMB iPr Me
69:31
iPr
H O M OTBS
?
O
Aldol O Reaction Me Me
H Me OTBS Me O H OH O
TESO
MeO O TrO
O TrO
H O B(cHex)2 OTBS
H OTBS
TESO O H
H Me Me Me O H OH O TESO O H
TESO
OTBS
The stereochemical determinants from each fragment were evaluated Model Studies
MeO O TrO O H Me H pentane, -78 C O TrO B(c-Hex)
2
OTBS
O MeO O
Me O Me MeO O O H Me Me Me OH TrO
H OTBS
H OTBS
H O OTBS
OTBS
D. A. Evans
Chem 206
Bafilomycin A1
HO
Me Me
tBu O O Si
tBu O Me
Me
OMe Me
Required: Syn aldol addition Aldehyde Fragment: Target contains syn aldol retron wilth anti-Felkin relationship at 1 & 2 Enolate Fragment: Can the needed enolate facial bias be built into the reaction??
Me
Me
Me
OMe Me 60%
Enolization Conditions: PhBCl2, i-Pr2NEt, CH2Cl2, -78 C. Me Me OMe O Me O O Me2CHCHO Me Me OTBSOTES Me Me Me Me tBu O Me2CHCHO Me Me Me diastereoselection >99:1 Me O Si tBu O Me Me Me OMe Me OH Me HO Me O Me OMe O OH O Me OMe Me Me Me OH
diastereoselection >95:5
OTBSOTES Me Me
TMSO
tBu OH O O Si
tBu O Me
diastereoselection 62:38 9
Me
Me
Me
Bafilomycin A1
D. A. Evans
Chem 206
R. Mahrwald, Diatereoselection in Lewis Acid Mediated Aldol Additions, Chem. Rev. 1999, 99, 1095-1120 S. G. Nelson, Catalyzed enantioselective aldol additions of latent enolate equivalents Tetrahedron: Asymmetry 1998, 9, 357-389. Mukaiyama Aldol Reaction, E. Carreira In Comprehensive Asymmetric Catalysis, Jacobsen, E. N.; Pfaltz, A.; and Yamamoto, H. Editors; Springer Verlag: Heidelberg, 1999; Vol III, 998-1059.
BM
O X R1
HBM
O X
slow
OH R2 R1
Reaction Mechanism: "Closed" versus "Open" Transition States The Mukaiyama aldol reaction proceeds through an "open" transition state. The two illustrated competing TS orientations do not differ significantly in energy. For most reactions in this family there is not a good understanding of reactans-pair orientation. There is a prevalent view that the anti-periplanar TS is favored on the basis of electrostatic effects.
X O H X R1 TMSX R2 H C Me R2 O O L M R L H R O C C M R TMSO R2 OTMS R O M C C H R R R2
Catalytic Version: Slow step in the catalytic variant is protonation of the intermediate metal aldolate
M
O H R2 X
M
O
slow
O TMS R2 R1
anti-periplanar TS "Open"
synclinal TS "Open"
Other events are also taking place: Carreira Tet. Lett 1994, 35, 4323
D. A. Evans
Chem 206
Denmark has designed a nice substrate to distinguish between synclinal and anntiperiplanat transition states: Denmark, J. Org. Chem. 1994, 59, 707-709
OTMS Ph Me
synclinal
TMS
56:44
OTMS Ph R Me O OTMS Ph
S
Me MX H O HO
56:44
OTMS Me3C O Me BF3OEt2 PhCHO OTMS Ph O H H Me3C C C M Me Ph OTMS
antiperiplanar
AP
>95:5
D. A. Evans
Chem 206
OTMS Me Me iPrCHO
TBSO R Me
OH R Me
TBSO R Me
OH R Me
OTBS
BF3OEt2
O R Me
OH
OTBS R
Me
OTMS
Me
Me
favored
O C RL TMS C H C
Me Me 95 : 5 (80%) Enolsilane Face Selectivity 90 : 10 A(1-3) control is good for the (E) enolsilane
Me
H Me
O H Me OTMS Me Me O H Me Me
OTBS
BF3OEt2
O R Me R = iPr
OH
OTBS R R
OH
OTBS R
Me
Me H
TBSO R Me
OH
OTBS R
Me
Me
R = iPr OTBS R
BF3OEt2
O R Me
OH
OTBS R R
OH
OTBS R O H
Me 91 : 9 (75%)
Me
Me
Felkin : anti-Felkin 87 : 13
D. A. Evans, D. M. Barnes
Chem 206
W. Roush, J. Am. Chem. Soc. 1985, 107, 8186-8190. Tetrahedron Lett. 1988, 29, 5579-5582.
BnN O
OH Chex
Me
Me Ms N B O OH
EtCHO
Me
Chex OH
D. A. Evans, D. M. Barnes
Chem 206
OH Me O H Me Me Me
76%
Me 96:4 97% ee Me
C OH Ph O Me H2C C CHB(OH)2 HO B Ph O
CH2 Me Me Ph O O B OH
OH
96:4 Me 93% ee
H 2C C
Me
S. Masamune, J. Org. Chem. 1987, 52, 4831-4832. H. Yamamoto, J. Am. Chem. Soc. 1982, 104, 7667-7669 Tetrahedron Lett. 1986, 27, 1175-1178.
HO Me OH
OH Me > 99% ee
Me B
Me
H. C. Brown, J. Am. Chem. Soc. 1983, 105, 2092-2093. J. Org. Chem. 1991, 56, 401-404. J. Org. Chem. 1992, 57, 6614.
Ts OH 98% ee R Me B R2 Me R1
CH3CHO
OH Me R1 = H, R2 = Me: ee = 90% R2 R1
R1 = Me, R2 = H: ee = 90% R1 = H, R2 = OMe: ee = 90%
Ts
H. C. Brown, J. Am. Chem. Soc. 1988, 110, 1535-1538. See also: Tetrahedron Lett. 1990, 31, 455-458.
Ts
Me B H
1) THF, RT 2) CH3CHO
H OH
OH Me ee = 94%
H N 3) 2
D. A. Evans, D. M. Barnes
Chem 206
The Allylboron Reagents Add to Carbonyl Compounds via a Zimmerman-Traxler Transition State
Masamune, Sato, Kim, Wollmann J. Org. Chem. 1987, 52, 4831 Me Me B + RCHO Me H H Me R H H R Me H H Me O B Me O B Me HO Me HO R Me anti:syn, 96:4 HO R Me
PhCHO
95% ee
favored
favored
R Me enantioselection: 95-97%
disfavored
HO R Me Chex O Chex
O B Me Me
OH
PhCHO
Me Me
Ph
OH Me ee = 85 - 94%
R. Hoffman, Chem. Ber. 1986, 119, 2013-2024. Chem. Ber. 1988, 121, 1501-1507. ACIEE, 1986, 25, 1028-1030.
R*O Ti R*O Me Me
R*OH =
R = alkyl, aryl
O O H HO O H O O Me Me Ph R H O O
Me
Me Me Me Ph
Chex H O Me H O B Me O Chex
B H O Cl
M. Riediker, R. Duthaler, ACIEE, 1989, 28, 494-495. In Organic Synthesis via Organometallics, 1991, 285-309. J. Am. Chem. Soc. 1992, 114, 2321-2336. Duthaler Chem. Rev. 1992, 92, 807
D. A. Evans, D. M. Barnes
Chem 206
+ BH3-THF
BLn*
O O
OH
OiPr Ti OiPr
1
Me Me Me SiMe3 E/Z = 61/39
H. Yamamoto, Synlett 1991, 561-562.
OH Ph OH OH
Ti(OiPr)4, 4 sieves CF3COOH or TfOH
+ PhCHO
20 mol % BLn*
O O
O Ti O
2
OH R
R Catalyst 1 2 1 2 Yield (%) 88 98 66 95 42 78 ee (%) 95 92 94 92 89 77
SnBu3
O SnBu3 O
Ti
Ph Chex
+ n-C7H15CHO
O H
1 2
Many Other Metals Have Been Employed in the Allylation Reaction ...
Pb: S. Torii, Chem. Lett. 1986, 1461-1462. Mo: J. Faller, Tetrahedron Lett. 1991, 32, 1271-1274. Cr: Y. Kishi, Tetrahedron Lett. 1982, 23, 2343-2346. P. Knochel, J. Org. Chem. 1992, 57, 6384-6386. Sb: Y. Butsugan, Tetrahedron Lett. 1987, 28, 3707-3708. Mn: T. Hiyama, Organometallics, 1982, 1, 1249-1251. Zn: T. Shono, Chem. Lett. 1990, 449-452. Ba: H. Yamamoto, J. Am. Chem. Soc. 1991, 113, 8955-8956.
Handout 26A
EWG
+
R R'
cat. base
R R'
EWG
EWG
J. Janey
J. Janey
Chem 206
X R R'
cat. base
R R'
EWG
p. p. Leading References: Langer, P. Angew. Chem. Int. Ed. Engl. 2000, 39, 3049-3052. Ciganek, E. Org. React. 1997, 51, 201-350. Basavaiah, D.; et. al. Tetrahedron, 1996, 52, 8001-8062. Drewes, S. E.; Roos, G. H. P. Tetrahedron, 1988, 44, 4653-4670.
CO2Et +
MeCHO
5% DABCO 25 C, 7d
OH Me CO2Et
Me
Me
OH CO2H
HO2C
94% yield
Me
EWG
cat. base
R2 XH R1 EWG CO2Me
+
RCHO
OH R CO2Me
R = alkyl or aromatic
94% yield
All reactions run neat in a sealed tube with 1.5-2 equivalents of acrylate. Hoffmann, H. M. R.; Rabe, J. Angew. Chem. Int. Ed. Engl. 1983, 22, 795-797.
OH
cat. bases:
N N DABCO N quinuclidine
n-Bu3P:
3-hydroxyquinuclidine (3-QDL)
J. Janey
Chem 206
O H O
1 eq DABCO CH2Cl2, r.t., 2.5 h
+ N
Cl
O
X-ray 81% yield
EWG
O H
+
O Cl
R 3N +
Or...
OH O H OH
+
Drewes: "...the counter ion was chloride (presumably originating from the dichloromethane...)."
p. p.
O
1 eq DABCO
E2 elimination... R' O
R'CHO
:B H H H O
OMe
+ N
H H
Cl
EWG EWG NR3 NR3 + + initially formed eliminates E1cB is also possible
PhCHO
1.0 eq
OH Ph
O OR
rate = Kobs[aldehyde][alkene][amine] pseudo-second order if [amine]constant addition to aldehyde is r.d.s. because the dipole is increased by further charge seperation acrylonitrile and methyl acrylate studied enolate geometry not considered ethereal solvent inhibits reaction whereas alcohols (especially diols) accelerate reaction huge volume of activation: V of -79 cm3 mol-1 (the Diels-Alder is -35 cm3 mol-1) found by plotting lnkobs vs. P. 5000 bar increases rate by 1.1 x 106 Reaction is reversible (i.e. a Grob type fragmentation), thus mechanism could be ternary, with no discrete enolate intermediate (supported by V and temperature effects).
1.3 eq R Me Et Bn n-C10H21 t-Bu 2-adamantyl CH2CH2F CH2CH2Br CH2CF3 CH2CH2OMe CH2CH2NMe2 (CH2)6Cl
time (days) yield (%) 6 89 7 79 For aryl substituted benzyl ethers, no clear 2 88 relation between values and reactivity was 14 75 observed. 65 65 62 40 Trends hold for furfural. 3 81 2 NR The products undergo retro Baylis-Hillman, i.e. the reaction is reversible. 15 h 58 4 89 8 82 15 NR Caubere, P.; et. al. Tetrahedron 1992, 48, 6371-6384.
J. Janey
Chem 206
Reaction is accelerated for a wide variety of aldehydes when conducted at 0 C Temperature effect not seen with acrylonitrile (cannot form enolate) Author concludes that one enolate must react faster than another (i.e. a kinetic versus a thermodynamic enolate).
OH N
>
N N
>
>>
+ NR3 O
R 3N +
CO2Me OMe
+ R 3N
O OMe
Z
NMe2 NMe2
>>
OAc N
or
N O N 3-Quinuclidone 6.9
Proton sponge 12.0 (7.50)
N
DBU (~12)
3-Acetoxyquinuclidine
p. p.
Sterics also important: Me2NH > Me2NEt > MeNEt2 > NEt3 10.75 (9.00) Many, many phosphines screened...the winner: n-Bu3P ~9 n-Bu3P is only a slightly better catalyst than DABCO. E + NR3 O +
Enolate Geometry
O OMe
...or could accelerate protonation of intermediate, as any alcohol additive will accelerate reaction R 3N
OMe
O OMe
+ R3N
+ R 3N
O OMe
Z Kinetic
O H P P
unreactive
O OR
Temperature Effects
*
CO2Me
0.1 mol% DABCO
*
MeO
4 eHOMO + NR3 better conjugation into *
OH Me CO2Me
MeCHO
2M in dioxane 74% yield
+ NR3
MeO
25 C 1 week 0 C 8 hours!
J. Janey
Chem 206
Lewis Acid Catalysis
1 eq DABCO
OH Ph CO2t-Bu
CO2Me
1.2 eq
5% DABCO
PhCHO
MeCN, r.t., 1 d 5 mol% ligand, 5 mol% metal
PhCHO
Et2O, 0 C, 20 h 1.0 eq yield (%) trace 12 40 63 72 (81)a 25 12 trace ClO4
LiClO4 (mol%) 0 5 10 50 70
Relative Reaction Rates ligand none + R3N (+)BINOL (+)diethyl tartrate (+)diisopropyl tartrate (+)TMTDA (+)hydrobenzoin (+)triphenylethanediol (+)TADDOL ethylene glycol triethanolamine salen box N-methylephedrine Sc(OTf)3 3.3 9.4 5.2 3.5 4.1 3.5 3.2 2.9 3.3 4.65 2.31 3.6 2.87 5.8 3.2 4.4 6.3 5.2 10.8 4.0 Yb(OTf)3 3.6 14.4 9.7 9.5 8.0 16.2 5.2 4.5 Eu(OTf)3 3.5 12.8 5.5 4.6 3.6 5.8 2.2 3.8 La(OTf)3 4.7 14.6 7.3 8.1 4.0 5.3 5.9 4.7
O Li OMe
p. p.
Stablize enolate?
Ether was found to be optimal from solvent screening. General for a variety of alkenes and aldehydes. Kobayashi, S.; Kawamura, M. Tetrahedron Lett. 1999, 40, 1539-1542.
no enantioselectivity observed DABCO loading dropped to <10 mol% with (+)-BINOL rac -BINOL showed no rate acceleration Aggarwal, V. K.; et. al. Chem. Commun. 1996, 2713-2714. Aggarwal, V. K.; et. al. J. Org. Chem. 1998, 63, 7183-7189.
J. Janey
Chem 206
H R' MeO
+ H NR 3 O H H
+ R 3N
H H
O
+ R 3N
H R'
O
H R' OMe
H H OMe
Assumptions: E enolate formed
MeO
H H
+ O H NR3
H R' CO2Me
H R'
+ O H NR3
+ R 3N
H H
+ R 3N
H R'
H H CO2Me
R' CO2Me
H CO2Me
p. p.
+ R 3N
H OH
+ R3N
OH H
HO H
H + NR3 H CO2Me
H HO
H + NR3 H CO2Me
MeO2C
H R'
MeO2C
H R'
R'
R'
OH CO2Me
J. Janey
Chem 206
CN
+
OH PhCHO
1 eq E/Z ratio 1.2 : 1 1.4 : 1 1.5 : 1 3.1 : 1 4:1 Base DABCO 3-QDL NEt3 E E/Z ratio 1:1 2:1 4:1 r.t.
OH CN Me
+
Ph
Ph Me
Z
CN
Me
1 eq Solvent neat THF CHCl3 CH3CN MeOH
p. p.
E and Z crotononitrile is easily isomerized under the reaction conditions. Products did not undergo retro-Baylis-Hillman. Rozendaal, E. L. M.; Voss, B. M. W.; Scheeren, H. W. Tetrahedron 1993, 49, 6931-6936.
J. Janey
Chem 206
H R' MeO
+ Me NR 3 O H H
+ Me NR 3 O H H R' H
+ H NR 3 O H Me R' H
Assumptions: E enolate formed E2 favored over E1 pathway, only after rotation of ammonium to anti conformation -NR3+ is orthogonal to face (stereoelectronics) only one face of enolate considered, thus there are an additional 4 stereoisomers possible starting geometry of methylcrotonate and in situ isomerization not considered retro-Baylis-Hillman not considered
MeO
MeO
+ H NR O 3 H Me H R' CO2Me
+ Me NR O 3 H H R' H CO2Me + R 3N
+ H NR O 3 H Me R' H CO2Me + R 3N
p. p.
+ R 3N
OH H
Me OH H
Me H OH
H OH
MeO2C
Me R' H
MeO2C
H R' H
MeO2C
H R' H
MeO2C
Me R' H
H MeO2C
Me OH H
Me MeO2C
OH H
Me MeO2C
H OH
H MeO2C
Me H OH
NR3 R' +
NR3 R' +
NR3 R' +
NR3 R' +
OH CO2Me Me R'
OH CO2Me Me R'
OH CO2Me Me
J. Janey
Chem 206
O
RCHO, 10% DABCO CH2Cl2, 0 C, 12 h
R = Et MeOH, CSA
R1 R2 OH
anti R2 Me Me Me Ph Conditions DABCO, 4 d 3-QDL, 1.5 d DABCO, 6 d DABCO, 10 d 3-QDL, 60 d DABCO, 55 d DABCO, 7 d DABCO, 3.5 d DABCO, 11 d yield (%) 55 60 42 42 30 62 80 28 43
R1 CO2Me
+
O R O R
R2 OH
syn
CO2Me
anti:syn 70:30 72:28 70:30 37:63 35:65 69:31 26:74 46:54 89:11
MeO2C OH
Me
Rh(I), H2 (85%)
n-Pr -OC(Me)2OCH2Me Me
p. p.
Me MeO2C OH Me
NHCO2t-Bu N-Phthalimidyl
-N(CO2t-Bu)C(Me)2OCH2-
Leahy, J. W.; et. al. J. Am. Chem Soc. 1997, 119, 4317-4318.
Varying the amount of catalyst only affects the rate, not selectivity.
N S O O
H H
XcN
t-BuO2C N Me
Ciganek, E. Org. React. 1997, 51, 217-218.
N S O O O
O H syn selective H
O O R O R R O
O
+ NR3
XcN O
O
+ NR3
O XcN R3 N +
O R
R R
J. Janey
Chem 206
OH CO2Me
10 mol% cat. neat, r.t. 9-94 h
CHO +
CO2Me N
18-83% yield 2-19% ee
R Cr(CO)3
H +
CO2Me
excess
OH R H Cr(CO)3
time (h) 93 6 7 58 93 8
1
h, air CH3CN yield (%) 87 89 92 90 85 97 dr >98:2 >98:2 92:8 84:16 >98:2 >98:2
R R'O P Ph R'O R
p. p.
dr determined by 200 MHz H NMR N-Tosyl arylimine chromium complex also reacts Kundig, P. E.; et. al. Tetrahedron Lett. 1993, 34, 7049-7052.
CO2R2
OH
20 mol% (S)-BINAP CHCl3, r.t. 3-14 d
N R1 N
CO2R2
R1
2.4 eq R1 H H H Me Me
a
R2 i-Pr Et Me Me Me
time (d) 4 3 4 14 3
OH CO2Et
75% yield (40% isolated) 14% ee
(-)-CAMP =
P Me OMe 62% ee
other phosphines screened gave ~racemic products: DIOP, NORPHOS, BPPFOH, and MOP Soai, K.; et. al. Chem. Commun. 1998, 1271-1272.
J. Janey
Chem 206
MeCHO
OH Me CN
0-81% yield 3-17% ee
H H
N H O
H H
H O
(-)-quinine, (1R,2S) N-methylephedrine, S-(-)-nicotine, S-(-)-N-methylprolinol screened (-)-menthyl acrylate ester gave 100% de with aromatic aldehydes and DABCO under high P Isaacs, N. S.; et. al. Tetrahedron: Asymm. 1991, 2, 969-972.
MeO
O H
N+ R O H
Me
MeO
O H
N+ H O R
Me
O Me
+ RCHO
OH R
O Me R
OH
O Me R
OH
O Me
p. p.
R n-Pr i-Pr c-hex
minor
major
n-C9H19 10 kbar
C hydrogens control face of the aldehyde bulky R should enhance selectivity, a trend that they say is "...clearly visible." H-bonding plays a "clear role" as O-acyl quinidine gives no enantioselectivity
Alternative:
N H H
3-QDL, quinine, cinchonine, cinchonidine, O-acetyl quinidine, N-methylprolinol, N-methylephedrine also screened ee is highly pressure dependent, optimized pressure is shown in table Marko, I. E.; Giles, P. R.; Hindley, N. J. Tetrahedron 1997, 53, 1015-1024.
major
H MeO H
O
O
N+ H H R H
Me
J. Janey
Chem 206
OH Ar
O Me
O
15 mol% cat.
Me
Me
O2N
O2N
yield (%) 45 23 33 60 67 66 9 68 63 ee (%) 47 34 19 35 16 42 11 15 21 Author's model:
time (h) 12 12 28 16 28 16 24 17 24
O2N H N
N N H
H OR OR
cat. =
H HO
p. p.
racemic alcohol product can be easily resolved by kinetic resolution with Sharpless asymmetric epoxidation other chiral DABCO's made, but not tested...
O H Ph N H H N Ph Me R
+ N
H N N H Ph Ph H N H Ph N Ph O
+ Na
O H NO2 Me
O O R
+ N
+ Na
O H NO2
favored
disfavored
Barrett, A. G. M.; et. al. Chem. Commun. 1998, 2533-2534. Hirama, M.; et. al. Tetrahedron: Asymm. 1995, 6, 1241-1244.
J. Janey
Chem 206
OH Ar
O Me
O
15 mol% cat.
Me
Me
O2N
O2N
yield (%) 45 23 33 60 67 66 9 68 63 ee (%) 47 34 19 35 16 42 11 15 21 Author's model:
time (h) 12 12 28 16 28 16 24 17 24
O2N H N
N N H
H OR OR
cat. =
H HO
p. p.
racemic alcohol product can be easily resolved by kinetic resolution with Sharpless asymmetric epoxidation other chiral DABCO's made, but not tested...
O H Ph N H H N Ph Me R
+ N
H N N H Ph Ph H N H Ph N Ph O
+ Na
O H NO2 Me
O O R
+ N
+ Na
O H NO2
favored
disfavored
Barrett, A. G. M.; et. al. Chem. Commun. 1998, 2533-2534. Hirama, M.; et. al. Tetrahedron: Asymm. 1995, 6, 1241-1244.
J. Janey
Chem 206
OH R R
O O
ester +
CF3 CF3 R O R S O O
RCHO
O N+ O
OR' OH H
ee (%), R p-NO2 Ph (E)-PhCH=CH Et i-Bu i-Pr c-Hex t-Bu yield (%) 58 57 50 40 51 36 31 -(config) 91 (R) 95 (R) 92 (R) 97 (R) 99 (R) 99 (R) 99 (R) -yield (%) 11 --22 18 25 23 --
RCHO
dioxanone
Et H N O N+ H
O X=R O
H CO2R' Et
Y=R
Et H O N+ H O H
O
p. p.
O H
CO2R' H R
H O H
X
O
Y N
CO2R' H R
RCHO
RCHO
Quinidine and other acyclic derivatives showed no enantioselection and very low reactivity. Free hydroxyl on quinoline is essential for enantioselectivity. Reactions conducted at room temperature showed lower enantioselection. Racemic ester does not react to give dioxanone under the reaction conditions. Hatakeyama, S.; et. al J. Am. Chem. Soc. 1999, 121, 10219-10220.
R OH R
R
R O O R O S O O R S OH O OR'
O OR' R
O R
O
cat. =
N
prepared in 65% yield from quinidine in 85% phosphoric acid and KBr (100 C, 5 d).
OH
J. Janey
Chem 206
OH R
O H R
yield (%) quant. 92 98 91 quant. ee were all <10% phenol also accelerates reaction other acrylates also tolerated
p. p.
Favored PM3 minimized: C-N bond to enolate constrained to 1.6 Catalyst orthogonal to opposite face of the enolate leads to same major enantiomer after elimination. 16 mol%
O O
Ca
O R H
Ph
CHO
OH Ph
62% yield, 56% ee Ikegami, S.; Yamada, Y. M. A. Tetrahedron Lett. 2000, 41, 2165-2169.
Disfavored
J. Janey
Chem 206
EtO2C
:PR3
CO2i-Bu
CO2i-Bu CO2Et B
Nu
CO2R
10 eq
CO2Et A Ph
cat. =
CO2R
+ PR3
i-Pr CO2i-Bu
:PR3
:PR3
O CO2Me
O CO2Me CO2R
Et t-Bu
i-Pr
CO2i-Bu R 3P +
CO2Et
p. p.
CO2i-Bu
R 3P +
CO2Et
O COMe
Et 67 56
O COMe CO2Et O
Et 83 48
CO2i-Bu
+ R 3P +
O CO2i-Bu
R 3P +
COMe O
COMe CO2Et O
CO2Et
CO2Et
other catalyst and conditions give lower regio- and enantio- selection EtO2C Zhang, X.; et. al. J. Am. Chem. Soc. 1997, 119, 3836-3837. Lu, X.; et. al. J. Org. Chem. 1995, 60, 2906-2908.
Et
31
41
NO2 CO2Et
NC
CO2Et
Me 47 45
NC
CO2Et CO2Me
Ph
cat. =
Me
Me
J. Janey
Chem 206
Author's proposal:
:PR3
CO2R
Nu
CO2R
:PR3 H+ shift
The Baylis-Hillman reaction provides convenient access to valuable allylic alcohol building blocks which may serve as synthetic equivalents to anti-propionate aldol addition products. The basics of the reaction mechanism are understood, but the mechanistic details still remain elusive at best.
+ PR3
CO2R
NuH + PR3
CO2R
+ Nu
Nu
+ PR3
CO2R
Few examples of a general, diastereoselective Baylis-Hillman have been reported and the successful ones are rather limited in scope. Only one synthetically useful enantioselective, base catalyzed Baylis-Hillman reaction exists. There is no rational design, nor models for asymmetric catalysis.
p. p.
OR
vs. + NR3 Z
OR
The asymmetric, catalytic Baylis-Hillman reaction is very promising and attractive methodology, but remains an elusive goal of chiral Lewis base catalysis.
H R NR2 + O OR
vs.
R H NR2 + O OR
for substituted acrylates, must control enolate facial selectivity chirality on catalyst may also gear ester substituent to influence aldehyde approach
or
O X
R H NR2 + O OR
X R2 O R1 N H O R OR
O R H R H
R R
O R R
R R
D. A. Evans
Rb
Problem 19. The following transformation was recently reported by Barriault and Deon in conjunction with their synthesis of arteanniun M (Org. Lett. 2001, 3, 1925-1927). Provide a mechanism for the illustrated thermal rearrangement(s) of A to B. Where stereochemical issues are at stake, provide clear three dimensional drawings to support your answer. H Me H Single product diastereomer Me OH
DBU
OR toluene, 120 C
Me
OH
A
N N
OR
Problem 83. Chiral methyl groups are commonly used to probe the stereochemical outcome of biological reaction mechanisms. Many interesting strategies have been developed to synthesize chiral methyl groups in high enantiomeric excess. The first approach, designed by Arigoni (Chem. Commun. 1975, 921), is illustrated below.
D O D OMe D T
HO2C
H
D T
260 C
*
H
Provide a mechanism for the following transformation that accounts for the (H,D,T) stereochemistry of the chiral methyl group. You do not need to account for the stereochemistry at the starred carbon (it was not determined by the investigators).
OH Me Me Me Me
Problem 184. The key step in Kim's synthesis of perhydrohistrionicotoxin, 3, was the conversion of intermediate 1 to ketone 2 in a single acid-catalyzed transformation (Chem. Commun., 1997, 2263). Provide a mechanism for the conversion of 1 to 2 that accounts for the observed stereochemistry. OH C5H11 Me OMe H OH n-Bu 1 O p-TsOH/H2O O O H n-Bu 2 3 n-Bu H steps HN HO
Problem 203. Provide mechanisms that account for the stereoselective formation of the products obtained by treatment of aldehyde A to the conditions shown below. Briefly comment on the difference in reactivity under the two sets of conditions (JOC, 1998, 7586). O O OH B N H Ts A O 10 mol% SnCl4 H 0 C O
240 C
Ts N
O O C H
O N Ts
Problem 233. Snapper and co-workers have reported an approach to the [5.3.0] ring system that is commmon to a number of sesquiterpenes(JACS 2001, 123, 5152). One cited example is alismol whose structure is provided for reference. Upon thermolysis, the illustrated tetracyclic ester is transformed into the illustrated bicyclic ring system in 64% yield (eq 1). H CO2Me >130 C H TBSO OTBS Provide a plausible mechanism for this transformation. Your answer should include an explanatin of the somewhat unusual stereochemical inversion of the center carrying the flagged "red" hydrogen. CO2Me H (1) Me Me H HO
Me
Alismol
Seminar Topics
H O
OH R R
Covered in this Seminar: Asymmetric Ene (Metallo-Ene not covered) Chiral Auxilaries Catalytic/Promoted
Chiral
+
H R
R = Si, Sn Reviews: Snider in Comprehensive Organic Chemistry, 1991, vol 2, 527. Mikami, Chem. Rev. 1992, 92, 1021. Mikami, Advances in Asymmetric Synthesis, 1995, 1. Bolm, ACIEE, 1995, 34, 1717. Mikami, Advances in Catalytic Processes, 1995, 1, 123. Mikami, Pure & Applied Chem., 1996, 68, 639.
History: Alder, Ber., 1943, 76, 27. Alder, Ann., 1962, 651, 141.
Me
Me O
O O H
*RO OH
Me
*R = 8-Phenylmenthol
Alkene
O
Product
Yield
99 %
92 %
Whitesell, JCS CC, 1982, 989. Whitesell, Tetrahedron, 1986, 42, 2993.
R=TBS 89 %
O H R *RO
SnLn O H
Me
SnLn
2 equiv.
*RO OH R R'
*R = 8-Phenylmenthol
>97 % de Alkene
O *RO OH O *RO OH
Product
Yield
94 %
3:1
H
84%
O OR *RO OH OR
R=H
"Dominant product"
Whitesell, JCS CC, 1982, 989. Whitesell, Tetrahedron, 1986, 42, 2993.
R
3
2 equiv.
R'
*R = 8-Phenylmenthol
OH
Product
*RO H OH O *RO
2
Me
3
OH O *RO
2
one compound
3
86 % yield
OH
Whitesell, JCS CC, 1982, 989. Whitesell, Tetrahedron, 1986, 42, 2993.
+
R
*R = 8-Phenylmenthol
O *RO
SnLn H O R H
O H *RO
SnLn R O H H
O *RO OH
R *RO
OH
Note: cis-butene does not isomerize in presence of SnCl4 or SnCl4 / isopropyl alcohol at -78 oC Isomerization does occur in the presence of gyloxylate
OH H Me Me Ph O Me H O O
OH H COOR* H COOR*
+
H
Excess
8 : 1 (72 % yield)
H Ph
OH H H COOR*
+
H Me
O H
one diastereomer Whitesell, JACS, 1988, 110, 3585. Whitesell, JACS, 1986, 108, 6802. Whitesell, JOC, 1985, 50, 3025. (81 % yield) Note: 1 gives opposite bridgehead selectivity
O H *RO N Bn
Me Me O *RO NBn Me
2 equiv. SnCl4, 20 oC
*R = 8-Phenylmenthol
97 % de 76 % yield
O H *RO N Ts O
2 equiv. SnCl4, 0 oC
*RO NTs
*R = 8-Phenylmenthol
OMe
Me OTBS
Me2AlCl
OTBS OTBS OH SMe
99 % ee 100 % yield
Referenced in Mikami, Chem. Rev., 1992, 92, 1021 Kuwajima, Annual Meeting of the Chemical Society of Japan, 1991.
O H N S O O O R O *RO OH R
R= Et
H N S O O O O
% de 84 : 16 90 : 10 75 : 25 89 : 11
% Yield 78 50 93 43
n-Pr
SnCl4 ZnBr2
Most Reactive Conformation according to PM3 and Ab initio calculations Chapuis, Helv. Chim. Acta, in preparation
Me
CHO
88 % ee 86 % yield
Me
Me
O Me Zn Me Me Me O
CHO
3 equiv. Zn BINOL
Me
OH
CH2Cl2, -78 to 0 oC
3 equiv. Zn BINOL
CHO
CH2Cl2, -78 to 0 oC
Me Me
Me
Me
3 equiv. Zn BINOL
CHO
one compound
OH Me
CH2Cl2, -78 to 0 oC
Me Me
(R)- citronellal
Me
(R)-isopulegol
Me
Note : ZnBr2 gives 95:5 ratio of products of idenical configuration See: Nakatani, Syn. Comm., 1978, 147.
CHO
one compound
Me
Me
Me
(S)- citronellal
(S)-isopulegol
O R R N
O O
R O N O
+
O Me Me O O
Me
Me
Me
R= H
Me
-SCH2CH2S-
CFCl2CF2Cl/ CH2Cl2
Me
+
C6F6 H SMe
OH
SMe
88 % ee 88% yield
SiPh3
Note: Use of less reactive aldehydes (ie Chloral) afforded lower % ee and stoic. LA were required Use of MS is required for catalytic reaction
O Al O Me
SiPh3
Preliminary Result:
OH OH
(R)
OEt OH
H O
CH2Cl2, -30 oC
86 % ee 82 % yield Nakai, JACS, 1989, 111, 1940. Nakai; Mikami, JACS, 1990, 112, 3949.
Cat. Mol %
% yield
% ee
(R)
OEt OH
73
98
10
87
94
1.0
98
94
92
89
Reaction conditions: Ethyl glyoxylate, -30 oC, 3 hr, MS, CH2Cl2 Nakai, JACS, 1989, 111, 1940. Nakai; Mikami, JACS, 1990, 112, 3949. Nakai, Org. Syn., 1993, 14.
Olefin
O OEt OH O OEt OH
Products
O
E 91 % yeild 98 % ee
OEt OH O
Z 9 % yeild >90 % ee
39 % yeild 91% ee
OH
OEt
Z 4% yeild >90 % ee
O OEt OH
83 % yeild 92% ee
OH
OEt
Reaction conditions: Ethyl glyoxylate, 5 -10 mol % cat., -30 oC, 3 hr, MS, CH2Cl2 Nakai, JACS, 1989, 111, 1940. Nakai; Mikami, JACS, 1990, 112, 3949.
Additive BINOL-(OH)2 + (i-PrO)2TiCl2 CH2Cl2 + Additive TiCl4 CH2Cl2 Method B ref: Reetz, Chem. Ind. (London), 1986, 824. Method A
BINOL-(OLi)2
For reaction of -methyl Styrene and ethyl gloxylate (CH2Cl2, -30 oC) Additive 4 A MS (g/mmol) Method A 5 0 5 then filter Additive 4 A MS (g/mmol) 0 0 5 5
Yield 100 81 96
% ee 97 10 97 Method B
Yield 95 90 100 98
% ee 93 95 95 96
Note : By 13C NMR no Ti BINOL complexation occurs until MS are added. (i-PrO)2TiCl2 is a viable catalyst for the reaction.
X X O O Ti X X Ti O O
L*Ti
O COOEt
RCHO Slow
(R)(S)-(BINOL Ti X2)2
For chiral poisoning of racemic BINOL Complxes see: Faller, TL, 1996, 37, 3449. Mikami, Nature, 1997, 385, 613.
Note : For X-ray crystal structure of dimeric ((PhO)2TiCl2)2 See: Watenpaugh, Inorg. Chem. 1966, 5, 1782. Mikami, Tetrahedron, 1992, 48, 5671. Mikami, JACS, 1994, 116, 2812.
(i-PrO)2TiBr2 (R)-BINOL +
n
(R)
R OH
Enophile
O H COOMe O H COOEt
n= 0 1
% Yield 85 70
% ee 87 94
0 1
80 60
72 86
OR
COOMe O
(i-PrO)2TiBr2 (R)-BINOL +
H COOMe OTBDMS OR COOH
1 (89 % ee)
OTBDMS
COOMe
2
n-C5H11 OH OH OTBDMS
isocarbacyclin
1 : 2 ratio 92 : 8 Mikami, TL, 1996, 47, 8515. Mikami, Synlett, 1995, 29.
(i-PrO)2TiCl2 (R)-BINOL
OEt O
OR Me
O OEt OH
+ H
Me Me
R = Dimethylthexylsilyl
OR Me Me O
O OEt OH
Me
OR Me Me
Mikami, Annual Meeting of the Chemical Scoiety of Japan, 1990 and 1991. See : Mikami, Synlett, 1992, 255.
RO
Me
O OEt
Me
O OEt
OR
OH
OR
OH
Me
O OEt O OH
O X H
OH Me X
OH Me
trans
cis
Me
Me
X=
H
time 24 h 24 h 48 h
% Yield 73 50 66
trans % ee 70 84 55
3 2 1
O O -CH2-
Type I
Mikami, TL, 1991, 32, 6571. Mikami, Tet. :Asymm., 1991, 2, 1403.
O R R
n
O H Me
OH
n=
4 3 2 1 5
R= H or Me H Me
% yield NR 43 40
% ee -91 82
0 1
H
Type II
Mikami, TL, 1991, 32, 6571. Mikami, Tet. :Asymm., 1991, 2, 1403.
OAc Me
OAc
+
CHO
Me
Me
H Me
H O
OH H O Me OAc CHO M
H O
CHO Me
AcO
Me
Trichothecene Anguidine
+
XPh H O
(i-PrO)2TiCl2 (R)-BINOL
OEt PhX
O OEt OH
X= Se 95 % yield >99 % ee
+
H O
OEt
O OEt OH
O COOEt
OH
Ligand BINOL
Br
Yield 94
(R)-Ipsdienol
OH OH
84
92 (>99 % ee)
Mikami, JCS CC, 1995, 2391. Mikami, JCS CC, 1993, 327.
Br
(R)
OEt OH X X O O O H R OR Me OEt OH O X X HH H O O O H R RO H CH3
OR
R= Dimethylthexylsilyl
Me
+
Cl3C H Me
OH
Me
2 equiv.
22 % ee 55 % yield
Me
BF3 Complex
OEt
+
R H Me
OH
OMe
2 N HCl Et2O
R
OH
O Me
OH R
O OMe
CH2Cl2
OH
O OH
TBSOCH2 Ph
t-Bu
Ph
PhCHO
Only branched aldehyde which reacts
N Ti O O i-Pr-O O-i-Pr
Br
75
CHO
O MeO H O
Ph
+
Me
OH COOMe
yields 78 - 82 %
Ligand R=
R
% ee 12 38 25
H Br
OH OH
Ph + Yb(OTf)3
TMS
29
O H O OET +
OH
+
COOET
COOEt
Me O N Cu Ph
Me O N Ph
Diels-Alder % ee 85 90
Ene Product % ee 83 78
2 TfO
Jorgensen, Tetrahedron, 1996, 52, 7321. For optimization of hetero Diels-Alder reaction products See: Jorgensen, JCS PT 2, 1997, 1183.
Work from the Evans Groups "C2-Symmetric Copper(II) Complexes as Chiral Lewis Acids. Catalytic Enantioselective Carbonyl-Ene Reactions with Glyoxylate and Pyruvate Esters". Evans, D. A.; Tregay, S. W.; Burgey, C. S.; Paras, N. A.; Vojkovsky, T. J. Am. Chem. Soc. 2000, 122, 7936-7943.
Me O N Cu Me3C CMe3 N Me O
2+
O
Me
Me O
2+
O
Me Me O N Cu Ph Ph N
2+
N Cu Me3C H O 2
N OH2 CMe3
2 SbF6
2 SbF6
2 TfO
olefin
producta
O
(S)
OEt OH O Me Me Me OH O Ph Me Ph OH O OEt OH C4H9 C4H9 O OEt Me OTBDPS OTBDPS OH O OEt Me OBn OBn OH O OEt Me OH O OEt OH C3H7 H 7 C3 OH O OEt OEt OEt
2 3
1 10
83 92
96 (S) 92 (R)
2 3
1 10
97 99
93 (S) 89 (R)
2 3
1 10
95 97
96 (S) 76 (R)
2 3
1 10
89 81
96 (S) 92 (R)
Regiochemistry 75 : 25 90 : 10
2 3
1 10
72 85
96 (S) 91 (R)
one regioisomer
2 3
10 2
62 88
98 (S) 92 (R)
one regioisomer
1 3
10 10
95 70
98 (S) 94 (R)
10
96
98 (S)
E: Z 96 : 4
However, (S,S)-Ph-Box Cu (OTf)2 gives (R) configured alcohols: Tetrahedral Cu center?? Jorgensen, JOC, 1995, 60, 5757.
000 000 000 000 000 000 000 000 000 000 000 000 0000 000 0000 00 000 0000 00 000 0000 00
(S)
OEt OH
"Faced with the choice between changing one's mind and proving that there is no need to do so, almost everyone gets busy with the proof. "
An Organizational Format for the Classification of Functional Groups. Applications to the Construction of Difunctional Relationships
D. A. Evans
27A-00-Cover page 11/17/03 1:11 PM
D. A. Evans
Chem 206
http://www.courses.fas.harvard.edu/~chem206/
"A Theoretical Derivation of the Principle of Induced Alternate Polarities." A. Lapworth J. Chem. Soc. 1922, 121, 416. "The Electron Theory of Valence as Applied to Organic Compounds." J. Steiglitz J. Am. Chem. Soc. 1922, 44, 1293.
Monographs:
Hase, T. A. "Umpoled Synthons. A Survey of Sources and Uses in Synthesis".; John Wiley & Sons, Inc.: New York, 1987. Ho, T.-L. "Polarity Control for Synthesis"; John Wiley & Sons, Inc.: NY, 1991. Ono, N., "The Nitro Group in Organic Synthesis", Wiley-VCH, 2001
O N O
R H R
1) HO 2) H3O +
R O R
The von Richter reaction is illustrated in the accompanying equation. Please provide a plausible mechanism for this transformation taking into account the following observations. (a) If 15N-labeled KCN is used, the N2 formed is half labeled; (b) 3-bromo-benzonitrile does not form 3-bromo-benzoic acid under the reaction conditions.
Br
KCN
Br
+ heat, aqueous EtOH
N2
CO2H
NO2
Stoltz and co-workers recently reported the interesting rearrangement illustrated below (JACS 2003, 125, 13624). Please provide a mechanism for the illustrated transformation. Your answer should include clear 3-D drawings where relevant. the answer may be found in the database.
D. A. Evans
27-00-Cover Page 11/18/03 4:53 PM
MeO
O N2 H Me
AgOBz, Et3N THF, 45
MeO
O Me
95% yield
D. A. Evans
Required Reading:
Chem 206
"An Organizational Scheme for the Classification of Functional Groups. Applications to the Construction of Difunctional Relationships." D. A. Evans Unpublished manuscript. "Methods of Reactivity Umpolung." D. Seebach Angew. Chem. Int. Ed. Engl. 1979, 18, 239. "Nitroaliphatic CompoundsIdeal Intermediates in Organic Synthesis"' Seebach, D. et. al, Chimia, 1979, 33, 1-18. Papers of Historical Interest: "Arthur Lapworth: The Genesis of Reaction Mechanism." M. Saltzman J. Chem. Ed. 1972, 49, 750. "A Theoretical Derivation of the Principle of Induced Alternate Polarities." A. Lapworth J. Chem. Soc. 1922, 121, 416.
Lapworth was among the first to understand and conceptualize the effect of heteroatomic substituents on the reactivity of individual carbon centers, and how this effect is propagated through the carbon framework of organic molecules. Lapworth's Theory of Alternating Polarities: "Latent Polarities of Atoms and Mechanism of Reaction, with Special Reference to Carbonyl Compounds." A. Lapworth Mem. Manchester. Lit. Phil. Soc. 1920, 64 (3), 1. "The addition of electrolytes to the carbonyl compound invariably proceeded as if the carbon were more positive than the oxygen atom, and invariably selected the negative ion; for example:"
C O C NC H NC O H
"The Electron Theory of Valence as Applied to Organic Compounds." J. Steiglitz J. Am. Chem. Soc. 1922, 44, 1293. "Displacement of Aliphatic Nitro Groups by Carbon & Heteroatom Nucleophiles." R. Tamura, A. Kamimura, N. Ono Synthesis 1991, 423. "Functionalized Nitroalkanes as Useful Reagents for Alkyl Anion Synthons." G. Rosini, R. Ballini Synthesis 1988, 833. "Conjugated Nitroalkenes: Versatile Intermediates in Organic Synthesis." A. G. M. Barrett, G. G. Graboski Chem. Rev. 1986, 86, 751. Monographs: Hase, T. A. "Umpoled Synthons. A Survey of Sources and Uses in Synthesis".; John Wiley & Sons, Inc.: New York, 1987. Ho, T.-L. "Polarity Control for Synthesis"; John Wiley & Sons, Inc.: New York, 1991.
27-01-Historical 11/17/03 12:57 PM
"The extension of the influence of the directing, or "key atom," over a long range seems to require for its fullest display the presence of double bonds, and usually in conjugated positions...."
C C C O NC H C C C O NC H
The "key atom" is the one with the most electronegative character, in this case the carbonyl oxygen. anionoid/cationoid nucleophilic/electrophilic
The Lapworth polarity designations can be used to form the basis of a functional group classification scheme.
D. A. Evans
Chem 206
Polar rxns form the basis set of bond constructions in synthesis Generalizations on conferred site reactivity will therefore be important
O
The actual reaction associated with this transform is the addition of organometals to carbonyl substrates.
O M CH3 CH3 OM CH CH3
CH3
CH
+M CH3
When one considers the polar resonance structure for the C=O group it is clear that an O atom is very good at stabilizing an adjacent (+) charge through resonance.
R (+)
(+) R
R
TA
O () C CH2 (+) () CH2 OH (+) ()
TB
R
A B
() (+)
A: A: +
B+ B:
It is evident that the heteroatom functional groups, =O and -OH, strongly bias the indicated polar disconnections.
A B
In the transforms illustrated above, symbols (+) & () are used to denote the particular polar transform illustrated. In the present case there is NO INTRINSIC BIAS in favoring one transform over the other. Let's now add an OH functional group (FG) to propane at C-2 and see whether one creates a bias in the favoring of one or the other transforms:
OH CH3 CH () OH CH3 CH (+) CH3 () CH3 (+)
Me CH2 C H 2C
TA
CH CH2 OH OR CH C O
disfavored
H 2C
TB
favored
D. A. Evans
Chem 206
Functional groups activate the carbon skeleton at the point of attachment by either induction & resonance. Induction (+) (+) () ()
C
Resonance (+) (+) Symbol
F1
C
()
F2
C
(+)
F3
C
() ()
F4
A 3rd hypothetical FG, designated as A, may be defined that has an unbiased charge affinity pattern as in 1. Such an idealized FG's activates all sites to both nucleophilic and electrophilic reactions, and as such include those functions classifies as either E or G. The importance of introducing this third class designation is that it includes those functional groups having non-alternate charge affinity patterns such as 24.
(+) C () C (+) C () C (+) C A A A 2 3 4
()
G
Hypothetical A-function
(+) (+) (+) C C C 1 A
E = electrophilic at the point of attachment A = ambiphilic at the pont of attachment G = nucleophilic at the point of attachment For simplicity, we will designate three FG classes according to the designations provided above. E & G-Functions: To organize activating functions into common categories it is worthwhile to define "hypothetical" functional groups E, and G, having the charge affinity patterns denoted below. Hypothetical E-function
(+) () (+)
FG-Classification Rules In the proposed classification scheme the following rules followed in the assignment of class designation of a given FG. Activating functions are to be considered as heteroatoms appended to or included within the carbon skeleton. Activating functions are inspected and classified according to their observed polar site reactivities. Since proton removal and addition processes are frequently an integral aspect of FG activation, the FG, its conjugate acid or base, and its proton tautomers are considered together in determining its class designation. The oxidation state of the FG is deemphasized since this is a subordinate strategic consideration.
Hypothetical G-function
() (+) ()
Given the appropriate oxidation state of the carbon skeleton, such functional groups confer the indicated polar site reactivity patterns toward both electrophiles and nucleophiles. Any FG that conforms either to the ideal charge affinity parrern or a sub-pattern thereof will thus be classified as either an E- or G-function. Representative E-functions:
Me CH2 CH2 Br H O C C (+) C (+) C C () C C () C (+) C (+) C (+) C (+) C E1 E2 E3 E4 (+) () (+) C C C
E
exception: exception:
Me CH2 C H 2C H 2C
O N
CH CH2 OH OR CH C O
X, X = halogen
Also consider all combinations of of above FGs; e.g =O + OR
D. A. Evans
Chem 206
conjugate acid HO N CHR
Typical G-class functions are the Group I-IV metals whose reactivity patterns, falls into a subset of the idealized G-FG 5.
() H 2C CH () CH2 Li
FG
C ()
FG
C (+)
The Reaction:
A-functions are usually more structurally complex FGs composed of polyatomic assemblages of nitrogen, oxygen and their heavier Group V and VI relatives (P, As, S, Se). Typical A-functions, classified by inspection, are provided below
O + N CH2R O
base
O + N CHR O
El(+)
O +N O
R El
pKa ~ 10
NO2 SR PR2
N(O)R
+
N2
O () + N CH2R O
SR2
These FG's are capable of conferring both (+) and () at point of attachment.
X: N R H X: N (+) X:
Nu()
() N
O () (+) + N CH2 CH O R
Nu
R (+) H
R () H
X = OR, NR2
Remarkably, the dual electronic properties of oximes were first discussed by Lapworth in 1924 before the modern concepts of valence bond resonance were developed.
O () (+) + N CH CH R O
()N
(+) X:
X = OR, NR2
R () H
R (+) H
D. A. Evans
Chem 206
O () (+) + N CH CH R O
R ()
NO2 H (+) R
R 3N EtOH
R NO2
Overall Transformation:
O +N O
R H R
1) HO 2) H3O +
R O R
Mechanism
R NO2
O +N O
R H R
HO
O +N O
R R
H+
HO +N O
R R
nitronate anion
nitronic acid
H+
O MeO
O Me
O2N (+)
R 3N EtOH Me
O2N O HO N H HO
+
R R
HO N HO
R R OH
H 2O -H
+
HO +N HO
R R
nitronate anion
nitronic acid
H+ H 2O HO +N HO R (+) R
Reduction:
O2N
HO N HO
C()
R R OH
+ O H
-H
O2N
The resonance features which have been exploited:
() N O Pinnick, Org. Reactions 1990, 38, 655 X:
C(+)
Nef Reaction:
H 3O +
X: H
(+) X:
X = OR, NR2
R () H
R (+) H
O2N
C(+)
O2N
C()
D. A. Evans
Charge Affinity Patterns & the Nitro Functional Group Other Nonalternate Behavior of NO2 FG Representative examples: O2N
O +N O Ph 2 LDA O +N O
Chem 206
() ()
O +N O
CH2R
base
O +N O
H CHR H
C
Ph
C
Bn PhCH2Br O +N O Ph
base
O +N O
CH2 H
base O +N O CH2R
40% yield O N O H CH2 Bn CO2Et O CO2Et 2 LDA +N O 80% yield Seebach et. al. Tetrahedron Lett. 1977, 1161-1164 O +N O CO2Et PhCH2Br
nitronate dianion
nitronate dianion
O +N O
2()
() ()
O2N
O2N
Reactivity Patterns
2()
C(+)
PhCH2Br
+ NO2
EtI
O +N O
80% yield
D. A. Evans
Chem 206
C (+)
(+) NO2
(+)
O2N
NO2 H3O+
Nu()
(+)
Ph SnCl4 74% Ph SiMe3 Me TiCl4 65% SPh (+) () NO2 Pd(PPh3)3 N H CH(CO2Me)2 NaCH(CO2Me)2 Pd(PPh3)3 MeO SO2Ph NaO2SPh Pd(PPh3)3 CO2Et N(CH2)5 NO2 Me O R 3N CO2Et O
O2N
O2N
O2N
(+)
(+) NO2
(+) (+)
O2N
C
MeO CO2Et
D. A. Evans
Nonalternate Reactivity Patterns of Diazo Functional Groups The Diazo Functional Group
Chem 206
H +C N N R
H + C N N R
H + C N N R
Both (+) and () reactivity patterns suggested by resonance structures Rxns with acids:
H X H + C N N R + H C N N R H X
H+
N2
()
H H C X R N N
N Diazocarbonyl
N2
()
N2
(+)
Mechanism of activation is unclear for both Lewis and protic acids; activation may occur by protonation on C or O
Acid-Catalyzed Reactions
O N2
TFA, -20C
N2
O
()
N2
()
HO
CH2N2
N2
(+)
R
HO
(96%)
O
Mander, Chem. Comm. 1971 773 Tet., 1991 134
N2
(+)
Restriction: Starting ketone must be more reactive than product ketone Precursors to Carbenes:
H R C N N
+
()
N2
N N
(+)
H C: R
empty (+)
"Having become familiar with the peculiarities of diazoketone chemistry while preparing [other compounds] (and, I might add, inured to handling uncomfortably large quantites of diazomethane), it occurred to us that we might be able to substitute a diazo group for bromine."
Lewis Mander
H R
Cl3COCO
OCOCCl3 O
filled ()
Gibberrellic Acid
O
H (+, ) R C
E G
E,G
H C: R OMe
D. A. Evans
DiazoCarbonyl Insertations:
N2 OO R BF3OEt2
Chem 206
Web Problem 109. The following is a general reaction for the formation of pyrroles. In this condensation, any of the three reaction constituents may be widely varied. (Ono, "The Nitro Group in Organic Synthesis" Wiley-VCH, 2001. Chapter 10, pp 326-328). Siince it is not clear what the "inorganic" reaction product is, provide us with anything that is mechanistically sound using the reagents illustrated. Key descriptor for answer, "Nitro". O O Me O Me Ph NO2 NH3 Me N H Me Ph
Wolff Rearrangements
Web Problem 332. Stoltz and co-workers recently reported the interesting rearrangement illustrated below (JACS 2003, 125, 13624). MeO O N2 H Me AgOBz, Et3N THF, 45 MeO O Me
95% yield
Web Problem 188. Provide a mechanism for the following reaction that predicts the stereochemistry at the starred (*) carbon atoms (Valentin, TL, 1983, 1621). Key descriptor for answer, "Nitro". i-Pr H H NO2 O NO2 * ** N * i-Pr Me Me N O
AgOBz, Et3N
N2 O H Me H
Cope Rearr
O H C Me H H H
cis olefin
Wolff Rearr
Web Problem 150. Provide a concise mechanism for the indicated reaction in the space below. Key descriptor for answer, "Carbene". N2 O CF3COOH O MeO Web Problem 13. The following transformation was recently reported by Stoltz (J. Am. Chem. Soc 2002, 124, 12426). In addition to the illustrated product, styrene and dinitrogen are produced as by-products in this transformation. Key descriptor for answer, "Carbene". Ph O R N Ph N O
130 C styrene
C ()
Ph
HClO4
A
CH2N2
C (+)
N2 N Me H CH2N2 A
Intermediate
1
cat Rh2(OAc)4 N2
H Ph
N H
Me
Provide a plausible mechanism for this transformation and identify intermediate 1. Your mechanism should provide a rationalization for the product stereochemical relationship.
D. A. Evans, N. Finney
Hydrazone Transformations-1
O Me2N N CH2
+
Chem 206
Me2N RT, ca. 24h R' CH2Cl2 R 1. O3; 2. DMS
NO2 R'
R (+) H
R () H
C(+)
C()
C()
A
NO2 R' R
C(+)
(40-92%)
O
Bu
N H
N H
Pr
n-BuLi, 0C THF
Bu
N H
Pr
Bu
N H
Pr
PhCHO O Me H CH3CO2 H Me Me
O 95% HO H
Pr Ph
Bu
1. n-BuLi 2. H+/H2O
LiO
Pr H Ph
H O
N Me
tBu NH H
Barton, D. H. R., Ives, D. A. J., and Thomas, B. R. J. Chem. Soc. 1955, 2056.
For particulary hindered ketones: anhydrous hydrazine or formation of hydrazone under acid catalysis (hydrazine/hydrazine dihydrochloride), then basify. Under these forcing conditions, saponification, epimerization, and methyl ether cleavage can occur.
A A
O Me Me O OCH3
C() C(+)
H+, H2O
Mechanism
R 2C N NH2 + OH R2C ROH N NH R2C H N NH
tBu N Me Me O N H OCH3
hydrolysis 58%
C()
OH (RDS)*
R 2C H
N2
R2 C H ROH
R2 C H H RO
C()
An Organizational Format for the Classification of Functional Groups. Applications to the Construction of Difunctional Relationships
D. A. Evans
27A-00-Cover page 11/17/03 1:11 PM
An Organizational Format for the Classification of Functional Groups. Applications to the Construction of Difunctional Relationships
D. A. Evans Department of Chemistry & Chemical Biology, Harvard University, Cambridge, MA, 02318 Introduction Among the subdisciplines of chemistry the area of organic synthesis is probably the least organized in terms of unifying concepts and general methodology. This conclusion has been made quite obvious by the relative scarcity of critical monographs covering this important topic.1 The wide structural diversity of organic molecules, the vast abundance of organic reactions, and the restrictions imposed upon these reactions when applied to the synthesis of a complex structure all contribute to the magnitude of the problem of making generalizations in this area. However difficult the overall task of explicitly defining a priori a total synthesis of an organic structure may be, there are certain simplifying features which can be developed to generate logical sets of potential synthetic pathways to a given molecular target . Some of the general guidelines which help to define this task have been outlined.2 Recently, some of the problems associated with reducing synthetic design to a mathematical basis and the application of machine computation to synthetic analysis have been reported.3,4 Difunctional Relationships. One aspect of the synthesis of any polyfunctional target structure deals with strategies associated with the construction of arrays of relationships between heteroatom functional groups which may be denoted as F1, F 2 , etc. The general reactions illustrated below simply represent the union of two monofunctional organic fragments where the functional groups F 1 , F 2 provide the necessary activation for the coupling process. In these reactions, the oxidation states of the associated carbon fragments are purposely left undefined. In relating the generalized notation below to a real situation, if F1-C-C were an enolate, Equation 1 might be used to represent a generalized aldol or Mannich reaction while equation 3 might represent a Michael reaction.
F1 C C F2 F1 C C F2 C
(1)
F1 C C
F2
F1 C C C
F2 C
(2)
F1 C C
F2
F1 C C C C
F2 C
(3)
Henrickson has provided some useful generalizations on the construction of difunctional relationships which are worth summarizing. For example, he defines the construction span as the number of carbons linking F1 and F2. In the cases illustrated above, the product of the reaction illustrated in Equation 1 has a construction span of three. The construction fragments are then defined as the monofunctional reactants, such as F1-C-C and F1-C. In general, construction spans are limited to six or less. This is a consequence of the fact that the operational utility of a given functional group diminishes as it is removed
1) (a) Corey, E. J.; Cheng, X.-M. The Logic of Chemical Synthesis; Wiley, New York, 1979. (b) Fuhrhop, J.; Penzlin, G. Organic Synthesis: Concepts, Methods, Startimg Materials; Verlag Chemie, Weinheim, 1983. (c) Carruthers, W. Some Modern Methods of Organic Synthesis, 3nd ed.; Cambridge Univ. Press, Cambridge, 1987. (d) Organic Synthesis, The Disconnection Approach; Wiley, New York, 1982. (e) Payne, C. A.; Payne, L.B. How To Do An Organic Synthesis; Allyn and Bacon., Boston, 1969. (f) Ireland, R. E. Organic Synthesis, Prentice-Hall, Inc., Englewood Cliffs, 1969. 2) (a) Corey, E. J. Pure Appl. Chem. 1967, 14, 19. (b) Corey, E. J. Quart. Rev. 1971, 25, 455. 3) (a) Hendrickson, J. B. J. Am. Chem. Soc. 1971, 93, 6487. (b) Ugi, I; Gillespie, P. Angew. Chem. Int. Ed. 1971, 10, 914. (c) Corey, E. J.; Wipke, W. T.; Cramer, III, R. D.; Howe, W. J. J. Am. Chem. Soc. 1972, 94, 421. (d) Corey, E. J.; Cramer, III, R. D.; Howe, W. J. ibid. 1972, 94, 440, and earlier references cited therein. (e) Corey, E. J.; Howe, W. J.; Pensak, D. A. ibid. 1974, 96, 7724. (f) Blair, J.; Gasteiger, J.; Gillespie, C.; Gillespie, P. D.; Ugi, I. Tetrahedron 1974, 30, 1845. (g) Bersohn, M. J. Chem. Soc., Perkin I 1973, 1239. 4) (a) Thakkar, A. J. Fortschritte Chem. Forschung 1973, 39, 3. (b) Dungundji, J.; Ugi, I. ibid. 1973, 39, 19. (c) Gelernter, H.; Sridharan, N. S.; Hart, A. J.; Yen, S. C.; Fowler, F. W.; Shue, J.-J. ibid. 1973, 41, 113.
page 2
from the C-C bond being formed. The problem of site or ambident reactivity in systems possessing extended conjugation is the principal liability in the extension of the construction span. This point is illustrated below for both conjugate addition and enolate alkylation (Scheme I).
Scheme I The Problem of Ambident Reactivity
Nu(-) Nu MeO2 C R O
1,6 Addition
4 MeO2C 6 R
H+
-alkylation
OM MeO R
El(+) H
+
MeO El O
Nu Nu(-) H+ MeO2 C R
1,4 Addition
-alkylation
El(+) H
+
MeO El
The objectives of the present discourse are to present an organizational format which can serve to correlate strategies for the construction simple pairwise functional group relationships. As a result of the overwhelming predisposition of nature to employ polar rather than free radical processes in the biosynthesis of organic compounds the chosen organizational format reflects this bias in reaction type. The designation of reactions as polar is recognized to be rather arbitrary since known reactions vary widely in their polar character, ranging from essentially nonpolar radical reactions and weakly polar electrocyclic reactions to strongly polar ionic processes. Of primary concern in this discussion will be those reactions that involve charged species at some point along the reaction coordinate. Charge Affinity Patterns. In order to describe an organizational model for the (4) A: B+ classification and synthesis of heteroatom-heteroatom A B (difunctional) relationships in organic molecules, two familiar (5) ideas will be employed. The first is that in a given target molecule A B A: + B: the various bonds can be ionically "disconnected" (eq 4, 5). That is, if the A-B bond could be cleaved heterolytically, the indicated set of polar fragments would result. This antithetic process suggests ionic precursors suitable for the construction of the target molecule via polar coupling processes. The second well accepted idea is that functional groups determine site reactivities on a carbon skeleton based upon known reactions. That is, the oxygen atom in both acetone and anisole dictates the site reactivities that are displayed for each molecule with nucleophilic and electrophilic reagents. Thus, if the molecule A-B contained one or more functional groups proximal to the bond to be disconnected, () (+) A: A B B+ (6) one pair of ionic precursors, eq 6 or 7, would be strongly favored as plausible precursors. In such a case the favored ionic (7) A: + B: precursors to A-B could be symbolized with either (+) or (-) in the A B target molecule, e.g.5 As an example, two possible polar disconnections for ketone 1 are illustrated below. The parity labels in the target structure suggest plausible monofunctional precursors from which the target structure can be assembled by polar processes. It is also evident that the heteroatom functional groups, =O and OH, strongly bias the indicated polar disconnections.
cheme II Polar Disconnections and Charge Affinity Pattterns
TA
O() R C CH2 (+) () CH2 OH (+) () O () R C CH3 (+) () O() R C CH (+) () CH2 (+) OH 2 () CH2 (+) O ()
TB
5) The use of the symbols, (+) and (-), in no way represents formal positive or negative charges and will always be bracketed to denote this distinction. Other forms of notation have been considered such as (0) and (1) to denote a potential site of electrophilicity or nucleophilicity; however, the chosen symbols convey more direct information to the organic chemist.
() (+)
page 3
For any given atom or heteroatom assemblage which is defined as a functional group linked to a carbon skeleton, the parity labels, (+) and (-), may be employed to denote the positional polar site reactivity, or charge affinity pattern which the functional group confers upon the carbon framework. For the simple molecules shown below (Scheme III) containing a homogeneous set of activating functions, E, there are associated charge affinity patterns 2 - 5 of which each is a sub-pattern of the generalized structure 6. Note that the carbonyl function is defined as =O rather that C=O in this discussion. You might contemplate why this functional group is defined in this fashion.
Scheme III Charge Affinity Patterns of Common Functional Groups
H3 C H3C H 2C CH 2 CH 2 CH CH 2 H C CH 2 OR H2C CH C O (+) C () C (+) C E4 O Br C C () C C (+) C (+) C (+) C E1 E2 E3
2 3 4 5
C OH (+) C
(+) C
() C
(+) C
The notion that an organic structure can be viewed as an "ion assemblage" has an interesting history originating with the work of Lapworth and others.6, 7 Although the ion assemblage viewpoint was developed historically to predict site reactivity in both aliphatic and aromatic systems, this description of an organic structure is equally instructive in defining rational sets of synthetic pathways for a given target structure employing heterolytic processes as the primary set of coupling reactions. Indeed, the thought processes associated with the construction of organic molecules operate intuitively to recognize many subunits of a given structure in terms of polar fragments. The present use of parity labels to denote viable polar fragments simply formalizes this intuition. Classification of Functional Groups (FG). In order to organize general strategies that have been developed to construct heteroatom-heteroatom relationships from monofunctional precursors it is useful to develop a self-consistent classification scheme for single functional groups (FG) based on the concepts of polar disconnection and conferred site reactivity towards nucleophiles and electrophiles. The proposed scheme recognizes the dominate inductive and resonance components of various substituents and establishes8 broad categories for activating functions which correlate similar conferred chemical properties to carbon.9 Four possible functional group categories (F1-F4) are shown below. Those FGs which are more electronegative than carbon provide inductive activation defining the electrophilic potential at the point of attachment denoted as (+). In a complementary fashion, FGs which are less electronegative than carbon provide inductive activation creating nucleophilic potential at the point of attachment denoted as (). Since FG activation through induction and resonance are independent variables which contribute to the overall FG reactivity pattern, four possible classes of functional groups can be defined (Scheme IV). This discussion is reminiscent of the classification of FGs according to their impact on electrophilic aromatic substitution.10
Scheme IV Classification of Functional Groups
Induction Resonance (+)
C
(+)
F1 C
()
F2 C
()
F3 C
(+) (+)
()
(+) ()
() ()
F4
Symbol
6) (a) Lapworth, A. Mem. Proc. Manchester Lit. Phil. Soc. 1920, 64, 1. (b) Lapworth, A. J. Chem. Soc. 1922, 121, 416. (c) Lapworth, A. Chem. Ind. 1924, 43, 1294. (d) Lapworth, A. ibid. 1925, 44, 397. For an excellent review of Arthur Lapworth's contributions to chemistry see: Saltzman, M. J. Chem. Ed. 1972, 49, 750-753. 7) (a) Vorlnder, D. Chem. Ber. 1919, 52B, 263. (b) Stieglitz, J. J. Am. Chem. Soc. 1922, 44, 1293. 8) See reference 3c for an alternate classification scheme for functional groups. 9) For an analysis of the relative importance of field and resonance components of substitutent effects see: Swain, C. G.; Lupton, Jr., E. C. J. Am. Chem. Soc. 1968, 90, 4328. 10) March, J. Advanced Organic Chemistry, 4th ed.; Wiley-Interscience: New York, 1992; pp 507-512.
page 4
E & G-Functions. From the preceding discussion, one might opt for the creation of four classes of functional groups; however, for the sake of ypothetical E-function simplicity, three FG class designations will be chosen. To organize activating (+) () (+) C C C E functions into common categories it is worthwhile to define "hypothetical" 11 having the charge affinity patterns denoted in 6 functional groups E, and G , 6 and 7 respectively. Given the appropriate oxidation state of the carbon skeleton, such functional groups confer the indicated potential site reactivity patterns ypothetical G-function towards both electrophilic and nucleophilic reagents. Any functional groups () (+) () whose reactivity pattern conforms to the ideal pattern or to a sub-pattern of these C C C G hypothetical functions will be thus classified as an E- or G-function respectively. 7 For example, the halogen and oxygen-based functional groups in four molecules illustrated in Scheme III may be classified as E-functions since their respective charge affinity patterns conform to a subset of the charge affinity pattern of the hypothetical E-function. A-Functions. A third hypothetical function, A, (A for (+) (+) C C A 9 amphoteric!) can be defined which has an unbiased charge ypothetical A-function affinity pattern as in 8. Such an idealized functional group (+) (+) (+) () () C C C A C C A 10 activates all sites to both nucleophilic and electrophilic reactions and, as such, include those functions classified as either E or G . 8 (+) The importance of introducing this third class designation is that C A 11 it includes those functional groups having non-alternate charge affinity patterns as in 9, 10 and 11. The differentiation of polar reactivity patterns can be described in an alternative manner. Starting with an ideal A-function, one could imagine a process in which the reactivity pattern is gradually polarized towards E- or G-behavior (Scheme V). Since site reactivity is not an on-off property but varies continuously over a wide range, one could further subdivide A-class functions into those functions with a bias towards E-class or G-class properties. Such a bias could be denoted by the dominant subordinate charge affinity notation in 12 and 13; however, for the concepts to be presented in this discourse, such A-function subclasses are nonessential. It should be emphasized that the purpose of the E- and G-classification is not to rigidly pigeon-hole functional groups based on site reactivity, but only to separate those which are strongly polarized toward E or G behavior. The decision has been made to avoid the pursuit of an overly detailed FG classification scheme since such attempts will dangerously oversimplify problems since an essentially contiguous function cannot be segmented in to discrete parts. Scheme V Alternate vs Nonalternate Reactivity Patterns
Hypothetical A-function
(+) (+) (+) C C C C () C A () C G () C () () C A () C () C () C () C A
12
13
(+) C
(+) C
(+) C
Hypothetical E-function
Hypothetical G-function
11) The symbol E was selected to denote electrophilic at the point of attachment to the carbon skeleton Unfortunately, the symbol N cannot be used to represent those FGs which are nucleophilic at the point of attachment since this is also the symbol for nitrogen. To avoid this conflict, the symbol G was chosen for this FG class designation.
page 5
FG Classification Rules. In the proposed classification scheme the following rules are followed in the assignment of class designations to functional groups. s Activating functions are to be considered as heteroatoms appended to or included within the carbon skeleton. s Activating functions are inspected and classified according to their observed polar site reactivities. s Since both proton removals and addition processes are frequently an integral component in functional group activation, the function, its conjugate acid or base, and its possible proton tautomers are considered together in determining its class designation. s The oxidation state of the FG is de-emphasized since this is a subordinate strategic consideration. E-Functions. For example, carbonyls and carbonyl derivatives will be represented as =X where X may be either oxygen or substituted nitrogen. Well recognized exceptions to the polar class designations illustrated in Scheme I may be found in the chemistry of CO and HCN. In these instances the carbon bearing the heteroatom exhibits well-defined nucleophilic properties. Accordingly these two functional groups will be classified as A-functions by inspection (vide infra).
(+) Table I. Common E-Functions: Symbol: C
OR NR2 O NR E O N
exception: exception:
X, X = halogen
G-Functions. Typical G-class functions are the Group I-IV metals whose reactivity pattern, falls into a subset of 7.
()
2C
() C
(+) C
() C
A-Functions. A-functions are usually more structurally complex FGs composed of polyatomic assemblages of nitrogen, oxygen and their heavier Group V and VI relatives (P, As, S, Se). Typical Afunctions, classified by inspection, are provided in Table II.
() Table II. Common A-Functions: Symbol: C
NO 2 SR PR2 NOR S(O)R P(O)R2 NNR2 SO2R
+
A N2 N
N(O)R
+
SR2
PR 3
Functional groups possessing the following general structure, =N-X where X is a hetroatom bearing a nonbonding electron pair, have an expanded set of resonance options which create either an electrophilic or nucleophilic potential at the point of attachment. Remarkably, the dual electronic properties of oximes were first discussed by Lapworth12 in 1924 before the modern concepts of valence bond resonance was developed.
s These FG's are capable of conferring both (+) and () at the point of attachment.
X: () N R (+) H R N H X: N (+) X:
X = OR, NR 2
R () H
page 6
A Case Study: The Nitro Group. As an example, the class designation of the nitro function is determined by an evaluation of the parent function, its nitronic acid tautomer, as well as conjugate acid and base 14 and 15.
H-tautomer
O HO CH2R
conjugate base
O
conjugate base
HO
+N O
+N O
CHR
+N O
CHR
+N
HO
CHR
nitronic acid
nitronate anion, 14
15
From the collection of transformations of the nitro group one finds that the dominate mode of reactivity of the nitronate anion 14 is that of a G-function while the protonated nitronic acid 15 mirrors the reactivity of an E-function.
14 O + N O
HO
()
CHR
FG
15
+N
HO
FG
The typical behavior of nitronate anions 14 is summarized in the representative transformations provided in Scheme VI. These moderately nucleophilic species, although they are not readily alkylated, readily undergo aldol and conjugate addition reactions.
cheme VI Selected Reactions of the Nitronate Anion
The Reaction:
O +N O CH2R O +N O CHR
base
O
qq
El(+)
CHR
O +N O
R El
pKa ~ 10
O () + N CH2 R
+N O
It is no surprise that the charge affinity pattern of this FG may be extended by conjugation, and ,-unsaturated nitro compounds readily participate in conjugate addition reactions (Scheme VII).
Scheme VII Selected Reactions of the Nitronate Anion
O O CH CH R +N O O () (+) CH CH R O +N O O (+) (+) (+) () (+) CH2 CH R
The Reaction:
+N O
+ CH CH R
Nu()
Nu
+N O
Nitro aromatics:
(+) X: N R () H
+N O
X:
X: N R H
() N R (+) H
X = OR, NR2
page 7
The non-alternate behavior of the nitro functional group is dramatically illustrated in the transformations provided in Scheme VIII. In both instances the derived anions 16 and 17 are highly nucleophilic.13 The non-alternate charge affinity patterns of these nucleophiles is provided.
Scheme VIII Deprotonated Nitronate Anions
O +N O O +N O
C H CH3
LDA -78 C
O +N O 16 O
C
CH3
()
FG
Li
()
(8)
CH3 C CH3
CH2Li C
n-BuLi -78 C
+N O 17
() ()
FG C C
(9)
CH3
The nitro group also exhibits the potential of undergoing direct displacement under specific conditions, a general transformation characteristic of E-functions. A recent review by Tamura provides numerous literature precedents for this general class of reactions.14 while table III provides some of the cited reactions. Although the NO2 group cannot be considered as a general leaving group, there are a number of conditions under which this moiety can be exploited, particularly when it is either allylic or tertiary.
O + N O R CH R
Nu()
Nu
R CH R + NO2
(+)
FG C
(10)
Table III. Representative Substitution Reactions of the Nitro Group (eq 10).
NO2 Pd(PPh3)3 Me N H CH(CO2Me)2 NaCH(CO2 Me)2 Pd(PPh3)3 Me Me SO2Ph Pd(PPh3)3 Me Ph SPh SPh NO2 NaO2SPh Me 3 SiCN TiCl4 73% Me SPh TiCl 4 65% Me Me NO 2 NO2 N(CH2)5 Ph SnCl4 74% NO2 Anisole SnCl4 94% SiMe3 Me SPh CN Ph Me t-Bu OMe Ph
A particularly useful transformation of the nitro group is the Nef Reaction, a process which transforms NO2 into =O (Scheme IX). A recent comprehensive review of this transformation provides a detailed discussion of this process.15 In addition to the Pinnick review, Seebach has also written a comprehensive review of the diverse chemistry of the nitro functional group.16
13) (a) Henning, R.; Lehr, F.; Seebach, D. Helv. Chim. Acta 1976, 59, 2213-2217; (b) Seebach, D.; Henning, R.; Lehr, F.; Gonnermann J. Tetrahedron Lett. 1977, 1161-1164. 14) Tamura, R.; Kamimura, A.; Ono, N. Synthesis 1991, 423-434. 15) Pinnick, H. W.; Org. Reactions 1990, 38, 655-792. 16) Seebach, D.; Colvin, E. W.; Lehr, F.; Weller, T.; Chimia 1979, 33, 1-18.
page 8
O R H R R O R
s Mechanism
O +N O
R H R
HO
O +N O
R R
HO +N O
R R
G-Property
nitronate anion
nitronic acid
H+
HO N HO H + O H
R R
HO N HO
R R OH
H 2O -H
+
HO +N HO
R R
E-Property
The Diazo Functional Group. This functional group provides one of the best illustrations of an A-function. As illustrated in Scheme X, both () and (+) polar site reactivity is observed in is reactions with carboxylic acids.
Scheme IX The Nef Reaction
O R H R
s Overall Transformation:
+N O
1) HO O
R R
s Mechanism
O +N O
R H R
HO
O +N O
R R
HO +N O
R R
G-Property
nitronate anion
nitronic acid
H+
HO N H HO + H O
R R
HO N HO
R R OH
H2 O -H
+
HO +N HO
R R
E-Property
The same overall reactivity pattern is expressed by the diazo functional group in the TiffeneauDemjanov ring expansion reaction17 wherein diazomethane functions as the nucleophilic agent in the first step and the functional group is lost as a leaving group in the subsequent step (Scheme XI).
Scheme XI The Tiffeneau-Demyanov Ring Expansion
O + HO CH2 N2 O
CH 2 N2 EtOH
-N2
N2
()
N2
(+)
17) For a monograph on ring expansion reactions see: Hesse, M. Ring Enlargement in Organic Chemistry; VCH: New York, 1991.
page 9
Sulfur-Based Functional Groups Sulfonium Salts. The dual electronic behavior of sulfur functions may be illustrated in the reactions of sulfur ylids which are excellent examples of A-functions. As illustrated in Scheme XII, sulfonium salts are effective in carbanion stabilization, a characteristic of G-functions, and sulfonium salts are effective leaving groups, a characteristic of E-functions.
Scheme XII. Sulfonium Salts: Modes of Reactivity
R + S CH3 R R + S
qq
s Carbanion Stablization:
R
+
H
+
CH2
()
R 2S C
R
pKa (DMSO) ~ 18
+ S CH3
Nu:
S N2
R S R
Me
Nu
(+)
R 2S C
The non-alternate reactivity pattern of trimethylsulfonium ylids is revealed in the cyclopropanation of unsaturated ketones as illustrated in the case below (Scheme XIII).18
Scheme XIII. Reactions of Sulfonium Ylids: Conjugate Addition
qq
Me Me
+ S CH2
(+)
Me
+
S Me
(+)
R 2S C
()
R 2S C
Me
+
S Me
O O
Sulfones. Other types of sulfur-derived functional groups exhibit reactivity profiles similar to that exhibited by sulfonium salts. A number of excellent applications of the arylsulfonyl functional group illustrate this point. Two applications utilizing the sulfone functional groups are presented below. The phenylsufonyl moiety strongly stabilizes carbanions and may be equated with the CN FG in its potential for hydrocarbon acidification.19 In addition, this FG is a respectable leaving group in selected situations. In comparisons with sulfonium ions (Scheme XV), arylsulfonyl-stabilized carbanions are more nucleophilic than sulfonium ylids (G-property), while ArSO2- is a poorer leaving group than Me2S- (EProperty).
Scheme XV. Sulfones: Modes of Reactivity
Me Ph Me O S O Me Ph Me O S O BuLi Me O S O Me Li Ph
pKa ~ 25
18) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 87, 1352-1364. 19) For an excellent compilation of pKa data for organic functional groups in DMSO see: Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456-463.
page 10
Julia's use of phenylsulfonyl carbanions in the synthesis of trans-chrysanthemic acid provides the justification for defining this functional group as an A-function (Scheme XVI).20
Scheme XVI. The Julia Chrysanthemic Acid Synthesis
Me Me Me O Li Ph S O Me (+) O OEt Me OEt OLi Me Me SO2Ph
()
R2SO2 C R2SO 2
(+)
C
The dual electronic properties of the sulfone functional group are illustrated in the Julia synthesis of vitamin A (Scheme XVII).21 In this application, the E-property of the FG is exploited in the base-induced elimination reaction to generate the fully conjugated polyene.
Scheme XVII. The Julia Vitamin A Synthesis
Me Me Me SO2Ph () Li Me Br Me Me CO 2R Me CO 2R Me Me Me SO2 Ph Me CO2R
()
R2SO2 C
Me KOH/MeOH
Me
Me
- PhSO 2
SO2Ph Me R (+)
O OR
Me
(+)
R2SO2 C
For additional reading on the utility of the utility of sulfones in organic synthesis a monograph on this subject has recently appeared.22 Several other reviews providing extensive literature coverage are worth reading.23 Organoboranes. The boron atom exhibits many of the common reactions normally attributed to metals, and when bound to carbon, serves as an excellent source of nucleophilic carbon.24 The transformations provided in (Table IV) represent but a few cases which demonstrate the G-properties of this activating function.25,26,27,28,29,30,31
20) (a) Julia, M.; Guy-Rouault, Bull. Soc. Chim. Fr. 1967, 1141. (b) Campbell, R. V. M.; Crombie, L.; Findley, D. A. R.; King, R. W.; Pattenden, G.; Whiting, J. J. Chem. Soc., Perkin Trans. I 1975, 897. 21) Arnould, D.; Chabardes, P. Farge, G.; Julia, M. Bull. Soc. Chim. Fr. 1985, 130. 22) Simpkins, N. S. Sulfones in Organic Synthesis, Pergamon Press, New York 1993. 23) (a) Trost, B. M. Bull. Chem. Soc. Jpn. 1988, 61, 107-124. (b) Magnus, P. D. Tetrahedron, 1977, 33, 2019-2045. 24) (a) Brown, H. C. Boranes in Organic Chemistry, Cornell University Press, New York 1973. (b) Cragg, G. M. L. Organoboranes in Organic Synthesis, Marcel Dekker, New York, 1973 25) (a) Kow, R.; Rathke, M. J. Am. Chem. Soc. 1973, 95, 2715. (b) Zweifel, G.; Fisher, R. P.; Horng, A. Synthesis 1973, 37. (c) Matteson, D. S. ibid. 1975, 147. 26) Negishi, E.; Abramovitch, A.; Merrill, R. E. J. Chem. Soc., Chem. Commun. 1975, 138. 27 For a recent citation on allylboron-based nucleophiles see: Wang, Z.; meng, X. J.; Kablaka, G. W. Tetrahedron Lett. 1991, 32, 5677-5680 and references cited therein. 28) Marshall, J. A. Synthesis 1971, 229. 29) (a) Brown, H. C.; Rhodes, S. P. J. Am. Chem. Soc. 1969, 2149, 2149. (b) Hawthorne, M. F.; Dupont, J. A. J. A m . Chem. Soc. 1958, 80, 5830. 30) (a) Pelter, A.; Subrahmanyan, C.; Laub, R. J.; Gould, K. J.; Harrison, C. R. Tetrahedron Lett. 1975, 1633. (b) Pelter, A.; Harrison, C. R.; Kirkpatrick, D. ibid. 1973, 4491. (c) Pelter, A.; Harrison, C. R. J. Chem. Soc., Chem. Comm. 1974, 828. (d) Naruse, M.; Utimoto, K.; Nozaki, H. Tetrahedron 1974, 30, 3037.
page 11
Reaction
base
R B R R Me R O OBR2 B R
CH2
26 R B R
Cl
()
Ph
C Me
27 R 2B
() R R
()
Me
OTs
Me
OTs
Me ()
28
HO
B(OH)2
B(OH)3
Ph Cl Ph ()
29 R 2B
Ph
HO
(HO)3B
C
Cl
30 R
R R'
B R
El(+)
El + R'
El
() (+)
B R
C
R2B R'
B R
The potential for non-alternate charge affinity patterns for boron have been revealed in the reactions of acetylenic and vinylic boron ate complexes (Table IV, entries F, G).30,31 These compounds exhibit high nucleophilicity towards a variety of electrophiles to the boron atom. The origin of such -nucleophilicity could be a consequence of conjugation32 (e.g., 19) not observed with the heavier metallic elements which are attacked by electrophiles to the metal where the alternate mode of conjugation 1 8 is possible.33 In principle, both types of conjugative stabilization are possible with a range of organometaloids; however, in practice this is not the case. It would be expected that the effects of
31) (a) Utimoto, K.; Uchida, K.; Nozaki, H. Tetrahedron 1973, 30, 4527. (b) Utimoto, K.; Uchida, K.; Nozaki, H. Chem Lett. 1974, 1493. 32) (a) Harmon, G. D.; Traylor, T. G. Tetrahedron Lett. 1975, 939, and reference cited therein. (b) for example of delocalization of type 25 involving R3B see Hanstein W.; Traylor, T. G. ibid. 1967, 4451; (c) for the reaction of vinylsilanes electrophiles see Miller, R. B.; Reichenbach, T. ibid. 1974, 543, and references cited therein. 33) Kitching, W. in "Organometallic Reactions," Vol. 3, E. I. Becker and M. Tsutsui, Ed., Wiley-Interscience, New York 1972, pp. 319-398.
page 12
conjugation, such as that illustrated in 24, would be more important in those systems having shorter C-M bonds, a situation which may be unique to boron. It is noteworthy that the other group III and IV organometallic compounds, R3MCH=CH2 (M = Al, Si, Ge, Sn) react with electrophilic reagents to the metal. These elements all exhibit polar reactivity patterns common to G-class functions.
M H El
18
+
C
R H H
R H C
-attack
R R
M H
-attack
R R
+
M C H El
19
C H
H C H
(11)
El(+)
Metals. In deriving a class designation for metals, M, bound to carbon, two reaction types are considered. Metals undergoing exclusive substitution at the metal-carbon bond by electrophiles, El+, are classified as G-functions (eq 12), while metals which are involved in redox processes (eq 13) are classified as A-functions since such organometallic compounds also exhibit G-type behavior.
() (+)
R
(+)
M
()
+ El(+) + Nu()
R R
El Nu
+ +
M(+) M()
(12) (13)
TlX2 I The organic chemistry of Tl(III),34and 2 KI (14) (eq 14-16) illustrate the role of metals as - TlX leaving groups (reductive elimination). Oxidative addition reactions of metal carbonyl anions and alkyl OMe OMe MeOH halides provide examples of the reverse process.36 C A (15) - TlX In general, transition metal-mediated cross-coupling OMe TlX2 reactions provide a useful illustration of the APdX classification of redox metals (eq 17).37 The CH(CO 2 Me)2 NaCH(CO2 Me)2 (16) assignment of charge affinity labels to R1 and R2 in - Pd(0) this case is arbitrary. Employing polar processes as the basis set of synthetic reactions, existing functional groups may reductive R (+) elimination (17) be organized according to their known chemical L M R R + LnM n properties. Any number of positions may be taken R () relative to the classification of atom reactivity. The M = Pd, Fe, Cu, Ni goal of this section has been to define a general classification scheme which may be used to organize the multitude of different strategies which have been developed to construct pairwise functional group relationships in organic molecules.
Pd(II)35
Taylor, E. C.; McKillop, A. Acc. Chem. Res. 1970, 3, 338. Trost, B. M. Acc. Chem. Res. 1980, 13, 385-393. Ellis, J. E. J. Organomet. Chem. 1975, 86, 1. (a) Neuman, S. M.; Kochi, J. K. J. Org. Chem. 1975, 40, 599. (b) Normant, J. F. Synthesis 1972, 63. (c) Tamao, K.; Kiso, Y.; Sumitani, K.; Kumada, M. J. Am. Chem. Soc. 1972, 94, 9268. (d) Tamaki, A.; Magennis, S. A.; Kochi, J. K. ibid. 1973, 95, 6487.
page 13
Classification of Difunctional Relationships. One of the basic assumptions employed in synthetic design involves the maximum utilization of existing functionality at all intermediate points in the construction of a polyfunctional molecule. Such guidelines aid in minimizing the number of side reactions and protection-deprotection steps during the assemblage operation. In the synthesis of even simple difunctional organic molecules, the relative positioning of the two activating functions on the carbon framework strongly influences the reaction types that will usually be employed to establish the difunctional relationship. Using the general notation developed in the previous section for activating functions, two distinct classes of difunctional relationships which may be defined between ideal E- and G-functions which may be defined are illustrated in Table V. Paths. Difunctional relationships between heteroatoms having "matched" charge affinity patterns will be defined as consonant while unmatched relationships will be labeled dissonant. It should be pointed out that the charge affinity notation is unnecessary to define the appropriate relation; other parity labels could serve equally well. For example, the number of bonds between E- and G-functions could be used to define the appropriate relationship. Employing E-functions for the purpose of illustration, the two carbonyl groups in 20a have a matched charge affinity pattern along the potential construction path. Since they are separated by three atoms they can be defined as 1,3-consonant (1,3-C). The symbol notation 20b transmits information relative to the EE' positioning along the construction path and since the E-symbol represents a homogeneous class of electronically equivalent functional groups, a common symbol is employed. In those cases where it is necessary to recognize oxidation states of carbon to derive a symbolic structural notation, one may easily do so.
Table V. Consonant & Dissonant Difunctional Pairwise Functional Group Relationships
Consonant Relationships
O Me O Me Cl Me NMe2 OMe OMe Me O OMe O E1 E2 E2 OR NH 2 O CO2 R Me E2 O H OTHP O OMe E E1 E2 E1 E1
Symbol
Notation
Dissonant Relationships
Symbol
G
Notation
Li
CH2 Cl
1,1D
1,3C
1,2D
1,4D
1,5C
1,4C
Li O G E O O
O E E
D-cycles
O NH E
C-cycles
O O E1 E2
1,2D, 1,4D
(+) O Me O OMe ()E 1 E 2 () O (+) E2 (+) E1 (+) (-) symbol deleted for convenience
(+) () (+)
20a
20b
21a
21b
page 14
Cycles. In cyclic structures, a heteroatom attached to or contained within the cycle creates a relationship with itself. For non-arbitrary mathematical considerations it is convenient to define an evenmembered ring with or without a single functional group as consonant and corresponding odd-membered rings as dissonant. For the bicyclic ketone 21a, both of the oxygen heteroatoms, denoted as E1 and E2, establish consonant relationships with each other via all bond paths and individually by virtue of their position either attached to or contained within an even-membered ring. Consonant and Dissonant Bond Paths. In contrast to the uniformity with which consonant relationships may be established through common classes of polar processes, the synthetic methods and functional groups required for the construction of the bonds define a D-relationship are quite varied and involve either more steps, more functional groups or more reactive intermediates than reactions leading to C-paths. This statement will be reinforced in a series of case studies (vide infra); however a single case is presented to reinforce this assertion. Consider the Michael transform executed on the 1,5- and 1,4-diketones shown below (eq 18, 19). In the first instance, the transform may be executed using only the functional groups illustrated; however, this is not possible with the dissonant dicarbonyl relationship since one of the resulting polar fragments will be electronically mismatched with its associated FG. In the illustrated disconnection (eq 19), the electronically mismatched fragment is the carbonyl anion.
O O (+) () (+) R 2
Michael
O R 1 (+) (+) () ()
O (+) R2
(18)
1,4-Dissonant Relationship
R 1 () O
(+) () (+) R 2
Michael
O R1 O () (+) () (+) R 2
(19)
Acyl anion
Nef
O () NO 2 (+) R 2 () NO2 R1 (+) O
Michael
R1
One possible solution to the construction of this dissonant relationship is through FG manipulation. In the present instance the application of the Nef transform (vide supra) provides the opportunity to match the charge affinity patterns so that the Michael transform may be properly executed. The use of Afunctions in this fashion is just one of a number of strategies which may be employed to construct dissonant difunctional relationships. In conclusion, dissonant pairwise relationships, either identified in simple acyclic molecules or within complex cyclic structures, generally pose a greater synthetic challenge and represent seams of lower flexibility within the carbon framework. At this point, it may be instructive to the reader to contemplate a synthesis strategy based on how and when D-relationships are incorporated into target structures. This point will be addressed later in the discussion. Synthesis of Consonant Difunctional Relationships. E2 Every complex polyfunctional molecule may be analyzed structurally CH2OH (+) in terms of its individual consonant or dissonant construction paths or (+) (+) cycles. For example, in the alkaloid lupinine (22) all possible construction (+) paths interconnecting E1 and E2 are consonant. On the other hand, N E1 mesembrine (23) 38 contains the potential dissonant paths and cycles (+) (+) illustrated in heavy lines. Consonant paths within the polyatomic 22 (lupinine) framework define seams in the structure that may be constructed using aldol and related condensation processes.
38) (a) Curphey, T. J.; Kim, H. L. Tetrahedron Lett. 1968, 1441. (b) Keely, S. L.; Tahk, F. C. J. Am. Chem. Soc. 1968, 90, 5584. (c) Stevens, R. V.; Wentland, M. P. ibid. 1968, 90, 5580; (d) Shamma, M.; Rodrigues, H. R. Tetrahedron 1968, 24, 6583.
()
(+) ()
(+) R2
(20)
page 15
s Regarding the number of different possibilities available for the synthesis of a consonant difunctional relationship interconnected by n bonds, there exists a set of n different connective operations that may be employed to establish any bond along the construction path from monofunctional or consonant polyfunctional precursors.39
OMe OMe E1 E2 E1 E2 Ar Ar Ar
23
E1 E2 E1 E2
Me
23 (lupinine)
In the analysis of potential routes to structures like lupinine, identify the shortest consonant bond path and then proceed to carry out all polar disconnections along that bond path (Scheme XVIII). Since there four bonds interconnecting =O and N (E1 and E2), there will be four associated transforms which one may execute using the illustrated functional groups. In each set of precursors the intrinsic polar reactivity patterns of the heteroatoms are accommodated in the coupling process. The resulting adducts containing the requisite nitrogen-oxygen relationship may then be ranked in order of desirability by considering criteria such as chemical feasibility of the coupling step, ease of subsequent transformation to the target structure, and availability of precursor fragments. In the present example, transforms A and B might be more highly ranked that transform C while transform D might be discarded since it does not lead to structural simplification.
Scheme XVIII
Ar Ar equivalent to: E1 (+) (+) E2 () () Ar Ar O HN Me Ar equivalent to: E E 1 (+) () (+) 2() () E1 (+) (+) E2 () () Ar HO Ar equivalent to: E E 1 (+) () (+) 2() RO2C N Me Ar Ar equivalent to: () E1 (+) (+) E2 () () HO N+ Me N+ Me
(+) In those cases when a given consonant or dissonant relationship is 6 4 separated by a significant number of bonds, it is strategically worthwhile to consider the option of incorporating additional functions to aid in the 2 (+) R R E1 (+) construction of the desired target molecule. The relative placement of such a O 24 functional group is of prime importance in dictating the subsequent polar disconnections that are perceived in generating a plausible synthetic tree. This point is illustrated when considering plausible precursors to ketone 24 (Scheme XIX). In this structure, the =O FG establishes a 1,5-relationship with itself on the six-membered ring. Through the addition of an appropriate second
39) The presence of a quaternary or bridgehead center along the construction path limits bond construction to those adjacent to the center.
page 16
activating function to the target molecule 24, an expanded set of potential disconnections is created. In the placement of the second FG, the charge affinity pattern of the resident FG should be used. For example, consider the installation of a second FG, E2, at the (+) sites on the ring to set up aldol or Claisen transforms. In a complementary fashion the addition of C-E2 fragments to the () sites will open up the execution of the two possible Dieckmann transforms.40 The preceding analysis leads to the three precursors 26a-26c. Each of which contains a 1,5-consonant difunctional relationship between the carbonyl functions. These subgoals now become the focus of the next level of analysis wherein the preceding logic is again applied. It should be emphasized that the precursors illustrated in Scheme XIX are not inclusive but represent one set which leads to the generation of a synthetic tree based upon aldol and related reactions. The point to be emphasized is that in the first stage of the analysis where functionality is being added to the target structure, consonant, rather than dissonant relationships should be created.
Scheme XIX
(+)
A
E1 E2 R E2
Aldol
equivalent to: O OH OH equivalent to: E1 E2 R O R R O Me
O R
25a
E1 (+) (+) R
26a
O
Aldol
O
Me R
25b
26b Dieckmann
RO 2C R R
C
() E1 () E1 () R R
RO 2C equivalent to: O
25c
D
E1 E2 R equivalent to: O
Dieckmann
R CO2R
26c CO 2R
25d
40) To be completely rigorous with regard to this analysis, the addition of C-E2 to the 4-position should also be considered; however, the E1-E2 construction span from such a precursor is sufficiently large as to render this precursor less attractive than the other precursors 25a-25d.
D. A. Evans
Krista Beaver
Chem 206
Arndt and Eistert, Ber. Dtsch. Chem. Ges. 1927 60B 1122 Pettit, JOC 1986 1282
Diazo Transfer
O O R' RSO2N3, base R=Me, Ts, etc. R N2 Regitz, ACIEE 1967 733 O R' R , hv or M R' N N O R acid R' N N O R For temporary activation of carbonyl compounds prior to diazo transfer, see Danheiser, JOC 1990 1960 R'
Diazocarbonyl
Diazonium
Acyl Transfer
cyclopropanation insertion rearrangement ylide formation displacement rearrangement solvolysis
O O O N O N2 ROH R O O N2
Krista Beaver
Chem 206
Diazocarbonyl
Diazonium
Common acids include BF3OEt2, HBF4, TFA, etc. Mechanism of activation is unclear for both Lewis and protic acids; activation may occur by protonation on C or O
Acid-Catalyzed Reactions
O N2 TFA, -20C (96%) HO O Mander, Chem. Comm. 1971 773 Tet., 1991 134 "Having become familiar with the peculiarities of diazoketone chemistry while preparing [other compounds] (and, I might add, inured to handling uncomfortably large quantites of diazomethane), it occurred to us that we might be able to substitute a diazo group for bromine." O N2 TFA -25C, 2 min (82%) OMe O Mander, JACS 1980 6626 Lewis Mander OCOCCl3 O O
Cl3COCO
Gibberrellic Acid
Krista Beaver
Chem 206
Olefins as nucleophiles:
Me O
Me
Mander
Ring expansion:
Me Me O Me O Me BF3OEt2 EtO2CCHN2 (81%) Me O Me O Me CO2Et
Me Me
Jasmone
Me
Br
Aplysin
Me O Me
Me
Rearrangement:
N2 O O BF3OEt2 O O N2 OBF3 R
Substitution:
N2 R O H O S N O O Me Me CO2CH2CCl3 ROH, BF3OEt2 ">60%" N O RO H O O S Me Me CO2CH2CCl3
Polyene cyclizations:
O BF3OEt2 N2 Me Me H 46% 12% Me O + TESO Me O
Tetrahydrofuran Synthesis:
R O BF3OEt2 BnO2CCHN2 (53 - 87%) O CO2Et R OH
Krista Beaver
Chem 206
Deamination:
H 2N H O S N O O Me Me COOH NaNO2, Br2 Br Br O H O O S N O Me Me COOH R N2
Aldol-type reactions:
O Li + R1 R2 O O R N2 OH R1 R2
(90%)
Me COOH
O O
Me Nu
COOH H
Ester alkylation:
O + O N2 Li CO2Et HO N2 O CO2Et Rh2(OAc)4 100% O CO2Et O
Nu = Br, Cl, F Ingold, Nature 1950 179 For other examples, see McKervey, Chem. Rev. 1994 1091
Gilbert-Seyferth Reagent:
(MeO)2OP H + N2 R1 O R2 KOt-Bu
R1
R2
Mechanism?
CF3COOH O
Krista Beaver
Chem 206
Structures generally contain bridging ligands and contain a Rh-Rh single bond Reaction pathways are highly sensitive to steric and electronic effects
Me O L O Me Rh O O
Rh(II) N2 H 3C O +
H 3C
CH3
Rhodium Carboxylates:
Me O L
Rh2(OAc)4, Rh2(tfa)4, Rh2(oct)4, Rh2(tpa)4, Rh2(pfb)4 Rh2(acm)4, Rh2(cap)4, Rh2(CF3CF2CF2CONH)4 Padwa and Doyle, JACS 1993 8669
O O Rh O
Rhodium Carboxamidates:
Rhodium Acetate
Me
MLn B
L nM
LnM CR2
R 2C N 2
LnM CR2 N2
Conclusions: These results imply that the metal is involved in the transition state Reaction pathways can be controlled by tuning the ligands on the metal
Krista Beaver
Chem 206
Reviews
O-H Insertion: Moody Tet. 1995 10811 C-H Insertion: Sulikowski Tet. Asymm. 1998 3145
H O Me CO2Me
When X is carbon: Only intramolecular processes are generally useful 5 - membered ring formation is favored in general Order of selectivity: methine > methylene > methyl
Me
OMe
HO
O Me CO2Me
HO Me
Rh2(OAc)4 (75%)
Chorismic Acid
Me O TMSO H O OH Me O NH N2 O
CO2Et
Thienamycin
Salzmann, JACS 1980 6161
Krista Beaver
Chem 206
Generalizations: Cyclopropanation
O R1 catalyst R OEt R2
N2 Ph
Me Me
CO2Me
Reviews: Davies, Ald. Acta. 1997 107 Davies, Tet. 1993 5203 For subsequent reactions: Calter, Evening Seminar 1992
Electron rich olefins work best Both concerted asynchronous and stepwise mechanisms have been proposed Cyclopropanes can participate in tandem reactions
O +
(87%)
AcO H3CO
Diastereoselection > 99:1 Cu(TBS)2 TBSO O O + OBn O BnOH2C 50% ee OBn OH Me O O N2 (84%) TBSO H Me O O O TBSO H Me O O
BnO BnO
O O N2 Rh2(5R-MEPY)4
BnOH2C
Et2AlCl (80%)
97% ee
Diastereoselection 93:7 O
For a review of catalytic enantioselective carbene reactions, see: Doyle, Chem. Rev. 1998 911
HO Me O H CO2Me
TBSO
Me O O
Antheridic Acid
Krista Beaver
Chem 206
N2 Ph CO2Me Rh2(TBSP)4 Me
hv
(35%) E H3CO
+ 6 other products
N2
N H
N H
OCH3 +
Staurosporine
N H N H
Ph Ph CO2Me 1. KMnO4, NaIO4 2. Me2SO4, K2CO3, acetone (97%, two steps) Ph (82%) H CO2Me CO2Me O Me H Me O H Me H
Li2CuCnAr2
Confertin
Me OTBS
Krista Beaver
Chem 206
Reviews:
Padwa, Chem. Rev. 1991 263 Padwa, Chem. Rev. 1996 223 Barnes, Evening Seminar, March 16, 1993
H
X is generally S, O or N and can be sp2 or sp3 hybridized Ylides often undergo sigmatropic rearrangements or cycloadditions [2,3]-Sigmatropic rearrangement:
Ph SPh O O OMe N2 Rh2(OAc)4 E S O
(86%)
H O H O
CO2Et
Tigilane Skeleton
O N O H H Me
Acorenone B
N Bz
N Bz
O Et O
Et O
CO2Me
Vindoline Skeleton
Me
CO2Me
Krista Beaver
Chem 206
N O H N2 R1 H O N H O N H CO2Me CO2Me
Arndt-Eistert Homologation:
OMe OMe O O 2N Me OMe N2 Ag , H2O
+
Rh2(acam)4 or Rhodium Acetamidate Rh2(acm)4 OMe OMe O 2N Me OMe Evans, JOC 1993 471 Rh2(oct)4 Rh2(pfb)4 Rhodium Octanoate Rhodium Perfluorobutyrate Rhodium Trifluoroacetate Rhodium Trifluoroacetamidate Rhodium Triphenylacetate Rh2(cap)4 COOH Rhodium Caprolactamate
O M N M
N H O
CO2Me
N N H CO2Me
Rh2(S-TBSP)4
N Ts
CO2
O R TMS O O Rh O O R O O Rh O R O
Rh2(S-DOSP)4
CO2
Me O
All ligands on Rhodium are bridging through the carboxylate or the amide
(CH2)11CH3
Aphidicolin
O O H
O OE
D. A. Evans
Chem 206
http://www.courses.fas.harvard.edu/~chem206/
Hutchins, R. O. (1991). "Reduction of C=X to CH2 by Wolff-Kishner and Other Hydrazone Methods". Comprehensive Organic Synthesis. Trost and Fleming. Oxford, Pergamon Press. 8: 327. Shapiro, R. H. (1976). Alkenes from Tosylhydrazones. Org. React. (N.Y.) 23: 405. Addlington, R. M. and A. G. M. Barrett (1983). Recent Applications of the Shapiro Reaction. Acc. Chem. Res. 16: 55. Chamberlin, and Bloom (1990). Lithioalkenes from arylsulphonyl-hydrazones. Org. React. (N.Y.) 39: 1. Bergbreiter, and Momongan (1991). "Hydrazone Anions". Comprehensive Organic Synthesis. Trost and Fleming. Oxford, Pergamon Press. 2: 503.
Cume Question, November, 2000 Sorensen and coworkers recently reported the synthesis of ()-hispidospermidin (Sorensen JACS. 2000, 122, 9556). The Shapiro Reaction, along with methodology developed by Whitesell, was use in the construction of intermediate 3 from the indicated building blocks 1 and 2 (eq 1). R HN H O O H Me H Me Me Me O H Ph Me O Me O Me Me Me 1 2 ()-hispidospermidin
2,4,6-triisoproylbenzenesulfonyl hydrazine, HCl, CH3CN, 75% Intermediate n-BuLi (2.05 equiv)
Intermediate B
55% MgBr2, -78 C then add 2
Me
O Me O Me Me Me 3
(eq 1)
D. A. Evans
28-00-Cover Page 11/19/03 2:02 PM
Me
HO
Ph
D. A. Evans, N. Finney
Hydrazone Transformations-1
O Me2N N CH2
+
Chem 206
Me2N
NO2 R' R
R (+) H
R () H
C(+)
C()
C()
A
NO2 R'
C(+)
Bu
N H
N H
Pr
n-BuLi, 0C THF
Bu
N H
Pr
Bu
N H
Ph OBn
MgI2 CH2Cl2, 78
N H
Pr
Bu
1. n-BuLi 2. H+/H2O
LiO
Pr H Ph Ph
N H
N H
CO2Me CO2Me R
CO2Me CO2Me R H R X X
N Me
tBu NH H
N H
O Me Ph CO2Me CO2Me
H OCH3 Me O R
A A
O Me Me O OCH3
C() C(+)
H+, H2O
Lassaletta, J-M, et al. Chem Commun 2002, 498-499 OMe N H OCH3 H N H O dr = 90:10 D. Enders et al. Syn Lett 1999, 629-631 O O TBS N
TBSOTf
OMe N
tBu N Me Me O N
hydrolysis 58%
O CH2Cl2, 78
H O OTBS
D. A. Evans, N. Finney
Chem 206
Wolff-Kishner Reduction
O Me H CH3CO2 H Me Me H O Me R N 2H 4 , NaOCH2CH2OCH2CH2OH, (HOCH2CH2)2O reflux and then heat to 210C
R R
OH
Barton, D. H. R., Ives, D. A. J., and Thomas, B. R. J. Chem. Soc. 1955, 2056.
Mechanism
R 2C N NH2 + OH R 2C ROH R 2C H N N
N2
Me Me N NH R2C H N NH
O Me Me Me O
H N Me
H
:B
Me Me OH
NH Me
A
OH (RDS)*
C()
Me
N 2H 4 CH3OH,
Me
Me A
R 2C H ROH
R 2C H H RO Me Me WolffKishner NNH2 OH
C(+)
N2, H
C()
radical pathway
N2
polar pathway
Me Me OH
Me Me OH Me Me Me
20%
A
Me Me H N N H N2
C()
30%
Me Me
Me
G. Stork et al. JACS 1977, 99, 7067.
Br
Me
Me Me OH Me Me 76%
-B
HBr Me CH2
For stable hydrazones, strongly basic conditions favor the ionic pathway. C. Dupuy, J. L. Luche Tetrahedron Lett. 1989, 44, 3437.
D. A. Evans, N. Finney
Hydrazone Transformations-3
R C NNHTs + R O O BH R Ts
Chem 206
NaOAc3H2O
R C N NH H B OR RO
R H
Ts R R C N NH H R R C H H
CHO
R C N NH
B OAc RO OR
H N
Ts Ts
H N N
Ph Ph
LAH
Ph N R
-stilbene
N R
N Me
Ph
N Ph Me
Further Refinements Very mild reduction with NaBH3CN under slightly acidic conditions (pH 4-5). No reduction in the absence of acid; carbonyl, nitro, nitrile FGs unaffected. Aromatic, sterically hindered carbonyls very poor substrates.
59% A. R. Chamberlin, et al. Tetrahedron Lett. 1991, 32, 1691.
Me
RH
Me
N2 R
N Me
NHTs
NaBH3CN, CH3CO2H
94%
D. A. Evans
Hydrazone Transformations-4
The EschenmoserTanabe Fragmentation
Chem 206
CH3
TsNHNH2, AcOH CH2Cl2, RT
Me
NaBD3CN
CH3
O S Ar
NNHTs
base
O O CH3
+
Ph
HOAc
N N : N NH2
Et2O, 0C
Ph
H-
N N + H Ts
N Ts
O +
CH3 H
N N + CH3 O H
Ph H 3C
+
CHO
94%
Me Me Me
O Me 81%
Me Me Me Me
Ph
CH2
D. A. Evans, N. Finney
Hydrazone Transformations-5
Chem 206
MeO
RCH2 Me H
NH2 O
AcO [H]
S O
Ar
RCH2 MeO H MeO Me OAc H H HSO2Ts N N Ts Compactin, Wendler, N. L., et al. Tet. Lett. 1982, 23, 5501. MeO OMe H AcO H N H N OH 86% H OH Bu
Me
AcO
Me MeO OMe
The stereochemical course of the hydrazone reduction may be stereospecifically transferred via the 1, 3-rearrangement
86%
Me
O Me N
D. A. Evans, N. Finney
Hydrazone Transformations-5
Chem 206
Me O
Me O Et Me (Z)
Me Me
O O O
78 C
CHO
50:50
79% Me O O Me
O O
Me Me
(E) Et
Me
<5:95
81%
O H Me O O Me
Me H N H Me
TBS MeO
MeO
OMe
SO2Ar
H Me
Me
Me
H Me
Et
Me CHO Li
Me Me
Me
Cylindrocyclophane-F
(as above)
D. A. Evans
O C C (+)
HO Br
Chem 206
90% yield
Review: T. L. Gilchrist, Chem. Soc. Rev. 1983, 12, 53-72 Reactions with Nucleophiles
N Ph
OH Br
O Ph
HO Ph
H N N O
N NHPh
Ph H
R2NH
N NHPh
OH LiCuMe2 O
Ph
LiCuMe2
SPh H N
N R
Me O 92% yield
D. A. Evans
Chem 206
N R
Deprotonation of the monoanion occurs predominantly at the kinetically more acidic site giving after elimination the less substituted alkene product.
R + N2 TrisHN Me N C5H11 BuLi THF BuLi TMEDA/hexane Li C5H11
General Reviews:
Trost, Ed., Comprehensive Organic Synthesis 1992, Vol 6, Chapters 4.3 . Trost, Ed., Comprehensive Organic Synthesis 1992, Vol 6, Chapters 4.6. Shapiro, Organic Reactions 1976, Vol 23, pp 405-507.
Li C5H11 + Me 4:1
Li C5H11
(E):(Z) = 4:1
Mechanism:
SO2Ar NHTs N nBuLi N N Li Li nBuLi N
SO2Ar N N Li TsLi N Li
In THF solution regiochemical ratios generally reflect the starting hydrazone geometries
Me H O Li Me H O O 1. TsNHNH2 Me 2. LDA 65 % Me H O Me H Me
p. p.
O S NR O H O S NR O
nBuLi
Side Reaction
Li
80 %
the Triisopropylsulfonyl (Trisyl) group is used (Roberts Tet. Let. 1981, 22, 4895).
SO2 Me O Me + Me Me (2 %)
Nemoto et. al. JCS, Perkin Trans. 1 1985, 927. 1. TsNHNH2 2. K2CO3, Me Me O 1. TsNHNH2 2. LDA Me Me O O
Me O
via dianion
Regiochemistry
via trianion
O Me Me Me
Me Me (100 %) Me
O CO2Et
1. TsNHNH2 2. LDA
Me EtO2C (95 %) Me (5 %)
CO2Et
D. A. Evans
Trapping of the intermediate alkenyllithium
CH2R C6H13 C6H13 O R R RCH2Br Li C6H13 Br+ Br C6H13 NHTris N Cl BusLi Li Cl 0C 82 % TMEDA/hexane -78C CO2
Chem 206
Ph C 4H 9 Me (E):(Z) = 12:1
R R
OH
-"TsTBS" C 4H 9 Ph H Me
O O Me Et
SiMe3 C6H13
Me3SiCl
Applications
O Me Me O O Me H H 1. TsNHNH2, TsOH 2. nBuLi, TMEDA 82 %
Me Me O O H
p. p.
Aphidicolin
Carbonyl Transposition
NNHTs Me 1. 2.1 equiv. nBuLi TMEDA/THF 2. MeSSMe Me 3. 1 3quiv BuLi warm 2 eq. HgCl2 82 % Me SMe
Me
Me
Me Li Me Me
HO O
Me
Shapiro alternatives
CO2Me O H H 2N N Ph Me OMe Me OMe H CO2Me N N 2.7 eq. LDA 0C THF Ph - styrene -N2 Me H HO CO2Me
Me
Me OH OH
Me
Me
Me
Me Me Me
Me
Me
OMe HO Me
loroxanthin
D. A. Evans
A Recent Aplication of the Shapiro Reaction
Chem 206
Web Problem 24. Sorensen and coworkers recently reported the synthesis of ()-hispidospermidin (Sorensen JACS. 2000, 122, 9556). The Shapiro Reaction, along with methodology developed by Whitesell, was use in the construction of intermediate 3 from the indicated building blocks 1 and 2 (eq 1).
Part B (7 points). Provide a mechanism for the transformation of intermediate B to the illustrated product 3. Use 3-dimensional representations to illustrate the stereochemical aspects of this individual step.
X Li Me Me
MgBr2, -78 C then add 2
H Me 1
O Me Me O
O Ph 2
H Me O Me H Me Me
Me
HN
R H
MgBr Me Me
X Mg O O
Ph Me 2
Me O Me
Me
O Me
()-hispidospermidin
n-BuLi (2.05 equiv)
O Me HO Ph
Me O Me 3
Me
(eq 1)
Intermediate B
55% MgBr2, -78 C then add 2
Me
Me
p. p.
O Me HO Ph
Me O Me 3
Me
Me
O
Part A (8 points). Provide a mechanism for the Shapiro Reaction of 1 to intermediate B in the space below. Feel free to use a simplified analog of 1 such as 2,2-dimethylcyclopentanone to answer this question.
Br
H EtO2C
Me H H O Br O Problem: The syn relationship between Br and H renders the direct dehydrohalogenation with base unfavorable (relative to other potential reactions. Solution; proceed via the hydrazone.
H O N Me Me SO2Ar H 2N N H Li N N Me Me Me Me
n-BuLi (2.05 equiv)
N SO2Ar
Li N N Li Me Me
O S Ar O
D. A. Evans
Chem 206
Me
Me CH2 Me
base
R
:
R' N NTs
R N+ N
R'
Me
ca. 180 C
N NHTs
Me
45% 55%
Me
Me
R
:
Me
CH3Li, Et2O, 0 C
Me
Me
quantitative
R'
products
Me
p. p. Bamford-Stevens vs. Shapiro
N NHTs
Me
Directed Bamford-Stevens
CH3 CH3 NNHTs NaOCH3, NMP, CH3
4% 63%
CH3
27%
R N
R' NNHX
CH3
trace
PhCH3, 145C
TMS
CH3 NNHTs CH3 2 eq. BuLi, 0 C
98%
Bn
Ph N TMS N Bn
PhCH3, 145C Rh2(OAc)4
TMS
Bn
66% (14:86 E:Z) R. H. Shapiro Org. React. 1976, 23, 405. T. K. Sarkar, et al. JCS Chem. Comm. 1992, 1184.
OM R R OM
2 electrons
O R O R
D. A. Evans
28A-00-Cover page 11/20/03 5:52 PM
O OH OH + O O HO OH
[O]
12%
O ONa O
OH
1. 2. 3. 4. 5.
Ketone Enolates Ester Enolates Carboxylic Acid Dianions Silyl Enolate Derivates Applications to Organic Synthesis
22% Also obtained a "high" yield of a-bromophenylacetic acid Proposed radical dimerization as mechanism for production of -diphenylsuccinic acid.
Ivanoff, Bull. Soc. Chem. Fr., 1935, 2, 76
Leading Papers: Saegusa, T. JACS, 1977, 99, 1487 Fox, M.A. JOC, 1988, 53, 3745 Narasaka, K. Chem. Letters, 1992, 2099
Chuck Scales
(AcO)2, 75 C
52%
O
Kharasch, M.S., McBay, H.C., and Urry, W.H., JACS, 1948, 70, 1269
Reaction Background
Coupling of Stabilized Anions
Synthesis of 1,4-Diketones
1) n-BuLi 2) Cu
II
X R)n M M X (R)n O R
O R O
M = C, P, S X = O, BH3, S
Mislow, K. JACS, 1973, 95, 5839 Tamaru, Y. JACS, 1978, 100, 1923 A. Muci and K. Campos, unpublished results
Type 1 Oxidants
-1e
O R
dimerization
O R O O R
73%
Type 2 Oxidants
OM OM R
E+
R
O E R R
O R O O
60%
Synthesis of 1,4-Diketones
Cross-Coupling of Methyl Ketones
O R
O R
O Ph O
O Ph O
83%
Yield R
Et
Cross-couple 68%
Dimer 1%
O Ph
O Ph O
80%
53%
1%
O Et O
63%
59%
O
4%
65%
2%
CuCl2
Ph Ph O O
Ph
28%
33% , coupling product No , coupling product seen , couple not produced from thermal rearrangment of , product
O O O O
Kobayashi, et al. TL, 18, 3741 (1977) Kobayashi, et al. Chem. Pharm. Bull., 28, 262 (1980)
Intramolecular Coupling
Ketone cyclization
O O
38%
2) Cu(OTF)2, i-PrCN
O
Dimers obtained from hindered enolates in moderate yields (40-60%) Prepared from kinetic and thermodynamic enolates
Frazier, R.H. et al. JOC, 1980, 45, 5408
Mn(OAc)3 AcOH 70 C
Tetraketone Synthesis
O O
22%
O Ph
Ph Ph O O
62%
Synthesized various aryl substituted 3,4-aroyl-2,5-hexanediones Observed that EDG favor oxidation and EWG disfavor oxidation (correlated to Hammett plot)
MnO2, reflux
H
48 hours
Leffingwell, J.C. JCS Chem. Comm., 1970, 357 Lacan, M. et al. Croat. Chem. Acta, 1973, 45, 465
OLi
SET
R
Radical
O R O R
Recombination
O RCH2 OR'
R OR' R O
+
2
Br
Yield R -H -Me -n-Bu -Me2 -i-Pr -Ph R' -t-Bu -Et -Et -Et -Et -Et CuBr2 85 81 63 25 20 75 Cu(O2C5H9)2 95 50 ---20 20 60
Br
THF
O
-78 C
O
2
10%
Exclusion of bromide source also leads to product Increasing alkyl substitution decreases yield of dimer Yield of a-bromoester increased with increasing alkyl substitution when copper (II) bromide used as oxidizing agent Yield of dimer not increased with copper (II) valerate Product obtained as an unspecified mixture of stereoisomers
OLi O O
95%
Intramolecular Coupling
Ester cyclization
COOR
R1
R2 O R3
(CH2)n COOR
R1 H Me Me Me
R2 H H Me Me
R3 t-Bu t-Bu Me Et
n 3 4 5 6
R Me t-Bu t-Bu Me
20% (undetermined mixture of stereoisomers)b >50% (undetermined mixture of stereoisomers)b 93% (0.6:1 cis:trans)a
Equilibration between cis and trans isomers noted for all reactions. Dimethyl adipate and dimethyl pimelate gave exclusively Dieckmann cyclization under the reaction conditions.
a b
Chung, S.K. et al. JOC, 1983, 48, 1125 Babler, J.H. et al. JOC, 1987, 52, 3462
CO2Me
O OMe
80 %
CO2Me MeO
1) LDA (2 eq) THF, -78 C 2) [O], DMF Temp. -78 0 -78 -78 Yield 71% 83% 76% 81%
H MeO2C
CO2Me H
Excellent yields with -substituted esters (i-Pr, BnO) Other Lewis acids (BF3.OEt2, SnCl4) do not promote oxidation ZrCl4 resulted in Claisen condensation products Not applicable for ketones or amides
Ojima, et al. Chem. Letters 1992, 1591
O HO Ph
Ph OH O COOH
COOH
+
I
COOH
16%
72%
Stereochemical Model
Li O O O O I L S
Belletire, J.L. et al. TL, 1984, 25, 5969
+
COOLi Li I COOLi
COOH
<10%
S L
"Dimerization reaction is much faster than nucleophilic substitution under the reaction conditions."
O HO R
R'
R OH R' O COOH
Ph
COOH
+
Ph COOH
HOOC
1 [O] eI2 1 16 23 2 40 38
COOH
O OH
OH OH
Formation of ,para coupling product 2 supports radical anion intermediate 31%, E,E only
COOLi COOLi
No rational for observed stereochemistry Also observed unspecified yields of , coupled product
Mestres, R. TL, 1988, 29, 6181
R R'
OLi
COOH
1) 2 eq LDA 2) I2 (1 eq) +
I COOH
OLi
70%
R COOLi I R R'
COOH
COOLi
12%
COOH
R'
C
R R'
Ph COOH
1) 2 eq LDA 2) [O]
Ph O O Ph O
COOLi
R' R
COOLi
Proposed initial step is SET to form radical anion (D). Radical anion (D) may iodinate, then form dimer (B) via SN2 reaction
COOH
Radical anion may form dimer directly, especially if R and R' are large (>H) Direct iodination of dianion neither supported or excluded by experiments
Yield
TMSO
TiCl4, CH2Cl2 RT
H MeO2C
CO2Me H
R' R R R'
CO2Me CO2Me
H H H H H Me Et
Stereochemical course under thermodynamic control No coupling from ketone-derived enol silyl ethers Generally poor yields; exclusively 1,3-trans product.
Chan, T.H. Tetrahedron, 1983, 39, 847
No Claisen type products observed SET (TiIV --> TiIII) followed by radical coupling mechanism proposed by both authors Other reagents (CuII salts, FeCl3) ineffective for coupling reaction.
a
Acrylonitrile Trapping
Me Me
OMe OTMS
CN MeO2C
CN CO2Me CN
Ojima, I. et al. TL 1977, 18, 2009 b Rhodes, Y.E. et al. Synth. Comm. 1985, 15, 301
CN
NC
CO2Me
TiCl4 CH2Cl2 0 C
MeO2C
NC
+
R R'
R H H Me
R' H Me H
Authors propose enoxyradical trapping by acrylonitrile, followed by dimerization , coupling Reactions with methacrylonitrile gave poor yields. Attempts to trap putative radical intermediate with FeCl3, CCl4, CBr4, and tributyltin hydride failed.
Rousseau, G. Tetrahedron, 1990, 46, 7011
O Ar O
OTMS
O Ph O
43-62% Oxidant
55%
Ph
# eq 1,4 1 0.5 2
Ref. a b c d
1) Et3N, TMSCl
t-Bu 2) (PhIO)n-BF3Et2O CH2Cl2, -40 C, then RT
Proposed Mechanism
OTMS OTMS R
+ -
All authors also reported yields for non-styrenyl silyl enol ethers. Yields are extremely substrate dependent. Generally, increasing steric hindrance decreases yields. All authors propose oxidation to cation radical, followed by loss of trimethylsilyl cation and radical coupling.
a b
(PhI -OBF3 )
R
O I(Ph)OBF2 R R
O R O
Kobayashi, Y. et al. Chem. Pharm. Bull., 1980, 28, 262 Saegusa, T. et al. JACS 1975, 97, 649 Moriarty, R.M. et al. TL 1987, 28, 873 d Ohshiro, Y. et al. TL 1992, 33, 5823
c
+ 1 eq
OTMS
O Ph O
93%
2 eq
OTMS
+ 1 eq
Ph
77%
2 eq
Moriarty, R., et al. JCS Chem. Comm., 420 (1985) Moriarty, R., et al. J. Chem. Soc. Perk. Trans. I, 559 (1987) Caple, R., et al. JOC, 54, 2609 (1989)
Less reactive substrate added first, followed by more reactive substrate. In all cases, trace amounts of dimers isolated.
Ohshiro, Y. et al. ibid.
H H
90%, 20:1
H COOH
H H 3C H CH
3
Cerorubenic Acid III Also observed for , olefins. Kinetic product can be isomerized in KOH/MeOH.
Snider, et al. JOC, 1990, 55, 4786
O O
O O
H O CH3
46-55% yield
OTMS
CH3
OTMS
77%
10 eq
Proposed Mechanism
+.
OTMS R R' O R OTMS O R
C16 Hexaquinacene
R' COCH3 COCH3
CAN
-TMS+
OTMS R'
R R'' R'' O
R'''
58%
Paquette, L.A. et al. JACS, 1978, 100, 1600 Ruzziconi, R. et al. TL 1993, 34, 721
Coupling of 2-acetylthiophene
O
S S O
BnO
85%
MeO CO2H
BnO MeO
OBn OMe
HCl, Ac2O
S O S
87%
A H2S, HCl
S S S
1) MeOH 2) BH3-THF 3) H+
BnO MeO
OBn OMe
73%
HO
HO
Kagan, J. et al Heterocycles, 1983, 20, 1941
OH OMe
MeO
BnO
61%
MeO CO2H
O O O O O
-78 C
OLi
OLi
O H
PhS H SPh
64%
OH O HO OH
HO
OTMS
2
Ag2O
MeO OMe OMe
MeO
O MeO
OTBDMS
Nc O Et
N Nc t-Bu
+2
CAN (2 eq)
Ph
2) [O]
MeCN, rt 30 min
t-Bu O
Ph
63%
1
O
Oxidant I2 CuCl2
OTBDMS N CO2Me
+2
Ph CO2Me
91%
Ph
Proposed Mechanism
O O OTBS Ph t-Bu O
CAN
N
-et-Bu
Ph
O Xp O
OTBS
+ + Ph
OTBS
-TBS+ H 3O
+
O t-Bu O Ph
J. Ellman and M. Dart, unpublished results Narasaka, K. et al. Chem. Letters 1992, 2099
D. A. Evans
28A-00-Cover page 11/20/03 3:14 PM
O Me
Me O
Me O
OH
93% ee
D. A. Evans
00-00-Cover page 11/20/03 5:29 PM
H H X N
N R R
H OH N H N
NMe2 H N R1 R N N R HH R2 N R
Reviews: Pracejus, H. Fortschr. Chem. Forsch, 1967, 8, 493. Morrison, J., Mosher, H. Asymmetric Organic Reactions; Prentice-Hall: Englewood Cliffs, 1971. Wynberg, H. Top. Stereochem. 1986, 16, 87. Relevant Group Seminars: Karl Scheidt, Asymmetric Catalysis with Chiral Lewis Bases (Part I), March 2001 Hemaka Rajapakse, Nonmetal-Based Asymmertic Catalysis (Part II), March 2001 Essa Hu, Asymmetric Catalysis with Chiral Lewis Bases (Part III), March 2001 Jake Janey, Asymmetric Catalysis with Chiral Lewis Bases (Part IV), March 2001
Preliminary Findings
Yamada, 1969:
Me Ph CHO H CONR2
N H
N O
Me Ph
preformed enamine
O Me
MeOH/benzene 1:9
Me Ph O
AcOH, H2O
Me Ph
CHO Me O
49% ee
Yamada, S. TL 1969, 10, 4237.
R = Me R = Et
O Me O
Me
O Me
OH
74% ee the use of protic solvents severly diminishes enantioselectivity other amino acids as catalysts lead to decreased chemical yield and enantioselectivity Eder, Sauer, and Weichert obtained the corresponding aldol condensation products in similar optical purity using 47 mol% L-proline and 1N HClO4
Hajos, J., Parrish, D. JOC 1974, 39, 1615. Eder, U., Sauer, G., Weichert, R. ACIEE 1971, 10, 496.
Me O
Me
Me Me O H HO O "major product" Me O
racemic
Me O
Me
CO2Me N H DMF O
racemic
OH O
"major product"
Me O Me O N H DMF CO2H
no reaction
Transition States
Agami, 1984-1986 Houk, 2001-2003
H N O Me CO2O O H Me O
H
-
O 2C H
N O
NH
general hydrogen bond energies -OH - - O 3.0-8.0 kcal -CH - - O 0.5-3.8 kcal
favorable (enamine) N-H---O hydrogen bond N-H anti to carboxylate electrostatically favored reaction is second-order in proline (non-linear effect observed) second proline acts as a proton shuttle, allowing enamine to be nucleophilic
Agami, C. TL 1986, 13, 1501. Houk, K. JACS 2001, 123, 12911. Houk, K., List, B. JACS 2003, 125, 16.
N-H---O hydrogen bond does not lower energy of transition state favorable O-H---O hydrogen bond additional NC-H---O hydrogen bond further stabilizes system reaction is first order in proline (supported by kinetic data) and no non-linear effect observed
for a discussion on R3N+-C-H---O=C bonds, see: Houk, K. JACS, 2002, 124, 7163.
30 mol% L-proline
Me NO2
OH
76% ee
NO2
% yield < 10
% ee -HO
compound
S N H CO2H HO N H CO2H Me S N H Me CO2H N H CO2H
% yield 67
% ee 73
N H
55
40
85
78
CO2H NH
< 10
--
> 50
- 62
List, B., Barbas, C. JACS, 2000, 122, 2395-2396 *Barbas, C. JACS, 2001, 123, 5260-5267
66
86
Me Me S CO2H N H 2
product R =
cat. 1 2 1 2 1 2
% yield 68 60 62 60 74 65
% ee 76 86 60 89 65 67
product R =
Cl
cat. 1 2 1 2 1 2
% yield 94 71 54 60 97 61
% ee 69 74 77 88 96 94
NO2
Br
DMTC 2 is catalyst of choice for aromatic aldehydes, although chemical yield decreases due to slower rate of reaction unbranched aldehydes yield no appreciable amount of product with proline catalyst 1 due to enolization and self-aldolization under reaction conditions (DMSO/acetone = 4:1)
List, B. JACS, 2000, 122, 2395. Barbas, C. JACS, 2001, 123, 5260.
+
R1 Me H R2
OH R2
product R =
O Me NO2 O Me O OH OH Me Me OH
cat.
% yield
% ee
1 2 1 2
65 57 60 <5
77 74 80 ---
1
NO2
24 35 21 41
67 90 69 89
OH R
+
Me
O R
20 mol% product R=
Me
1 % ee 70 67 * 73 * 72 product R=
Me Me Me Me Me
2 % yield 1 % yield 2 23 34 22 46 42 50 % ee 61 73 * 36
% yield 1 % yield 2 29 31 35 34 0 38 40 35
Me
use of cyclic ketones (cyclopentanone, cyclohexanone) result in moderate yield and diastereoselectivity, and up to 95% ee enone products arise from a Mannich addition-elimination sequence
List, B. OL 2001, 3, 573.
HN
H O
+H2O -H2O
R2
N Me O
H O
N Me HO
H O
R1CHO
H O O H Me R1 H N
R2 HN HO H O
R1 OH O
Me
+H2O -H2O
R2 R1 OH N Me O H O
H H
R2
Houk's calculated T.S. synclinal approach of aldehyde R1 in pseudo-eqitorial position C-H - - O distance ~ 2.4 DFT calculations in DMSO
List, B. JACS 2000, 122, 2395. List, B., Houk, K. JACS 2003, 125, 2475.
Synthesis of Anti-1,2-Diols
CO2H O Me OH H O R
20 mol% catalyst DMSO/acetone 4:1 24-72 hr, rt % ee >99 95 >99 -->99 --67 (32) 92 (78)
Me Me
OH R OH
N H 1
Me Me S CO2H N H 2
product R = cat. 1 2
Me Me
product R =
cat. 1 2 1 2
1 2 1 2 1 2
Me
Cl
2:1
Me Me O
1 2 1 2
Me Me
List, B. JACS, 2000, 122, 2395. Barbas, C. JACS, 2001, 123, 5260.
more substituted enamine formed due to: increased acidity of proton removed increased stability of enamine due to On.b. --> * C=C
OH R OH
product R =
O H O H O H Me O H Me OH Me OH OH Me Me OH Me Me
dr 4:1
% yield 80
% ee 99
product R =
O H Me O OH Me Bu O Me Me Bn Me OH Me Me
dr 24:1
% yield 82
% ee >99
3:1
88
97
H OH
24:1
80
98
14:1
87
99
19:1
75
91
3:1
81
99
reaction requires lower catalyst loading, shorter times, and only 2 equivalents of aldehyde donor
Trimerization of Acetaldehyde
3
Me O H
OH Me
90% ee
THF at 0C was found to be the optimal conditions for yield and ee (DMSO @ rt = 13% y, 57% ee, CHCl3 @ rt = 2% y, 68% ee) Mechanism:
O CO2H H Me
HN
-H2O +H2O
Me H
N CO2
N CO2H O Me O H
HN CO2H
Barbas, C. JOC, 2002, 67, 301.
O H
OH Me
Me
Me OH
N CO2
Mannich condensation
Propionaldehyde Trimerization
A method for carbohydrate assembly
O H OH OH Me Me Me Me OH 6% Me O H Me Me OH OH Me Me OH Me HO O Me HO O Me
3
H
O Me
1:2 :, 11% ee
47%
reaction analygous to an aldolase enzyme that furnishes the minor product shown above propionaldehyde added slowly dropwise in order to obtain trimer over dimer products enantioselectivity erodes with longer reaction times (after 10 hr product ee = 47%) substituent at C-6 variable by using 1 eq. of corresponding aldehyde and 2 eq. of propionaldehyde
Barbas, C. TL, 2002, 43, 9591.
L-proline
H
OH Me Me
L-proline
H
OH Me Me
1
O
2
O Me
L-proline
L-proline
Me
O H
OH OH Me Me Me H
OH OH Me Me Me
incubating isolated 1 with L-proline led to formation of 2 through epimerization (1:1 ratio of 1:2 after 96 hr)
Barbas, C. TL 2002, 43, 9591.
OH CO2Et CO2Et
product R = Me Et i-Pr
% yield 90 91 88 94
% ee
H H N O H H CO2Et O O
90 85 85 88 84 0
EtO2C R
n-Hex Ph
Jorgensen, K. Chem. Comm. 2002, 620.
91 97
protection of the aldehyde as the dioxolane prevents epimerization of the center during column chromatography
3 product R = cat. 1.5 mol% 1 2TfOH + 1.5 mol% 1 3 mol% 2 1.5 mol% 1 2TfOH + 1.5 mol% 1 3 mol% 2 % yield 3 60 72 37 13 % ee % yield 4 88 93 83 91 7 7 32 25
NO2
proposed mechanism similar to that of proline catalyzed reactions, with proton transfer from protonated tertiary N to O
Yamamoto, Tet. 2002, 58, 8167.
R'NH2
R
NR' H R
NHR' R
kAldol
Keq=1
kMannich
HN
20 vol%
1 equiv.
1.1 equiv.
94% ee
HN
PMP
NO2
R=
product
O HN PMP
% yield
dr
% ee
Me
2.5
Ar PMP
95
>20:1
99
Me Me O Me O HN HN
1
Ar PMP Ar
---
>20:1
94
OMe
Me OMe O HN
93
>20:1
98
PMP Ar
OH
List, B. JACS, 2000, 122, 9336.
Me OMe
92
>20:1
>99
Mannich
R
O H X
CO2H Me
Aldol
MeO N N H R H
H O Me X
H O
O O
N O H H
Me X
ArHN R X
List, B. JACS 2002, 124, 827.
O Me R
OH
O Me
R= CN H Me OMe
% yield 88 83 85 88
% ee 99 93 86 61
Variation of the catalyst: proline proves to be the best catalyst, with other catalysts affording reduced yield and optical purity. Reaction of acetone with isovaleraldehyde:
N H
26% y., 0% ee
20 vol% product
O Me O Me R2
% yield 86 R2 = Me allyl OH 72 79 62 47
dr ---
% ee 99
O Me O
81
>19:1
>99
20 vol% R= Me Et i-Pr n-Bu n-Pent % yield 72 57 81 81 89 71 dr 1.1:1 1.5:1 >10:1 3:1 >19:1 >19:1 % ee 99 99 93 99 >99 >99
aqueous workup or column chromatography may lead to decreased diastereoselectivities reaction has been performed in aqueous media (Barbas, TL 2003, 44, 1923)
Barbas, C. JACS 2002, 124, 1866.
20 mol%
N H
OMe H
NHPMP CO2Et R
DMSO, 24-48h, rt
20 vol% proposed transition state R= Et i-Pr n-Bu t-Bu n-Pent n-Hex % yield 44 52 54 57 78 68 dr 1:1 10:1 10:1 >10:1 >10:1 >19:1 % ee 75 82 74 92 76 76
For a review of SMP use in asymmetric synthesis, see: Enders, D. Synthesis 1996, 1403. Barbas, C. TL 2002, 43, 7749. N H H CO2Et MeO N H MeO N N H CO2Et H OMe
bettter?
OMe H H
Direct Amination 1
Addition of aldehydes:
O H R Cbz N N Cbz
Cbz N N H Cbz
1.5 equiv.
1 equiv.
% yield 97 93 94 99 95
H N H Me CO2Bn O
N
N
Direct Amination 2
Addition of ketones:
O R1 R2 EtO2C N N CO2Et O R1 R2 CO2Et N N H CO2Et R2 O CO2Et N N H CO2Et
1
product 1
O Me Me O Me Bn O Me O Et Jorgensen, JACS 2002, 124, 6254. Me N N CO2Et N N H CO2Et
2
% ee
10:1
80
95 (93)
CO2Et N H CO2Et
4.5:1
92
98 (94)
CO2Et N H CO2Et
3:1
99
99 (99)
---
79
94 (93)
OX Ph
O N
O O N H Ph
O O R N H Ph
H O N N
O
O H
O O R N H Ph
3 equiv.
1 equiv.
% yield 88 79 85 99
% ee 97 98 99 96
% yield 95 60
76
% ee 97 99
98
83
98
EWG
or
:Nu
enamine
imminium
Examples include: additions to: alkylidene malonates ,unsaturated nitroalkenes additions of: malonate esters nitroalkanes aromatics (Friedel-Crafts reactions) silyloxy furans Diels-Alder reaction Dipolar cycloaddition
28% ee
Kozikowski, A. JOC, 1989, 54, 2275. O
O BnN Me CO2Et
Me CO2Et
34% ee
Momose, T. J.Chem.Soc., Perkin Trans., 1992, 509.
NO2 Ph
7% ee
List, B. OL 2001, 3, 2423.
Enders:
O Me Me Ph NO2
NO2 Ph Me
H
O N O Enders, Synlett 2002, 26.
O O
N H
Me Ph
H
20 mol%
N H
N Me
EtO2C O
CO2Et Ph
THF, rt 59%
47% ee
Barbas, C. TL, 2001, 42, 4441.
O H R Ph NO2
20 mol%
N H
N O Et R O
NO2 Ph
Ph
R
Barbas, C. OL 2001, 3, 3737.
O Me OR Ph NO2
15 mol%
N H Me
R Me H
yield 75 79
dr 1:5 5:1
ee 69 98
Me
10 equiv.
CHCl3, rt, 7d
HH N Me H O Me N Ph H NO2 Me
with variation of aromatic group on nitroolefin: ee = 96-98% dr = 3.5:1 - 19:1 selection of aromatic groups used: tolyl, p-methoxyphenyl, p-chlorophenyl, 2-thienyl
5 mol%
N H CO2i-Pr CO2i-Pr
CO2Rb O Me Me NO2
5 mol%
N H Me
Me NO2 Me Me
CHCl3, rt 74%
68% ee
Yamaguchi, JOC 1996, 61, 3520.
versus
LUMO
E
HOMO HOMO
L.A.
00 0000 00 00
Diels-Alder Cycloaddition 1
H R O
5 mol% 1
R CHO R
MeOH-H2O, rt 12-24 hr
CHO
endo
exo
% yield 75 92 81 99 89
% ee(endo) % ee(exo) 86 86 84 93 91 90 90 93 93 93
Ph N H O N Me Me HCl Me
Diels-Alder Cycloaddition 2
R H R O X
CHO X
endo adduct
R Me
product
O Ph CHO Ph Me
% yield 75
exo:endo % ee 35:1 96
H
Me Me
82
CHO
94
O N Me Me Ph N H Me HCl
H H Me
Me Ph CHO R CHO Me Me
84 90 75 75
CHO OAc
89 83 90 90 85
Ph
Me
H H
OAc
72
CHO
Me
Me NTs CHO
(+)-Hapalindole Q
Nitrone Cycloaddition
Z Z N O R R1 H O Z N O R CHO R1 R CHO N O R1
endo Z R R1 Me Me Me Me Me Me Me Me Me H H H H H H endo:exo 94:6 93:7 95:5 92:8 93:7 98:2 93:7 95:5 99:1 81:19 86:14 85:15 80:20 81:19 91:9 yield 98 73 66
78 76 93 82 98 70 72 80
exo
ee (endo) 94 98 99
95 94 91 97 93 99 90 92
O N
Me Me
Bn Ph allyl Ph Me Ph Bn C6H4Cl-4 Me C6H4Cl-4 Bn C6H4OMe-4 Me C6H4Me-4 Bn 2-napth Bn c-Hex Bn Ph Bn Ph Bn C6H4Cl-4 Bn C6H4Cl-4 Bn 2-napth Bn C6H4OMe-4
Ph
N H
Me HClO4
catalyst
80 80 82 83
90 91 90 90
HClO4 proved to be the best Bronsted acid cocatalyst to promote only enantioselective catalysis high endo selectivity attributed to to favorable placement of R group away from geminal dimethyl substituents on catalyst
N Me
O R H O N Me Ph N H Me TFA Me
yield 83 81 80 87 79
90 72
catalyst use of N-benzyl pyrrole and N-allyl pyrrole give similar results
87% y, 90% ee
THF-H2O, 3-5 d
N Me
68% y, 97% ee
Alkylation of Indoles 1
The need for a new amine catalyst: 20 mol%
H N Me Me O Ph N H O N Me Me TFA N Me Me Me H O
58% ee
Indole is less electron-rich than pyrrole, so is less nucleophilic toward conjugate addition Second generation catalyst: a more reactive variant lone pair exposed CH3 - lone pair interaction
O N Me Me O N Me Ph N H Me Me Me Me
0000 0 00 0 00 00 00 00
MacMillan, D. JACS 2002, 124, 1172.
Ph
N H
00000 00 0 0000 0
Kinetic studies indicate rate of reaction influenced by imminium formation as well as carbon-carbon bond forming event
Alkylation of Indoles 2
R H N Me O N Ph N H TFA R O H O N Me
Me Me Me Me
ee 92 93 93 90
96 91
O N Ph N
Me Me Me Me
Me -83 n-Pr -60 i-Pr -50 Ph -55 CH2OBz -83 CO2Me -83
Alkylation of Indoles 3
H
H O
20 mol% catalyst
O
N R
R1
CH2Cl2-i-PrOH, 3-24 hr
N R
Indole Scope: R Me H allyl Bn H Me H Y H H H H H H Cl Z R1 temp(C) -87 -60 -72 -60 -60 -87 -60 % yield 82 72 70 80 94 90 73 % ee 92 91 92 89 94 96 97
Me MeO Me N CO2H Me N
1. 20 mol% catalyst
H Me O
2. AgNO3, NaOH
Br MacMillan, D. JACS 2002, 124, 1172. Br
Alkylation of Benzenes
Z H R2N X O Z X H O R2N OMe OMe N Me2N N
1 aniline 1 2 1 1 2 1 2 3 3 1 2 X Me Me Et CH2OBz CH2OBz CO2Me CO2Me Ph p-ClPh p-NO2-Ph p-NO2-Ph temp(C) -40 -20 -50 -20 +20 -20 -20 -50 -10 -10 -20 % yield 86 70 68 73
90 89
2 % ee 89 87 88
92 92
O N Ph N H
Me Me Me Me
HCl
catalyst other substituted anilines used with similar results catalyst loading can be lowered to 1% without significant loss of yield and enantioselectivity
90 97 84 92
97 82 87
87 82
92 90
Mukaiyama-Michael Reaction 1
Previous Michael additions with silyloxy furans:
O TMSO O Me N O O O
O H N Me O O O
Katsuki, Tet. 1997, 53, 17015 Desimoni, G. Tet. 2001, 57, 10203
note that Lewis acids promote 1,2-addition products when possible, such as ,unsaturated enals Optimized reaction conditions:
TMSO O Me R H O O
O Me O R H O N Me Me Me N H Me DNBA
% ee 92 84 98 99
90 99
Ph
catalyst
MacMillan, D. JACS 2003, 125, 1192.
Mukaiyama-Michael Reaction 2
Variation of the silyloxy furan
O TMSO X O R Me H O
O R O Me H
R H Me Et
X H H H
% yield 87 80 83
86 83 73
% ee 90 92 90
98 98 90
CO2Me H CO2Me H Me Me
10 mol%
Bn N H
neat, rt
R1
R2
% yield
84 58 75 95
% ee
89 77 92 88
NMe N Me CO2H
61 33 59 86 66 2
91 84 59 99 95 94
:Nu
Nitroalkane additions to ,unsaturated ketones has also been performed in good to excellent selectivity (Jorgensen, K. JOC 2002, 67, 8331.)
Jorgensen, K. ACIEE 2003, 42, 661.
20 mol%
Ph
10 mol%
Ph
OH
O Me
CH2Cl2, rt
O Me
86% ee
Barbas, C. ACIEE 2003, 42, 4233
Reactions are direct: Donors can be used without modification -- no need to deprotonate or silylate prior to reaction Electrophiles can be generated in situ (Mannich reaction) most of the time Catalysts are: inexpensive commerially available or easily prepared in both enantiomeric forms non-toxic recoverable Many reactions can be run at room temperature, under an aerobic atmosphere, with wet solvents Many types of reactions can be catalyzed; for some reactions, organocatalysis is the only highly efficient way known (Mannich and Mukaiyama-Michael additions) Reaction yield and enantioselectivity is highly dependent on solvent system so require "fine tuning" Only reactions that use ketones or aldehydes as donors (electrophiles for Michael additions) can be catalyzed Organocatalysis using small molecules is a field that has emerged only within the past decade. It is bound to receive increasing attention in the future; as a result, new catalysts will emerge which will allow for the catalysis of reactions previously unutilized in the realm of organocatalysis.
Summary
D. A. Evans
Chem 206
http://www.courses.fas.harvard.edu/~chem206/
General: Simpkins, N.S. Sulphones in Organic Synthesis, Pergamon Press, New York, 1993.
General: Magnus, P.D. Tetrahedron 1977, 33, 2019. Julia: Blakemore, J. Chem. Soc. Perkin Trans I. 2002, 2563. Electrophilic Properties: Trost, B.M. Bull.Chem. Soc. Jpn. 1988, 61, 107. SO2 Extrusion: Vogtle, F.; Rossa, L. ACIEE 1979, 18, 515. Ramberg-Bcklund Rxn: Paquette, L.A. Org. Reactions 1977, 25, 1. Triflones: Hendrickson, J.B. Org. Prep. Proc. Int. 1977, 175. Sulfoximides: Johnson, C.R. Tetrahedron 1984, 40, 1225
Cum Question, 1998: The stereoselective construction of trans olefins through carbanion-mediated condensation processes has still not been rendered general. One transformation that may be used in certain circumstances is the "one-step" Julia transformation illustrated below. PPProvide a mechanism for this transformation.
O S O
1
RS H
RS
+
RA
+
S O N H
Reading Assignment for this Week: Carey & Sundberg: Part A; Chapter 7 Carbanions & Other Nucleophilic Carbon Species Carey & Sundberg: Part B; Chapter 2 Reactions of Carbon Nucleophiles with Carbonyl Compounds
"Chemical Chameleons: Organosulfones as Synthetic Building Blocks" B. M. Trost, Bull. chem. Soc. Japan, 1988, 61, 107-124 (handout) Monday, November 24, 2003
RS RA
SO2
The cruel mechanistic problems that you should be prepared for in Chem 206 O O MeO MeO N O CO2Me O S Et Ac2O/HOAc 70% MeO MeO Padwa et al. JOC 1996, 61, 4888 N CO2Me
D. A. Evans
29-00-Cover Page 11/24/03 8:32 AM
D. A. Evans
Chem 206
Me
S N2
General: Julia: Electrophilic Properties: SO2 Extrusion: Ramberg-Bcklund Rxn: Triflones: Sulfoximides:
(+)
R2S
()
OH OH R
R2S
S CH3 R pKa ~ 18 O
Deprotonation:
Na H
pKa (DMSO) CH4 pKa (~56) NH3 pKa (~41) Sulfoxide ~35
CH3
S CH3 CH3
Na H
CH3
S CH3 O
Sulfide
(45)
R2S
C(+)
L L S: L
CH3
S CH3 O
S CH3 + L (+)
Nu:
S N2
+ Me Nu
CH3 CH3
S CH3 O S CH3
Sulfone
~ 31
HOH pKa 31
Sulfonium Salt
18.2 Excellent LG
R S CH3 R
Nu:
S N2
R S R
Me Nu
Oxo-Sulfonium Salt ()
O
R2S
C
(+)
Good LG
S CH3 O
Nu:
S N2
O R S O
+ Me Nu
D. A. Evans, K. Scheidt
Chem 206
Li
However, until recently little information was available on the solid state structures of these species:
"The Structure of Lithium Coumpounds of Sulfones, Sulfoximides, Sulfoxides, Thioethers, 1,3 Dithianes, Nitriles, Nitro Compounds, and Hydrazones." Boche, G. Angew. Chem., Int. Ed. Engl. 1 9 8 9, 2 8, 277.
Li
Li
The Li counterions are not associated with the charged carbon. The carbanions are largely trigonal.
D. A. Evans, K. Scheidt
Chem 206
O S
Me CLi
O S O CHLi
+ TMEDA
+ TMEDA
Li
Li
Li Li
Li
D. A. Evans
Reactions with ketones: ()
Chem 206
Reactions of Sulfones
PhS: Br Me H2O2 Me S Ph HIO4
Me
Me S
Me
Me Me S O S O Ph O H2O2 Ph
()
R2S
C
Me O Br :S Ph O
Me
Me Me O
O S Ph
O CH2 Me S Me
O CH2
(+)
R2S
Me
(Sulfinate anion)
"Twenty-five Years of Dimethylsulfoxonium Methylide (Corey's Reagent).", Gololobov, Y. G.; Lysenko, V. P.; Boldeskul, I. E. Tetrahedron 1987, 43, 2609. (electronic handout)
Reactions of Sulfones
Me O S
Me
S Me
Me O Me Me O
B ()
(+)
pKa ~ 25 ()
R2S R2S C
Me O S Me Nonalternate reactivity pattern revealed in consecutive reactions O CH2 O
C
O
R2SO2
Ph O
R + S CH3 R
(+)
R2SO2
Me Me O Li S Ph O
(+)
O
(+)
??
Ph
Me BuLi
Li Ph
R + S CH2 R
D. A. Evans, P. Carter
Me Me O Li S Ph O O
(+)
Chem 206
Me Me
SO2Ph O
1,2-addition ()
R2SO2
C
Me Me
PhSO2 MEMO O
Not observed
Me Me SO2Ph Me Me OEt
Me
1. MsCl, TEA 2. PhSLi, THF, RT 3. mCPBA
Me
SO2Ph
MEMO Me Me X MEMO Me Me
OTBS I OTBS
65 - 85% yield
Me
Me
OLi CO2Et H Me
()
(+)
R2SO2
R2SO2
Me Me
Me X= SO2Ph X=H H Me S S
Me 50% yield
SO2Ph Li
PMBO
Me
()
R2SO2
Br
TBDPSO
Al-Hg, aq. THF Reflux MeO
(+)
SO2Ph Me O PMBO S S
R2SO2 C
29-04 Sulfur chem-3 11/23/03 6:03 PM
90% yield
D. A. Evans, T. Dunn
Functionalization of cyclic Ethers
BuLi PhO2S O O SO2Ph El(+)
Chem 206
Me I
R2SO2
() C
ROH
Me H O OH H O
R2SO2
(+) C
El
O OR
El
O H Me H O
OH
Me
O H COOH Me OH O
Me
O O 90% yield
Ley et al, Synlett, 1992, 395; Ley et. al, Tetrahedron, 1992, 48, 7899
87% yield
Me N H O Me
Me
OPMB
O NHPh
O OH H
OTBDMS
Routiennocin
Bryostatin 2
D. A. Evans, P. Carter
Chem 206
major
H O
Me H
Me
OTBS
Good sulfone review: Trost, Bull Chem. Soc. Japan, 1988, 61, 107-124. Julia Review, Blakemore, J. Chem. Soc. Perkin Trans I. 2002, 2563. (electronic handout)
OTBDPS Me Me
Cytovaricin Synthesis:
Me H H
R2 X R1 SO2Ar SO2R
+ e-
R2 X R1
+ eR1
R2
+
Me R2 R1 TBSO DEIPSO Me
O H O H
OCH2OCH2CCl3
21
TESO
H CHO
Me
OAc
Na(Hg) SO2Ar
OH HO
21
OTES
3
Me TESO
Me Me O
OAc
TBSO
D. A. Evans, P. Carter
Chem 206
Phorboxazole B Synthesis
Br
46
The Mechanism:
13
O H
H
H H
19
O
4
S O I S O CH3
MeO Me
H
H
Me
O H O OH
33
MeO Me H
disconnection
38
N O
HO
MeO
I CH3 SO2
C39C46 Synthon
Br
OMeO O S S
N N
NaHMDS RCHO
Ph
N N
C9H19
Mechanism??
O2 S R H
N N
D. A. Evans, N. Finney
Chem 206
The overall set of reactions which establishes the equivalency of the hypothetical carbonyl anion 1 and its equivalent synthon 2 is shown below:
S S
Li R
Construction Step
S S
El R
El
1 Equivalent Synthons
O R1 C:
() CG
H 3O +
(+) CE
El
carbonyl anion
T2
El O C
O R1 C:
O +N O
R
()
H2O +H2O
S S
H R
RLi
S S
Li R O +N O H R El O2N C R
SH
El
() CG
(RS)2 C(+)
(RS)2 C()
Equivalent Synthons
O
Latest Innovations: A. B. Smith, JACS 2003, 125, 14435-14445 (Handout) O S R3Si S H R1 S R3Si LiO R1 S HMPA S Li R3SiO R1 S El(+) S El R3SiO R1 S
Nef Reaction
(+) CE
El O C R
C:
El
T2
tBuLi
D. A. Evans
Chem 30
Introduction. As you know, transform T1 conforms to the polar bias mapped on to the carbon skeleton by =O, while transform T2 does not. Although T1 is the more common transform, sometimes, because of the presence other functionality in either R1 or R2, the "reversed-polarity" transform is more suitable for the particular synthesis at hand. T1
O R1 C R2 R1 O C+ O C: + R 2: R 2: +
There is a clear need in nature to have both types of polar bond constructions exemplified by Transforms T1 and T2 (Eq 1-2). One such reaction is shown below. This reaction, which is enzyme-catalyzed, requires the cofactor thiamine which functions as the inversion operator in these biological processes.
O
Eq 1 Eq 2
T2
R1
OH H R1
O R1 O O OH R2 O: OH H 2C R2 OH C R2
H 2C OH
Ideally, one might visualize a catalytic agent (Q) which might react reversibly with an aldehyde in conjunction with inverting its charge affinity pattern. Nature has designed such reagents.
H2C OH
General Scheme
Charge Affininty Inversion Step: The structural constraints on (Q) are that it must be nucleophilic, add reversibly to aldehydes, and stabilize an adjacent carbanionionic center.
O R1 C H O OH H R1 C OH
R2 O
H2C
C:
+ Q:
R1
OH Q Equivalent synthons
+
O H 2C R2 OH C
Q:
Lets call (Q) a charge affininty inversion operator since in operates on RCHO and reverses the intrinsic polar reactivity of the RCHO carbon from (+) to ().
Overall Process:
R1
O C H
OH
Related transform:
OH R2
H2C OH
C:
+ Q:
R1
acidic proton
R S O P O O O P O HOCH2 OH OH HOCH2 S R R N C O N
OH
El
+ Q:
S R R N
S R
R1
El
Me Me Me
thiamine (Q:)
O C R1 H O: C N O R1 S R OH
Benzoin Condensation:
O C
OH Ar C
H C OH H 2C OH C: HOCH2 R N
C O Ar
Q H :CN
:CN
OH Q
HOCH2 R
Cyanide ion is the best example of a reagent which functions as an inversion operator. The benzoin reaction is restricted to aromatic aldehydes. Why?
Equivalent synthons
S R
H R1
Me
Me
Me
D. A. Evans
Basic Transformation:
O Ar S R H+ Ar OH S H R H2O Ar S H R
Chem 206
The Pummerer Rearrangement facilitates the transformation of a sulfinyl aldehyde transformation. The rearrangement may be initiated by either a Bronsted acid or an anhydride such as trifluoroacetic anhydride (TFAA). With the latter reagent, the transformation occurs at room temperature. O Ar S R OTFA TFAA Ar S H TFAOH S R Ar H
R +TFAO
O Ph S N
O Ph TFAA H N R Et N R H S N
Ar
R OTFA
Et
Leading References
De Lucchi, Miotti, et al. (1991). The Pummerer reaction of sulfinyl compounds. Organic Reactions 1991, 40: 157. Grierson, and Husson (1991). Polonovski- and Pummerer-type Reactions and the Nef Reaction. Comprehensive Organic Synthesis. Trost and Fleming. Oxford, Pergamon Press. 6: 909. Padwa, A., D. E. Gunn, et al. Application of the Pummerer reaction toward the synthesis of complex carbocycles and heterocycles. Synthesis 1997 1353-1377. Carreno, Applications of sulfoxides to asymmetric synthesis of biologically active compounds. Chem. Reviews 1995 95, 1717-1760. Kita, Y. and N. Shibata (1996). Asymmetric pummerer-type reactions induced by O-silylated ketene acetals. Synlett(4): 289-296. RHN
81% N H N
Et
OAc
The cruel mechanistic problems that you should be prepared for in Chem 206 O O N O S Et Ac2O/HOAc 70% MeO MeO Padwa et al. JOC 1996, 61, 4888 N O CO2Me
CO2Me
D. A. Evans
Chem 206
Mechanism??
MeO MeO N O
Exam 3, 2000: Question 5 (11 points). An interesting rearrangement which also results in the construction of this same ring system (Question 4) has been reported by Langlois & coworkers (J.Org. Chem. 1985, 50, 961). This rearrangement is illustrated below. Provide a mechanism for this transformation. N N
TsOH, THF 78 %
H N Me SMe
Et O
Pummerer Ac O S Et H O N MeO OMe SEt O N MeO OMe O SEt O N COOCH3 MeO N OMe OMe MeO O O COOCH3 Product O CO2Me N
OAc OAc
S Pummerer N
Et
Pummerer
O Me O OMe CO2Me H S O
H N Me O Et
Pummerer S Me
H N Me O Et
CO2Me
MeO
Endo [4+2]
Endo [4+2]
MeO OMe
CO2Me
S R1 S
N O O
Base
S O S
N O Li O H R1 R2
+
H O R2
R1
H R2
D. A. Evans
H H R2 O R1
H R2 H
R1
X
R3P+ B.E Maryanoff, A.B. Reitz, Chem. Rev., 1989, 89, 863 L.F. van Staden, D Gravstock, D.J. Ager,Chem. Soc. Rev., 2002, 31, 195 P.R. Blakemore, J. Chem. Soc., Perkin Trans. 1, 2002, 2563
R2P(=O)
(RO)2P(=O) R3Si
SO2Ph R1 Li
R2 R1
SO2Ph R2 OAc
H R1 H R2
2) Ac2O
C5H11
C5H11
E:Z = 80:20
C5H11
E:Z = 90:10
E:Z = >99:1
H R1
R2 H OAc
M
-Originally proposed mechanism for Na/Hg elimination, though Keck has shown this is not the case -Believed to be mechanism for SmI2 elimination
H R1 H R2 H R1
R2 H OAc
PhSO2 R1
H R2 OAc
OMe -NaOAc
Ph O S O R1 H R2
Na/Hg 1e-PhSO2Na
R1 H
R2
Na/Hg 1e-Using MeOD results in >90% Deuterium incorpration -After initial elimination, there is no equilibration, explaining why Na/Hg and SmI2 can give different results
H R1 H R2
Na
quench
R1 H
R2
Synthesis of Bryostatin 2
OTBS TBSO O H O SO2Ph Me Me O H TBSO 1) n-BuLi, THF, -78 C 2) Ac2O, DMAP 3) Mg, 20mol% HgCl2 Single Olefin Product (E) 64% over 3 steps OTBS OPMB Me Me O H OTBS OPMB
o
OTBS
Me Me
D.A.Evans, P.H. Carter, et al., J. Am. Chem. Soc., 1999, 121, 7540
TBSO Me Me PhSO2 O OTf TBSO O TBSO O NHPh OPMB n-BuLi (2eq) THF, HMPA Me Me O
HO O
Me
Me
OPMB
Me Me
OTBS OPMB Me Me HO OH O O O
Me
MeO2C
D.A.Evans, P.H. Carter, et al., J. Am. Chem. Soc., 1999, 121, 7540
Me Me O
OH H OH O Me O CO2Me
O OH
n-Pr
H29A-03 11/24/03 9:08 AM
BT
PYR
PT
TBT
Bt =
(benzotriazole)
R N N N
S R2CHO O2S
N OLi R2
S O2S R1
N O
Li
O S O R1 Li
R1
R2
N OH S
H29A-04 11/24/03 9:10 AM
SO2
R2 R1
O LiO S R1
R2 OBT
Diastereoselectivity of BT-Sulfones
O Li S O O R1 H R2 H
slow R1 R2
S O N SO2 H Li R1 BTO
SO2Li R2
R2 R1 Li BT + S O2 R1 H O R2 R1 Z E R2
N fast R1 H
O Li O S O R1 R2 HH
M Li Na K
Toluene
DME
Me + OHC
SO2-BT
DMF
OTIPS
92% 81:19
C8H17
OLi C8H17 Ph
slow
Ph
C8H17 SO2BT
anti
RCHO
Ph BTSO2
RCHO Ph
C8H17 Ph
NO2 Ph
40% E:Z = 98:2
Ph
60% E:Z = 92:8
-SO2
Ar C H H R1
R1 Ar
cis
OLi R1 Ar SO2BT R1 H O H
Ar
H C Ar H R1
CHO R R BTO2S
LDA, THF -78 oC to RT J.B. Baudin, et al. Bull. Soc. Chim. Fr., 1993, 130, 856
yield
E:Z
Me
S O H
Me
S O H
O S S H O O H R2 N
SO2BT H O O Li R1 OLi R2 R1 R2
or
Li
BT R1 H
R1
R2
Chelate (closed) Transition State favored for non-polar solvents, small counter-ions (Li) Non-chelate (opened) Transition State favored for polar solvents, large counter-ions (K)
LiO H R1
BT S
O R2 H
H Li O R2 R1
SO2BT R2 OLi R1 R2
BT R1 H
S O
N S
O S CH3 O
S N O O S O N
S N S O S O N SO2Me
Synthesis of ent-Bengamide E
TBSO OHC TBSO OTBS O OCH3 OCH3 LiHMDS DME -78 oC to RT 62% TBSO OCH3 OCH3 TBSO OTBS O
N S
O S O
OH
OCH3
H N
O NH
OH K.J.McRae, PhD Thesis, Research School of Chemistry, Canberra, 2001 J.B.Baudin, et al., Bull. Soc. Chim. Fr., 1993, 130, 856
OH
O ent-Bengamide E
Synthesis of LAF389
O S N + OHC O CH3 H3C O CH3 O OCH3 1) LiHMDS, -78 oC, THF CH3 2) TMSCl H3C 3) aldehyde 4) -78 oC: 1 hour 0 oC to RT: 1 hour 50 oC: 1 hour 45% single isomer, white crystalline solid CH3 H3C CH3 OH OCH3 O NH O L. Waykole, et al., Organic Process Research and Development, 2003, ASAP (Novartis Process Group) O LAF389 H3C O H3C O CH3 O O OCH3
O S O H3C H3C
H N
OH
OH
Synthesis of LAF389
S N + H O
TMS N S
O O S O Ph
t-Bu Ph
Ph TMS TBAF E:Z = 1:1 CH3 Ph Ph N S O O S O Ph L. Waykole, et al., Organic Process Research and Development, 2003, ASAP (Novartis Process Group) t-Bu Ph
MeSO3H E only
Ph
H3C H3C
Synthesis of LAF389
O S N + OHC O CH3 H3C O CH3 O OCH3 1) LiHMDS, -78 oC, THF CH3 2) TMSCl H3C 3) aldehyde 4) -78 oC: 1 hour 0 oC to RT: 1 hour 50 oC: 1 hour 45% single isomer, white crystalline solid CH3 H3C CH3 OH OCH3 O NH O L. Waykole, et al., Organic Process Research and Development, 2003, ASAP (Novartis Process Group) O LAF389 H3C O H3C O CH3 O O OCH3
O S O H3C H3C
H N
OH
OH
Synthesis of LAF389
S N + H O
TMS N S
O O S O Ph
t-Bu Ph
Ph TMS TBAF E:Z = 1:1 CH3 Ph Ph N S O O S O Ph L. Waykole, et al., Organic Process Research and Development, 2003, ASAP (Novartis Process Group) t-Bu Ph
MeSO3H E only
Ph
H3C H3C
Me
CHO
PYR-SO2
Me E,E temp -78 oC 0 oC 25 oC yield 35% 53% 67% Ratio E,Z : E,E 84:16 90:10 91:9
OTIPS
OMe
Curacin B N S Me
Me Me + PYR-SO2
OTIPS
Me Me
1-Phenyl-1H-tetrazol-5-yl Sulfones
N N N N Ph M Li Na K toluene 51:49 65:35 77:23 O O S O Me MN(SiMe3)2 H -78 C to RT
o
Me
n-C5H11
n-C4H9
n-C5H11 Me
n-C5H11
E:Z = 94:6
Me O2S
TESO
Me
Me O2S
PT
CHO OH Ph PTSO2 LDA, THF -78 oC to RT O2N Ph 100% E:Z = 98:2 Ph 0% NO2
Synthesis of Herboxidine
O O N + CH3 CHO N N N SO2Et KHMDS DME -60 C, 45min 93%, 93:7 dr
o
O O CH3
CH3 CH3 OH
CH3 O CO2All CH3 H O S N SO2 OMe Me PCBO Me Me O Me H 1) LDA, THF -78 C to -20 C 81%, 91:9 dr 2) K2CO3
o o
Synthesis of Herboxidine
CH3 O CO2H CH3 H Me O Me
OMe Me OH Me
Synthesis of (+)-Ambruticin
OTBS OTBS TBDPSO O O H + PT O S O Me Me Me Me O Me
tert-Butyl-1H-tetrazol-5-yl Sulfones
SO2Het Me 1) KHMDS, DME -60 oC, 2 hr 2) H2O Het SO2Het Me BT PT TBT yield 0% 20% 91%
O N N N N S
n-C9H19
39% 67:33 O N N N N S O 1) KHMDS, DME -60 oC, 30min n-C9H19 2) n-C9H19CHO -60 oC to RT
Diastereoselectivity of TBT-Sulfones
OLi R2 SO2TBT anti N N N N t-Bu O Li S O O H HR2 N t-Bu N slow R2 O N N SO2 H Li PYRO H SO2Li R2
R2 N N N t-Bu N S O2 Li + H O E R2 R2 N N N t-Bu N O Li S O O R2 HH Z
N t-Bu N fast H O
N N Li PYRO R2 SO2Li H
SO2 R2
Sulfone Synthesis
RX, BX = halide, tosylate, triflate SH N N S R N N
N N
N SH
N SH
N N
N N
t-Bu N C S
NaN3
1-phenyl-1-H-tetrazole-5-thiol tert-butyl isothiacyanate; 25g = $57.80 Sodium azide; 25g = $51.90 25g = $22.60
Sulfone Synthesis
N N N N Ph MCPBA (NH4)6Mo7O24-4H2O / H2O2 Na2WO4-2H2O / H2O2 Oxone CH3CO3H KMnO4 P.R. Blakemore, J. Chem. Soc., Perkin Trans. 1, 2002, 2563 Mo(VI) W(VI) S R [O] N N O S O R N N Ph
N N
N N
38% O PT S R [2,3] PT O S R
11%
H. Hilpert, B. Wirz, Tetrahedron, 2001, 57, 681 D.A. Evans, G.C. Andrews, Acc. Chem. Res., 1974, 7, 147
H29A-17 11/24/03 1:34 PM
Me
OTBS Me H O
NOT Amphidinolide-A
NOT Amphidinolide-A
OTIPS
OTIPS
Synthesis of Vinylsilanes
O Ph SiMe3 + O O S PT SiMe3 Ph Ph Ph
Ph
Smiles Ph
M-HMDS SiMe3 Ph Li Li Li
Conclusions
BT and PT sulfones have become useful funtional groups for the synthesis of olefins from aldehydes inexpensive starting materials sulfones can be made in high yield from alcohols olefination reactions occur under mild conditiions, and are typically high yielding and selective Stereochemical outcome is kinetically controlled in most cases. Though reaction conditions can often influence selectivities Polar solvents with soft counter ions often favor E olefins Non-polar solvents with hard counter ions often favor Z olefins
BT sulfones are most useful for the synthesis of conjugated dienes through reaction with ,unsaturated aldehydes R SO2BT + OHC
R2
R2
PT sulfones are most useful for the synthesis of non-conjugated (E) olefins R + R
SO2PT
OHC
R2
R2
PYR and TBT sulfones both produce high levels of cis selectivity, though yields are typically lower than BT reactions
D. A. Evans
Chem 206
http://www.courses.fas.harvard.edu/~chem206/
The pyridoxal co-factor (Vitamin B6) 1, facilitates the decarboxylation of -amino acids. Provide a mechanism by which 1 carries out this transformation.
H O O PhosphateO OH H2 N R OH -CO2 H2 N R O C O
Me
Cume Question, Fall 2001. The reaction illustrated below was recently reported by Murry and co-workers from the Merck Process Group (JACS 2001, 123, 9696-9697). Provide a mechanism for this transformation.
Tol + Ar1 H Ar2 N H Ar2 10 mol% 1 OCMe3 Et3 N, CH2 Cl2 35 C Ar1 O N H O OCMe3
SO2
S CH2 CH2 OH
Handout 30A: Homoenolates: Synthesis & Applications Mesembrine Syntheses: Keely, S. L.; Tahk, F. C. JACS. 1968, 90, 5584. Stevens, R. V.; Wentland, M. P. JACS 1968, 90, 5580 (handouts) Stetter, The catalyzed nucleophilic addition of aldehydes to electrophilic double bonds. Org. React. (N.Y.) 1991, 40, 407. Ahlbrecht, "Stereoselectivity of chiral homoenolate equivalents." Synthesis 1999, 365-390.
1 (used as catalyst)
The nucleophilic addition of aldehydes to electrophilic double bonds catalyzed by thiazolium salt 1 is referred to as the Stetter Reaction (Stetter, H.; Kuhlmann, H. Org. Reactions 1991, 40, 407). Provide a mechanism for this transformation.
O Me Me H O O 10 mol% 1 Et3 N, EtOH 60 C Me O Me
D. A. Evans
30-00-Cover Page 12/1/03 9:07 AM
D. A. Evans
Chem 206
Each substituent attached to carbon activates that carbon toward a polar reaction by either resonance or induction or both. Induction (+) (+) () ()
Those ideal FGs which create nucleophilic carbon at point of attachment. Exhibit strictly alternate charge affinity patterns.
F1
Resonance
C
(+)
F2
C
()
F3
C
(+)
F4
C
()
Li
CH2
()
CH
CH2
()
MgBr
Symbol
C (+)
C ()
C ()
E
CH3 CH2
(+)
C
Br
G
CH3
C
CH2
()
C C A
C
(+) (+)
G C C
C
MgBr
() ()
Real functional groups are assigned to a class designation by inspection of the chemistry of that FG, along with that of its conjugate acid and conjugate base Charge affinities of real functional groups form a subset of the ideal FG classes. E-Functions
CH3
A-Functions
()
() ()
(+) (+)
All sites activated equally for electrophilic & nucleophilic reactivity. Those ideal FGs which exhibit nonalternate polar site reactivity are included.
One might visualize a process wherein A-functions are gradually polarized towards either E or G behavior in response to changes in inductive and resonance effects. () () () (+) () (+)
(+) () (+)
E
(+)
C
()
C
OR CH3
() (+)
CH2
OR
CH
()
CH3
()
(+) ()
CH2
(+)
CH
(+)
CH2
Br
()
CH3
(+)
CH2
()
Br
CH3
(+)
CH2
()
NR2
C A C C
() () () () (+) ()
O is represented as:
() (+)
() (+)
E and not: C
C E2 E1
A-functions are some of the most useful FGs in organic synthesis because of the unique reactivity provided.
()
C A
D. A. Evans
Chem 206
A-Functions
()
(+) (+)
() ()
Functional groups derived from many of the transition elements Synthesis of Targets containing E-Functions
E
(+) () (+) ()
E
(+) () (+) ()
E
(+) () (+) ()
Given the resident E-function, the charge affinity pattern dictates the nature of the polar coupling process and thus functional groups to be employed in synthesis.
()
E#
(+) () (+) ()
C C
add E
E# C C
E C C
Charge affinity patterns are "matched." Pairwise relationship is "consonant".
(+) () (+) ()
E#
(+) () (+) ()
add E
E# C C C
E C
Charge affinity patterns are "unmatched."
(+) () (+) ()
E# E
(+) () (+) ()
Consonant & dissonant relationships may be established with E-E, E-G, or G-G pairings. Most target structures are composed of E-functions.
E
(+)
G
() (+) ()
C C
E
(+) ()
E' C
(+) ()
E
(+) () (+)
G C C
()
Cl
E E'
HO NH2 OH
symbolic representation
G Li E Cl
Classification: 1,2-D
symbolic representation
Classification: 1,1-D
D. A. Evans
Chem 206
Classification of Pairwise Difunctional Relationships A single FG residing either in or appended to a cycle may establish a FG
relationship with itself.
E E E E
1,2D
1,4D
OMe R
Consonant cycles
OMe R O
1,5C
OMe OMe
(+)
HN
C cycle
D cycle
Relationship: 1,5-C
Cl
(+) (+) (+)
OH O O O Me Me O O Me
Me
Dissonant Cycles
O
Relationship: 1,4-D
Me
1,2D
1,3C
OMe OMe
Me O
Me OR
Me
General Rule For [m,n] Sigmatropic Rearrangements: When the sum of m+n is even, the FG relationship is maintained, e.g. CC' When the sum of integers is odd, the FG relationship is changed, e.g. CD
Path-cycle interconversions such as those illustrated permute, but do not eliminate the relationship. i.e. D-bond paths are transformed into D-cycles.
D. A. Evans
Chem 206
Pairwise Relationships in Inorganic Reagents E-functions in their most stable oxidation states (HO, NH3, Cl ) are
represented as E(). There exist an important family of reagents which have E-FGs directly coupled: EE Reagents
Step I: There are 4 bonds interconnecting E & E'. Hence generate the 4 transforms leading to monofunctional precursors:
E# C C
E C C
RO
OLi Me RO
O Me O OH
[H]
O RO
OH Me
(+) () (+) ()
Br HO
Br HO OH H2N
NH2 NH2
E# C C
E C C
RO
OLi H
O Me RO
(+) () (+) ()
Me O OH Me
[H]
E# C C
E C C
RO
O Me
HO
(+) () (+) ()
RO
E
() (+) () Aldol, Claisen Mannich Rxns
E# C C
E C C
O Me
HO
O HO Me
[Ox]
O RO
O Me
(+) () (+) ()
(+) () (+) ()
E# C C
E C C
E#
(+) ()
Step II: Evaluate the efficiency of the 4 plausible routes to the target from available precursors. Given the oxidation state in the target, the second synthesis looks the best and the fourth looks the worst.
E C
(+) ()
(+) () (+) ()
E C
E C C C
E C
(+) () (+) ()
(+) () (+) ()
E () Conjugate Addition
If a quaternary center occurs along the consonant bond path, one is limited to bond constructions on either side of that restriction O Me Me O RO O Me Me O Me RO OLi Me RO Me O Me Me Me O Me OLi Me
E C C C
E #()
E
(+) () (+) ()
(+) () (+) ()
Consonant difunctional relationships can be constructed from just the functions illustrated & polar bond constructions.
RO
D. A. Evans
Chem 206
E# C
E C
Me N H H H Me
E
()
(+) ()
Resident E-functions do not provide required charge affininty pattern for coupling
(+)
(+)
E# E
(+) ()
E#
(+) ()
E (+)
This transform defined a path-cycle permutation of the D-relationship
The two permitted bond constructions along illustrated bond path flank the bridgehead carbon
Me
(+) ()
E
(+) (+)
Me H H Me H2C N+ H H HO H Me
In the illustrated polar disconnections, one of the fragments may exploit the charge affinity pattern of the resident FG while the other may not. Hence dissonant pairwise relationships may not be constructed via just the functions present in the target.
O (+)
Mannich Transform
Me N H H O H Me X O H H H Me
E# A
(+) ()
E#
(+)
A
()
Me + N
In implementing this strategy you must know all important 1,1-AE FG transformations
C
Me N S
A
S R
E
O
Enamine Acylation
Me H N H H Me
(CH2O)n , isoamyl alcohol
R H Me H R
R
HO
Option Selected:
O
H H
Ph trifluoroacetic
anhydride
R O N O R
1) OH 2) H3O +
CF3CO2 SPh R R O R R
D. A. Evans
Chem 206
OMe OMe
E2
(+)
Mesembrine
Curphey, T. J.; Kim, H. L. Tetrahedron Lett. 1968, 1441. Keely, S. L.; Tahk, F. C. JACS. 1968, 90, 5584. Stevens, R. V.; Wentland, M. P. JACS 1968, 90, 5580
lupinine
N
(+)
E1
(+)
Every complex polyfunctional molecule may be analyzed structurally in terms of its individual consonant or dissonant construction paths or cycles. For example, in the alkaloid lupinine all possible construction paths interconnecting E1 and E2 are consonant. Consonant paths within the polyatomic framework define seams in the structure that may be constructed using aldol and related processes.
N Me
Begin the disconnection process by focusing on the shortest consonant bond path. In this case, there are 4 bonds, hence 4 disconnections.
(+) (+) (+)
In the analysis of potential routes to structures like mesembrine, identify the shortest consonant bond path and then proceed to carry out all polar disconnections along that bond path. Since there four bonds interconnecting =O and N (E1 and E2), there will be four associated transforms which one may execute using the illustrated functional groups. Ar Ar CE2
equivalent to:
E2
(+)
(+) C
E2
(+) equivalent to:
CH2=O
T1
E1 (+) () (+) E2 () Ar
HN Me Ar
CC
(+)
(+)
E1
(+) (+) (+)
E1
(+) (+)
N Ar E2
(+) equivalent to:
equivalent to:
OH
()E1 (+) (+) E2 ()
HO Ar
equivalent to:
N Me
CC
(+)
(+)
E1
(+) (+)
RO2C
N Me
(+)
E2
(+) equivalent to:
CHO
Ar
equivalent to:
CE1
(+)
(+)
E1
(+) (+)
N H
T1
() E1
(+)
(+) E2 () ()
HO
N Me
(+)
E2 ()
(+) equivalent to:
OH2 CH2
CE2 (+)
(+)
(+)
E1
(+)
Now consider further analysis of T1: Again, select the shortest E1-E2 bond path and disconnect next to quaternary center. Dissonant element is localized in 5-membered enamine Ar Ar (+) (+) Ar
() () (+) E2 () equivalent to:
E1 (+) () (+) E2 ()
E1 (+) ()
Me
N Me
D. A. Evans
Chem 206
:CN
C O
Me
base
X
Ph
CH2
Can one design "catalysts" which will provide access to carbonyl anion equivalents in situ??
CN
Ph
CN
Equivalent to:
O Ph C
Ph OH Ph
OH El CN Ph
O H
N functional group?
OH
Hydrogen cyanide is a fairly good Bronsted acid (pKaHOH 9.5) Equivalent to:
O
H C N
Acetonitrile can be attacked be nucleophiles:
H+
() +
:C N
O R El R
OH Q El
Me C N
Nu:
N Me C Nu
(+)
Me C N
30-07 Inversion Operators-1 11/30/03 6:18 PM
H+
+ H 2C C N
() (+)
C C
D. A. Evans
Chem 206
Extensions of the Benzoin condensation concept are possible in some instances: O Ar H CO2Et
Reactions equivalent to the benzoin are catalyzed by biological co-factors to make (and break) dissonant difunctional heteroatom-heteroaton relationships NH2 H N N Me S OH The pka of this proton has been the subject of considerable study. The current estimates are that the value falls in the range of 16-20 but this number is not firm. F. G. Bordwell JACS 113, 985, (1991)
NaCN DMF Ar
O OEt O
44% yield
Me
Me
Me
Me O R C
Me O R C
The in situ use of cyanide ion as an inversion operator is limited. Greater generality may be achieved by multistep alternatives:
In the absence of electrophiles 1 & 2 dimerize as would be expected for carbene reactivity. Me Me N H S OEt CN O C
base
Me
N S
Me Me N S OLi
Me
O R
OEt R
O H
R Li R
O C Li R
OLi R R OLi
O C O
D. A. Evans
Chem 206
O Me Me OH
The Reaction
1,4D
Me
The Catalyst:
HO
The Conditions: 0.1 equiv catalyst, Et3N or NaOAc, EtOH or DMF at 60-80 C
Examples:
O
R N S
R N S OH
Me O O Me Me O
Equivalent to:
Me C
"The catalyzed nucleophilic addition of aldehydes to electrophilic double bonds.", Stetter, H.; Kuhlmann, H. Org. Reactions 1991, 40, 407. O Me Me 61% yield Me O O O Me Me Me O Ph Me O O Me
H O
41% yield
R O Me Me OH S Me H Me N
Me R Me O
OH O
Me H O
Me Ph O O
Me
21% yield
1,2D
Ph n-Pr H O
Ph
Hence dissonant relationships may made from E-functions if "inversion operator" is employed () (+) (+) ()
inversion operator
n-Pr Ph O
Ph
70% yield
C E
1,4-D relationships may also be made from E-functions if "inversion operator" is employed.
C E
C C E
C E
1,2D (+)
The is a fundamental strategy for handling the formation and cleavage of D-relationships in nature.
C E
(+) () (+) + C C C
inversion operator
C E
C E
1,4D
D. A. Evans
Chem 206
O R (+) () O (+) OH
Inversion operators are constructed from A-functions or molecules containing D-relationships. The pyridoxal Co-factor (Vitamin B6)
H PhosphateO N O OH Me O OH N Me H2N R
O O R
O
(+) C
() The reverse processe can be achieved under basic conditions: O R M O (+)C O R O M O O O R (+) () O (+) OH
The critical difunctional relationlship is that between =O & =N. This is a 1,4-D relationship
H+
O OH
()
The Reaction
-CO2
H2N R
O C O
Such consonant relationships may be readily made (and broken) via the resident functional groups. The analog reactions for dissonant relationships not possible. O For example: Me OH X Me O H O C O
1,2-D relationship
O R (+) OH N (+) (+) N (+) H R N H
H 2N R
OH
- H2 O
O C O
1,6-C relationship
N H R
H 2N R
Tautomerization
+ H2O
N
Me
O X
MLn
E X
D. A. Evans
Enolates
O M
tautomerism is generally not a problem because oxyanionic tautomer still acts as carbon nucleophile
Homoenolates
M
tautomerism is a much larger problem because it is often irreversible and oxyanioic tautomer rarely acts as a carbon nucleophile Nakamura in Comp.Org.Synth., 1991, 2, 441
Homoenolate Equivalents
Definition: species containing an ionic carbon to a moeity which can be converted into a carbonyl group Examples:
O O
O O
in situ protection
Y X
X = OR, NR2, etc. Y = H, R, OR, NR2, etc.
O NR
Werstiuk in "Umpoled Synthons", Hase, Ed.; Wiley: New York, 1987, Chap. 6 Ahlbrecht, Synthesis, 1999, 365 (chiral examples)
(+)-camphenilone
()-camphenilone
no racemization occurred in >4 days at 250 C in the absence of base proposed to proceed via a "homoenolate anion"
Me Me Me O
OtBu
Me
Me Me O
Me Me O
OTMS OR
TiCl4
if conducted in CDCl3 leads to a deep wine-red color; precipitates as purple needles in hexanes IR spectrum strongly supports coordinated carbonyl (C=O = 1603 for R = iPr in benzene) molecular weight by cryoscopy is 560-620 indicating dimeric structure later verified in solid state by x-ray crystal structure (Floriani)
Relevant bond lengths (A): Ti-C 2.081 Ti-O 2.072 C=O 1.235 Nakamura, J.Am.Chem.Soc. 1983, 105, 651 Floriani, Organometallics, 1993, 12, 2845
TiCl3
R R' A:B >95 : 5 60 : 40 78 : 22
A
TiCl3
Pr
Me Me Ph
Me Et
R'
A can be isolated, but B is too unstable; only detected by in situ quench with electrophiles (i.e. Br2, RCHO) if non-racemic starting material is used, quench with electrophiles indicates non-racemized A and totally racemic B i.e.
OTMS OMe
>99:1
1. TiCl4 2. E+
O MeO
E
+
O MeO
E Me
Me
1:1
> 99% ee
Me
Cyclopropane Synthesis
most common method
Cl O Me Cl O
OEt
2 Na
OTMS OEt
TMSCl
Me OEt
2 Na
OTMS OEt
TMSCl
OTMS
OTMS
Et2Zn CH2I2
Ruhlmann, Synthesis , 1971, 236. Salaun, Org. Synth., 1985, 63, 147 Murai, J.Org.Chem., 1973, 38, 4354
30A-04 12/1/03 11:20 AM
Alkoxide-Modified Homoenolates
Tuning Titanium Homoenolate Reactivity
Problem: trichlorotitanium homoenolates are not reactive enough for some applications can also lead to chlorinated byproducts Idea: replace 1 or more chlorides with alkoxides to increase nucleophilicity
O
i
TiCl3
+
O PrO O
i
TiCl2OiPr
+ 1/2 TiCl2(OiPr)2
PrO O TiCl3
+
TiCl2OtBu
+ 1/2 TiCl2(OtBu)2
PrO
PrO
Have not been characterized to the detail of the trichlorohomoenolates Appear to have "significant contribution from monomeric forms" (from molecular weight data) Are more reactive than trichloro homoenolates towards homoaldolisation Nakamura, J.Am.Chem.Soc., 1986, 108, 3745
O OTMS OR
OR OR
vacuum
ZnCl2 Et2O
RO
+ 2 TMSCl
Zn
OEt2 RO
Zn
C=O = 1645 cm-1 2 inequivalent methylene groups in 1H-NMR Nakamura, Organometallics, 1985, 4, 641
ZnCu
Benzene / DMA 60 C, 3-4 h
O EtO O Et
ZnI
Quantitative
ZnCu
Benzene / HMPA 25 C, 1 h
ZnI
Poor yield (~50%)
O MeO
Br
Ln, "pinch" I2
Enolate Homologation
Synthesis of Zinc Homoenolates
OTMS
1. MeLi, 25 C 2. ZnEt2, CH2I2
ZnX
less reactive than most zinc homoenolates can also be used to form aldehyde homoenolates
OTMS H
1. MeLi, 25 C 2. ZnEt2, CH2I2
O ZnX
O RO
SnBu3
TiCl 4
O RO
TiCl3
+ Bu3SnCl
R = Me, iPr
CH2Cl2
Isotope labelling studies showed rxn does not proceed via cyclopropane Substrates can easily be prepared by two methods:
O MeO O
i
Bu3SnH, 80 C, 4 h
O MeO O
i
SnBu3
SnBu3
PrO
PrO
Goswami, J.Org.Chem., 1985, 50, 5907 van der Kirk, J. Appl. Chem., 1957, 7, 356 Still, J.Am.Chem.Soc., 1978, 100, 1481
R' Cl
Yield
Aldehyde
O O H O H Me O O Ph
i
Et
n-Oct
Acidic
O n-Oct O Me
81
Pr
2.5
Neutral
67
i
PrO OH
Ph (85:15)
Et
H Ph
1.5
Neutral
EtO Cl
Ph
90
O
+
TiCl3
+ 1/2 Ti(OR)4
2 i
O PrO
PrO
CH2Cl2
1 hour
R1
O R2 R1
OH
A
Electrophile Benzaldehyde Crotonaldehyde Acetophenone R
i i
B
Yield (A or B) 90(A) 88(A) 66(A), 12(B) 93(B) 62(B) 91(B) 91(B) dr = 88 : 12 equatorial attack
Temp(C) 0 0 20 20 20 20 20
Pr Pr
i t
Pr Bu
Cyclohexanone
i Pr t
Bu Bu
Me
OTMS OEt
+ RCHO
cat. ZnX2
O R OTMS
CH2Cl2, RT EtO
TMSCl generated is essential (i.e. no reaction if removed in vacuo for stoichiometric case) Aldehyde Catalyst, yield ZnCl2 (30-50 mol%) ZnI2 (0.1-1 mol%) 84 94 89 84
PhCHO
Ph O O O2N n-Pent CHO CHO OBn
30A-08 12/1/03 11:27 AM
CHO CHO
91
95
--
84
--
ZnX2
X O EtO R OTMS EtO O ZnX
+
EtO
O R
SiMe3 H
RCHO
O
+ 1.2 eq
OTMS Me
1 mol% ZnI2 OTMS CH2Cl2, RT 77%
OEt
Ph
Ph Me
OEt O
- no reaction even with stoichiometric ZnCl2 Nakamura, J.Am.Chem.Soc., 1987, 109, 8056
EtO OTMS
1.5 eq +
O R1 R2
R2
R2 R1
2. pTsOH
R1
Yield 99 76 82 84 52 78
Ph Ph TMS Cl
t
H H H H
Bu
H Me
Ph
a
O O
Ti
OiPr OiPr
TMSOTf
O O
Ti
OiPr OTf
OiPr Ti
+ TMSOTf
O OEt OiPr Ti
+
O EtO Ph OTMS
O O
OTf
O R OEt
TMS H
RCHO
O
i
Me R
syn +
O
i
I Me
3. RCHO, THF, 0 C RT Method A 1. Activated Zn, 0.1 equiv. TMSCl CH2Cl2, RT, 1 hour 2. RCHO, 2 equiv. TMSCl CH2Cl2, RT Method B
Pr2N O Me
OH
Pr2N
Pr2N
anti
R OH
Method
Yield 79 82 87 95 61 60
syn:anti 94 : 6 13 : 87 85 : 15 25 : 75 96 : 4 38 : 62
Ph
o-MeOPh 2-furyl
A B A B A B
idea:
O R Xc
1. nBuLi 2. Zn(CH2I)2
ICH2Zn
O Xc R
1. Cl3TiOiPr 2. R'CHO
O R' OH R Xc
O
Xc = Me
Me
initial results:
O Xc
Bn
1. nBuLi 2. Zn(CH2I)2 3. H +
O Me Xc Bn 30-40%
McWilliams, J.Am.Chem.Soc., 1996, 118, 11970 But ReactIR showed disappearance of enolate and appearence of new species
Bn
OLi Bn Xc
Zn(CH2I)2 (ICH2)2Zn
Bn O
H
Xc Bn
ICH2Zn
O Xc Bn
idea: add an equivalent of alkoxide to take the place of the enolate in the higher order zincate
O Bn Xc
O Me Bn Xc
ROLi
McWilliams, J.Am.Chem.Soc., 1996, 118, 11970 Harada, J.Org.Chem., 1993, 113, 2958
BnO ICH2Zn O Xc R
R T (C) -20 -20 -40 -40 -50 -20
O R Xc
O R' OH R Xc
de (%) 99 82 82 80 76 64
Yield 59 58 50 44 53 53
Bn BocHN
Bn Me Bn Me Bn Bn
phenyl phenyl
iso-propyl n-butyl
Reactive Homoenolates
First Synthesis of a Metal-free Homoenolate
TMS O OMe
TBAT
Bu4N
O OMe
O OMe
TMS
O OMe
1. TBAT 2.
Ph Ph Ph
NHPh O
Ph
+
Ph N O
Ph
OMe
single diast. 22%
Ph
1:1 dr 60%
O
Mg anode, 2 e
TMS
-
O OMe
OMe
TMSCl, DMF
Fry, Tetrahedron Lett., 1999, 40, 7945 Nishiguchi, Tetrahedron Lett., 1992, 33, 5515
OTMS R
2
R2 R3 R4 O OEt
R3
R4
Enone
Product
Yield
Enone
Product
Yield
OTMS
93
O H Me O
78
OTMS Me H Me Me Me
75
(CH2)2CO2Et O OTMS
72:28
91:9
(CH2)2CO2Et OTMS
73
(CH2)2CO2Et Me Me
Me Et Me
(CH2)2CO2Et
Nakamura, J.Am.Chem.Soc., 1987, 109, 8056 Nakamura, Org. Synth., 1987, 66, 43
1.5 equiv.
O R Cl
O
4 mol% Pd(PPh3)4
EtO
Benzene / DMA
RT, 30 min
EtO O
Yield 100
Ph
90
Me Ph Cl
92
100
O O R2 Cl
5 mol% PdCl2(PPh3)2
Zn
Et2O, RT
R 1O O
R2
R 1O
note: only 0.5 equiv. of Zn species needed so both homoenolates are transferred R1 R2 Yield 93 when carried out in CDCl3 got quantitative O-acylation (with or without Pd) i.e.
Et
i
Ph
Me
Pr
81
Me Ph
t
OR1 OCOR2
Et
i
83
Pr
Bu
50
Me R OH
O NiPr2
MsCl / Et3N CH2Cl2 0 C, 1 h
Me
MsO
Silica Gel 1-3 days
Me R OMs
O NiPr2
NiPr2
Me
Ph
R O O
p-ClPh p-MeOPh
Bn
30A-14 12/1/03 11:34 AM
ZnI
X
+
O
1-4 mol% PdCl2(P(o-Tol)3)2 Benzene-DMA 60 C 0.5-1 h
EtO
Bu
OTf
MeO
96
Br
67
O2N
80
X
+
O
1-2 mol% PdCl2(P(o-Tol)3)2
Zn
THF, 0-20 C
X = I, Br, OTf
RO
RO
R = Et, iPr
Coupling Partner
Yield 90
Bu
I SiMe3
Me
87
Br X
X = OTf Br I 0 67 79
Me Br O
Nakamura, J.Org.Chem., 1987, 26, 8056 49
R1
1.5 equiv.
R2 OTMS+ ArOTf
O R2 R1
PdArLn
R1
R2
Ar
1-napthyl p-NO2Ph
Yield 84 68 65 58
-CH2CH2CH2CH2-CH2CH2CH2CH2H
n-Heptyl p-OMePh
Phenyl
1-napthyl
R1 R2
EtO
20 mol% CuCN THF / DMA RT, 24 h
SN2' +
1 R2
O EtO
R1 R
2
SN2
R1
R2
X OTs
OTs Br Cl
Yield 89 80 93 99 80
H Ph CO2Me
H H H
Br
O Cl R
2
O
i
Zn
R1
PrO O
+
SN2'
1 R2
PrO
R = Et, iPr
PrO R
2
R1
SN2
Allyl chloride
Yield
Ph Me Me Me AcO
Cl Me Cl Me
97 65
81
88 : 12
72
100 : 0
Cl
Nakamura, J.Am.Chem.Soc., 1987, 109, 8056
OTMS OR
R = Et, Pr, n-Hex
i
O RO O
O OR
Yields: 65-80%
O RO
PdArLn
evidence
OTMS OR
O RO
O RO
O X R EtO
O
2
1.2 equiv.
O X R
X
OR N
Zn
O X EtO R OH
O
2
2.4 equiv.
O X N R HO
OR
50-80% 80-90%
Zn
Mechanistic Considerations
TMSO OEt
R EtO O ZnX
H+
EtO2C
CO2Et R
problem: two steps have opposite electronic requirements appears amide and ester have right balance; ketone too electron poor to cyclize i.e.
O Me R EtO
O
2
TMSO Zn EtO O
Me
O OEt R
Leahy Cyclopentannulation
Synthesis of 3,3-disubstituted cyclopentanones
O R OHC
1
1.2 equiv.
2
EtO2C R2 R1 TMSO
H2SO5, EtOH 67% avg (from enal)
EtO
Zn
R2
O R R1
Substrates studied: R1 = R2 = n-Bu R1 = R2= Ph R1 = Ph, R2 = Me R1 = Ph, R2 = H
2
EtO2C R2 EtO2C R1
OH OEt
1. CH3MgBr, THF, 0C 2.
OH H H OH
OLi
67% -78 25 C
A possible mechanism:
Synthetic Examples
Depresosterol
OH Me Me Me H AcO H CHO H PrO
60%, > 6:1 dr
i
TiCl2OiPr Me H AcO
Me Me H O
OiPr
H H
Me O
Synthetic Examples
Depresosterol - completion of the formal synthesis
O CO2iPr R
R = steroid ring system 1. MsCl, Et3N 2. KOH, MeOH, 3. aqueous HCl 4. TBSCl, Et3N (reprotects steroid OH) 84%
OH Me
O Me R
1. LDA, -78 -10 C 2. CH2O (g) 3. aqueous HCl 70%, ~10:1 dr
OAc Me Me H Me H AcO
Triacetyldepresosterol Kashman Depresosterol
OAc Me OH Me
1. MeLi, THF, 45 C 2. Aqueous AcOH, rt
O O Me R OH
Nakamura, J.Am.Chem.Soc., 1985, 107, 2138 Kashman, Tetrahedron, 1981, 37, 2397
Synthetic Examples
Depresosterol - Maximizing Homoenolate Functionality
O O Me Me H O
Me
O Me
OH Me
OH Me
Me
OH Me
Synthetic Examples
Pumiliotoxin 251D
1. 2Ti Cp
OMe N Cbz O
Me Al Me Cl
Me N Cbz Me OH H O
6.2 eq
TiCl3
EtO
49%
2. 1 N HCl 87%
Me OH H
3 steps
H2, Pd/C
O N Cbz H Me OH OEt
N Me
Pumiliotoxin 251D
Gallagher
N O
100%
Me
"single diastereomer"
Nu via:
N H CBz
Ti Ln
O
Nu
Barrett, J.Org.Chem., 1999, 64, 1410 Gallagher, J.Am.Chem.Soc., 1991, 113, 2652
Synthetic Examples
EtO O
()-Cortisone
6 steps
O
() -
Me
Me
i PrO
O
2
Zn
2.6 equiv.
O
()
Me
Me OH
OTMS H
CuBrDMS, 0.15 equiv. O HMPA, 2.6 equiv. BF3OEt2, 4.8 equiv. i PrO >95:5 dr, >80%y
OH Me Me H O
()-cortisone Nakamura, J.Org.Chem., 1986, 51, 4324
O OH
7 steps
Synthetic Examples
()-Ginkgolide B
O O EtO2C
()
EtO
1.2 equiv.
2 Zn
CO2Et
OTES Bu
TMSCl, 2.4 equiv. CuBrDMS, 0.25 equiv. HMPA, 2.4 equiv. THF, 23 C, 4 h 82%
OTES tBu
h (366 nm) hexanes 100%, 98:2 dr
HO OH
O O
CO2Et
Me
HO O O
Bu
TESO
Bu
D. A. Evans
Chem 206
http://www.courses.fas.harvard.edu/~chem206/
Carey & Sundberg-A, p 337: Provide mechanisms for the following reactions.
OH NH2 CHO
NaNO2 HOAc/H2O
OH NH2
NaNO2 HOAc/H2O
D. A. Evans
31-00-Cover Page 12/3/03 8:35 AM
CMe3
CMe3
D. A. Evans. B. Breit
Carbocation Subclasses
Carbon-substituted R1 R3 R1 R3 Heteroatomstabilized
Carbocations: Stability
Hydride ion affinities (HI) Me CH2 27 Me2 CH 249 CH2 276 37 +21 H 2C CH 287 20 +81 18 Me3 C 231 HC C 386
Chem 206
O R2
R R3
R
N R2
276 H 3C
R2
C C
Ph
C
C C
CH2
Me
CH2 276
C C symmetrical bridging
H 2C
CH 256
CH2
239
open trivalent
hyperconjugation no bridging
unsymmetrical bridging
276
Stability: Stabilization via alkyl substituents (hyperconjugation) Order of carbocation stability: 3>2>1
R R C R H > R C R H > H C R H > H C H
Hydride ion affinities CH3+ CH3CH2+ (CH3)2CH (CH3)3C
+ +
Hydride ion affinities versus Rates of Solvolysis PhCH2Br rel rate HI -HI 100 239 0 CH=CHCH2Br Me2CHBr 52 256 +17 0.7 249 +10
The relative stabilities of various carbocations can be measured in the gas phase by their affinity for hydride ion. R + H RH + HI
Hydride Affinity = G HI increases C(+) stability decreases Note: As S-character increases, cation stability decreases due to more electronegative carbon.
J. Beauchamp, J. Am. Chem. Soc. 1984, 106, 3917.
H2C=CH+
C+
PhCH2+
Conclusion: Gas phase stabilities do not always correlate with rates of solvolysis
M. Shair, D. Evans
Chem 206
LA
R 3C
LAX
LA: Ag , AlCl3, SnCl4, SbCl5, SbF5, BF3, FeCl3, ZnCl2, PCl3, PCl5, POCl3 ... X: F, Cl, Br, I, OR Acidic dehydratization of secondary and tertiary alcohols
R3C OH + HX
- H2 O
R 3C
R: Aryl + other charge stabilizing substituents X: SO42-, ClO4-, FSO3-, CF3SO3From neutral precursors via heterolytic dissociation (solvolysis) - First step in SN1 or E1 reactions R 3C X
solvent
R 3C
+ X
Carbocation Generation
Hydride abstraction from neutral precursors
Ability of X to function as a leaving group: -N2+ > -OSO2R' > -OPO(OR')2 > -I -Br > Cl > OH2+ ... Addition of electrophiles to -systems
R R R R H H H R R R R H Provide a Mechanism of this transformation H2SO4
Br
chemistry
R
R 3C H
Lewis-Acid
R 3C
R RS RS R2N R 2N
H R 3C H = H
chemistry
H H
H H
H H
etc.
Lewis-Acid:
HC C CH2OH
Me O
D. A. Evans, B. Breit
Carbocations: Structure
Chem 206
Physical Evidence for Hyperconjugation: The Adamantyl Cation Bonds participating in the hyperconjugative interaction, e.g CR, will be lengthened while the C(+)C bond will be shortened. First X-ray Structure of an Aliphatic Carbocation 1.431
+
C
R+ H H H C C H H
+
100.6 1.608
Me
[F5SbFSbF5]
C
+
Me
CR
CR
Me
+
C
H H
+
C
H H
CR
CR
Me H H C
+
C
Me Me
1.582
1.092
110
Me Me Me
1.530
+
1.107
D. A. Evans, K. Scheidt
Carbocations: Structure
Chem 206
Me
[F5SbFSbF5]
C
Me Me
SbF5
Me Me
+
C Me
F5Sb F
SbF5
Me Me
2 SbF5
Me
Me Me
Me
1.466
1.421
+
1.622
1.439
1.621
98.2 1.608
F5Sb F
SbF5
1.551
D. A. Evans, K. Scheidt
Carbocations: Structure
Chem 206
Cl Cl
Cl SbF5
Cl
Cl + SbClF5
Me Me Ph F
SbF5
Me Me
+
C Ph +
SbF6
+
1.422 Cl 1.725 1.371
+
1.432 1.491
1.442 121.0
117.8 1.446
+
1.439
1.505
121.2
1.508
D. A. Evans, K. Scheidt
Chem 206
Ph + C AgSbF6
Cl
Me
Me
Me Me F5Sb F SbF5
+
Me H Me Me
Me
2 SbF5
2.092
1.467 1.739 **
1.495
+
1.467
+
1.442
1.855
1.503
C C
C C
hyperconjugation no bridging
unsymmetrical bridging
D. A. Evans, K. Scheidt
Chem 206
+
1.439
2.092
1.739
1.371
1.491
1.467
+
1.442
+
1.855 1.621 98.2 1.608 1.622
1.503
C
C C
C C
open trivalent
hyperconjugation no bridging
unsymmetrical bridging
symmetrical bridging
D. A. Evans, B. Breit
Chem 206
OSolv R R R R
As ring size decreases, the rate of hydrolysis also diminishes. Implying that the formation of the linear vinyl cation is disfavored due to increasing ring strain.
R D R OTf
H+
allyl cation
R D
C C
Hyperconjugation
Stabilization by Phenyl-groups The Benzyl cation is as stable as a t-Butylcation. This is shown in the subsequent isodesmic equations: H0r [kcal/mol] (CH3)3C + PhCH3 (CH3)3C + PhCH2Cl (CH3)3CH + PhCH2 (CH3)3CCl + PhCH2 3.8 - 0.8
A secondary kinetic isotope effect was measured to be KH/KD = 1.5 (quite large) indicating strong hyperconjugation and an orientation of the vacant p orbital as shown above.
P. J. Stang J. Am. Chem Soc. 1971, 93, 1513; P. J. Stang J.C.S. PT II 1977, 1486.
H 3C
CH2 276
H 2C
CH 287
HC
239 H 2C CH 287 298 The ring geometry opposes rehybridization (top) so the vacant orbital retains sp2 character. Additionally, the empty orbital lies in the nodal plane of the ring, effectively prohibiting conjugative stabilization. PhCH2Br 100 HI -HI 239 0 Me2CHBr 0.7 249 +10 CH=CHCH2Br 52 256 +17 +11
Phenyl Cations
D. A. Evans, B. Breit
Chem 206
Solvolysis rates represent the extend of that cyclopropyl orbital overlap contributing to the stabiliziation of the carbenium ion which is involved as a reactive intermediate:
OTs Me Me OTs Cl
krel = 1
OTs
krel = 1
OTs
krel = 1
Why??
krel = 106
krel = 108
krel = 10-3
CareyA, p 286
R
1.474 Me
Bridgehead Carbocations
Me Me
why so reactive?
1.444 1.534
10-7
10-13
104
Bridgehead carbocations are highly disfavored due to a strain increase in achieving planarity. Systems with the greatest strain increase upon passing from ground state to transition state react slowest. 24 why so reactive?
TsO
TsO
D. A. Evans, J.Tedrow
Chem 206
"The Synthesis and Isolation of Stable Hypervalent Carbon Compound (10-C-5) Bearing a 1,8-Dimethoxyanthrecene Ligand" Akibe, et al. JACS 1999, 121, 10644-10645 +
Me
OMe
CO2Me OMe
Me
MeO O C
OMe O
Me3O+BF4
B2F7
"The relevant CO distances are longer than a covalent CO bond (1.43 ) but shorter than the sum of the van der Waals radii (3.25 )."
2.428
+
2.428 2.452 1.483
+
2.452
For a recent monograph on hypervalent Compounds see: "Chemistry of Hypervalent Compounds", K. Akiba, Wiley-VGH, 1999
D. A. Evans, J.Tedrow
Chem 206
Ph
+
Ph
Fe
Fe
C Fe
R R Fe
R R
Cyclopropene MM 2
R. L. Sime, etal. JACS 1974, 96, 892 1.389 1.428 1.297
+
1.412
R C (OC)3Co C R
Co(CO)3
D. A. Evans, J. Tedrow
Chem 206
Nu = BnNH
Nu
Nu = CH(CO2Me)2
94% ee
Nu
91% ee
O S CMe3 1b, Ar = -naphthyl Me CHMe2
1+ Nu inversion L
OAc
1b
Nu, CH2Cl2, -20 C
94% ee
Nu
91% ee
Ar2P
Nu OAc Me CHMe2
Nu, CH2Cl2, -20 C
96% ee
Nu
97% ee
OCO2Et
1b
Nu, CH2Cl2, -20 C
Nu = CH(CO2Me)2 Nu = BnNH
94% ee
94% ee
conditions: 2 mol% [C3H5-PdCl]2, 2b
BocN
Ph
P S
Ph
Ph C1
C2 Ph
C2
Selected Bond Lengths: Pd-C1, 2.16; Pd-C2, 2.28 Pd-P, 2.29 ; Pd-S, 2.38
Selected Bond Lengths: Pd-C1, 2.17; Pd-C2, 2.26 Pd-P, 2.25 ; Pd-S, 2.36
C1
C2
Pd-C1, 2.16
Nu C1
Pd-C2, 2.28
Evans, Campos,Tedrow, Michael, Gagn, JACS 2000, 122, 7905
C2
Pd-C1, 2.17
Nu Pd-C2, 2.26
D. A. Evans
Chem 206
http://www.courses.fas.harvard.edu/~chem206/
Here is a typical carbonium ion question that you should be able to handle by the end of the course. Write out a mechanism for the following transformation. Me Me
BF3OEt2
Me H O
Me
CH2Cl2
60% yield
OBF4 Me
Me
Me OBF4 A. Srikrishna, Chem Commun 1994, 2259 Question 13. Final Exam, 1999. During Corey's synthesis of Aspidophytine (JACS, 1999, 121, 6771), the pivotal intermediate 3 was assembled by the union of 1 and 2 under the specified conditions. Provide a mechanism for this single-pot transformation. CHO OHC CO2R temp, 5 min Me3Si
2 1) mix at room 2) 2 equiv.
NH2 TFAA, 0 C
Ra N Rc
Rb Rd
3) excess NaBH3CN
D. A. Evans
32-00-Cover Page 12/5/03 8:52 AM
N OMe Me N Me H
3
M. Shair, D. Evans
Carbocation Rearrangements-1
OH CH2 NH2
Deamination " NO+ "
OH CH2
bridging T.S.
Me H Me Me Me
A B
C D
Me Me OH H A Me H Me
-caryophyllene alcohol
H Me Me H
equiv to
OH Me H Me Me Me
Me H Me Me h [2+2] O H H Me Me
MeMgBr
M. Shair, D. Evans
Carbocation Rearrangements-2
Chem 206
krel = 95
Carbocations: Neighboring Group Participation s Groups with accessable electron density (heteroatoms, arenes) and the correct stereoelectronic orientation (anti-periplanar) can "assist" in the ionization of a leaving group.
X: R R X R R Y R R
Nuc:
R R
Y-
X: R R
R R Nuc
H H Ph
L-Threo
OTs
+3
H Me
krel = 10
OTs O O Me
HOAc
O Me O
Me Me Ph
L-Erythro
M. Shair, D. Evans
Chem 206
References:
OCOCF3
OCOCF3
H Me
OCOCF3
OCOCF3
"These figures established the -effect as one of the kinetically strongest in organic chemistry": J. Lambert Data provide no distinction between open and bridged intermediates
SiMe3 E
H 2C
Si
occ pz
SiC pz empty
SiC
pz
Me3Si
SiMe2Ph
H
Me3Si SiMe2Ph Me3Si
SiMe2Ph
SiMe2Ph
CH2 H
versus
both silanes
yield the same product mixture. Hence, the reaction proceeds most likely via a common intermediate, a carbeniumion
M. Shair, D. Evans
Chem 206
General: Allylsilanes are more nucleophilic than alkenes HOMO is higher in energy due to negative hyperconjugation
( *)
CSi
Me3Si
SiC SiC
But
Ph H HF R Protodesilylation
Me3Si
Si
H
1
Me3Si is not sufficiently Lewis acidic to activate C=O through pre-association; however (RO)2MeSi is Lewis acidic enough to activate C=O through pre-association. These allylsilanes add to RCHO througl closed transition states X nM R1 O R2 R R1
OR
CSi
R
R Si
R H
CSi
R1
R R2
A1,3-strain minimized
Antiperiplanar TS
H
Synclinal TS
O X nM H
E E R R2 R1 R
+ Nu - NuSiMe3
SiMe3
SiMe3
Si
Calculations by Houk et al. show that the relative energy differences between the antiperiplanar and and synclinal transition states are negligible. Both the antiperiplanar and synclinal models predict a syn selectivity for the newly formed stereogenic centers. O H + Me3Si Me TiCl4 CH2Cl2 R Me O R H + Me3Si Me Hayashi, TL 1983, 2865. TiCl4 CH2Cl2 R OH R Me Me OH OH > 95:5 syn
R3
CSi
R H
+ Nu
R E
H Si
- NuSiMe3
R3 R H E
R21 R
R3 H R
E R2 R1
syn
major (trans)
minor (cis)
ca. 65
35
Catalytic Enantioselective Addition of Allylic Organometallic Reagents to Aldehydes and Ketones, Denmark and Jiping Fu, Chem. Rev. 2003, 103, 2763-2793 (handout)
B. Breit, D. Evans
Allylsilanes:
Chem 206
Si migration may be promoted by using hindered Si substituents OTiCl4 TiCl4 CH2Cl2 Si(iPr)3 Si (iPr)3 Me ?? O Me Me OTiCl4
diastereoselection: 97:3 (Pri)3Si 85% yield n-C4H9 Me Me OCH3 Me Me O Me diastereoselection: 96:4 68-70% yield 75% SiMe3 Me3Si Me O n-C4H9 MeO2C Ar (Pri)3Si Ph(Pri)2Si MeO2C MeO2C Ar SiR3 CO2Me ZrCl4 CH2Cl2 Ar SiR3 MeO
TiCl4
(83%)
17% Me 78% O
Me
SiMe3
EtAlCl2 CH2Cl2
B. Breit, D. Evans
Chem 206
1. Me3C+ is more stable than Me3Si+ in spite of the fact that Si is less electronegative than C.
H Si Me C H Me Me C C H Me H Me C C H Me Si Me H H C H H CSi bond length: 1.87
R1 R2 RETENTION
El El
R1 H Me3Si R2
+ Nu - NuSiMe3
CC bond length: 1.54 H H H CSi hyperconjugation is less pronounced than the anaologous CC hyperconjugation do to the impact of the longer CSi bond lengths.
H R1
El R2 SiMe3
( C(+) to silicon
Me Si Me Me3Si
Et Et OMe OMe
( C(+) to silicon
R TiCl4 R Me H Me OH SiMe3 Me O Me
CSi hyperconjugation is less pronounced than the anaologous CC hyperconjugation do to the impact of the longer CSi bond lengths.
Fleming p 289
3. According to Lambert, silicon has a propensity to stabilize carbonium ion via hyperconjugation (vertical stabilization) rather than bridging (nonvertical stabilization.
Me3Si Me3Si C H C H H Me3Si H H C C H H H H C C H H
( C(+) to silicon
N H Fleming p 148 Me Me NH SiMe3 (CH2O)n TsOH N H N
4. Silicon has a lower propensity to undergo WagnerMeerwein like rearrangements than carbon.
M. Shair, D. Evans
R1 R3 N R2 R4
Chem 206
Iminium Ions
X-
TFA
Me3Si
(Z)
Ph
N H H
H N
R1 N R2
R3 R4
(E)
TFA
N Me3Si Ph
H+, -ROH
Ph H N H SiMe3 N H H H
N
or Lewis Acid
R1 H
Oxidation of Amines
N HgX2 Me X H
Hg
X rds
Hg(0) Me N H HX
SiMe3
(Z) vinylsilane)
(E) vinylsilane)
N H Me
Only in the case of the (Z) vinylsilane is the emerging p orbital coplanar with C-Si bond. Full stabilization of the empty orbital cannot occur with the (E) vinylsilane.....hence the rate difference.
N
Hg(OAc)2/EDTA NaBH4
O Me
TMS Me R
Me
PPTS, MeOH 80C
TMS N H MeOH
H N H
Me
R steps
pumiliotoxin A
Me
OH
D. A. Evans, M. Calter
Review:
Chem 206
Heimgartner, H. In "Iminium Salts in Organic Chemistry"; Bohme, H., Viehe, H., Eds.; Wiley: New York, 1979; Part 2, pp 655-732. The 3-aza-Cope Rearrangement: Neutral Variant:
R
3 2
1
Me R
1
Me N Me
250oC, 1 hr
Me
[3,3]
Exothermic as written by ~7-10kcal/mole. First Cationic Case: Elkik Compt. Rend. 1968, 267, 623.
Ammonium Variant: p. p.
R R N
[3,3]
R R
Even more exothermic than the neutral version, since enamine lacks resonance and iminium salt has stronger p-Bond than imine does.
Me + N Me
Me Me
80 oC, 2-3 hr
Me Me
Me Me
No yields given.
H2O
2-aza-Cope Rearrangement:
2
OHC
Me Me
R N
1
[3,3]
R N
In the simplest case, degenerate. Steric effects, conjugation, or selective trapping of a particular isomer, will drive equilibrium. As with the 3-aza-Cope, the cationic version proceeds under much milder conditions.
Good way to allylate aldehydes: Opitz Angew. Chem. 1960, 72, 169.
R'' N R'' H
+
OHC R
R'
-H2O
R''
N R'' R
R'
+
1-aza-Cope Rearrangement:
1
R'''
[3,3]
2
1
The 3-aza-Cope rearrangement can be driven in reverse by judicious choice of substrates(i.e., incorporating the imine into a strained ring or by making R an acyl group).
H O
R'
H 2O
R'' R''
R' N R R'''
[3,3]
R'' R''
R' N R R'''
R R'''
D. A. Evans, M. Calter
Chem 206
H
2-aza-Cope
Ph
Ph
H 2O +
N H
PhCHO
Equilibrium between A and B driven towards B by conjugation of iminium double bond to the aromatic ring in B. Application to Yohimbine Analog Synthesis: Winterfeldt Chem. ber. 1968, 101, 2938. N H H OH CO2Me H OMe N H
p. p.
MeOH
..
N H
N H
Yohimbane
Yohimbine
NH
POCl3
NH
NaBH4
N C 3H 7 O
O N H
N H
NaBH4
NH
C 3H7
N H
OMe N H N C 3H 7 O
15-Methoxy-isoyohimbane
M. Shair, D. Evans
Chem 206
SiMe3
H 67% O N Me
CH2
Me BnO
Me
O
81%
The origin of the modest diastereoselection has not been attributed to 2-aza-Cope process.
[3,3]
SiMe3
H N O Me
CH2
BnO OH N O
HCO2H
29% Me
OAc
NaBH4, MeOH, 83%
O Me Me N
N OAc
Me Me
Ph
BnO Me HCO2 Me N
OAc
CSA, 60oC, 1.5 hr, 79%
Ph
O O
Ph
Ph
Me
[3,3]
Me
HO
OH HO
BnO Me
OH
N Me
Homo-chiral
Ph
(-)-hastancine
Me
N O Me
racemic product
Conclusion: 2-aza-Cope rearrangements afford a low-barrier to competing processes
M. Shair, D. Evans
Chem 206
2-Aza-Cope-Mannich sequence:
OR OR
N H HO
[3,3] HO NR2
HO
Ar
N Bn [3,3]
Ar
ROH2C O N O
N H Bn
Bn
O NR2 steps
OR O O NR2 N H
O H O N steps O HO O N Pancracine
equivalent to
N H N O H HO
strychnine Overman et al. JACS 1995, 117, 5776. Overman et al. JOC 1991, 56, 5005
HO
D. Evans, E. Shaughnessy
Chem 206
Prins reaction: Adams, D.R.; Bhaynagar, S. D. Synthesis 1977, 661 Prins & carbonyl ene reactions: Snider, Comprehensive Organic Synthesis, 1991, Vol. 2
Ph
Me X R2 Ph
-
>95% ee
OH
Me Me O
Ph
Me O Me
Cl4SnO Me Me
Prins
OH R1 - H+ R2
Cl4SnO Me Me
[3,3]
pinacol
O Ph
enantiopure
Ph H Cl4SnO Me Me O
Me Me
Me Me O
Me Me
>95% ee
>95% ee
If a [3,3] rearrangement were intervening, the product would be racemic. Overman, JACS 2000, 122, 8672 Overman, Org Lett 2001, 3, 1225
Pinacol Prins
Ph H Cl4SnO Me Me Me HO
Me
Cl4SnO
O Me Me
syn
Me
7:1 anti:syn
D. Evans, E. Shaughnessy
Prins-Pinacol Mechanism
Ph SnCl4 CH2Cl2 Me Me Me O O Me
-
Chem 206
Me N O (-)-Magellanine Me H OH
Ph Cl4SnO Me Me O
Me Me
Cl4SnO
Ph
[3,3]
Ph H O MeMe Me Me Aldol
pinacol O Me Me O Ph
enantiopure
The pivotal transformation O TESO SnCl4 CH(OMe)2 57% 1. OsO4, HIO4 2. Ph2CHNH3Cl NaBH3CN (-)-Magellanine Me N O H CHPh2 N O OH Me Steps H OMe H OMe
Homo-chrial
Cl4SnO
Me Me
>95% ee
Ph
OH
Ph Ph cyclization N Me Me
:OH
Ph
Ph O N Me
Ph
Me
[3,3]
Me Ph OH Me N Me Me Ph Mannich Ph O
Homo-chiral
N Me
O H OMe
O H OMe
racemic product
mixture of diastereomers
D. Evans, E. Shaughnessy
Chem 206
(-)-7-Deacetoxy-alcyoninacetate
trans-Kumausyne
Me I t-BuLi, THF, -78 C Me Me OHC Me O Me OMe Me TMS Me OHC Me OH [3,3] O Me R Me TMS Me R Me O TMS 1. TMS Et BF3OEt2 -78 C rt 73% 2. TBSCl HO H O O OTBS Et O O 1. H2, Pd-C, 88% 2. Swern, 100% OTIPS Me OH H Me BF3OEt2 (3 equiv.) CH2Cl2, -55 -20 C 79% O H OBn O O m-CPBA 72% 4:1 regioselectivity O H OBn O H PPTS, MeOH 64% OH TMS OH Felkin Control (Lecture 20) Me OH BnOCH2CHO RSO3H, rt OH 69% OH [3,3] O OBn O OBn OH
CHO O TMS
H CHO O H
O H
97%
D. A. Evans
Chem 206
Application to Leucasandrolide
Me OH O OMe O O O OMe O OH HO O O Me Me Me Me OH
El SiMe3
Prins
R O El
OH
OBn
OTBS
Control of hydroxyl center: see Lecture 20 Let El(+) = Lewis acid activated RCHO
SiMe3 RCHO R O F 3B BF3OEt2 base O R SiMe3 O O R O BF3 R Me I BnO OTBS Myers, JACS 1997, 119, 6496 base = Me3C N CMe3 R O No (little) control over this () stereocenter HO R R BnO O TMS H O R BF3OEt2 R BnO OH O R
aldol
H SiMe3
Prins
R O
OX R
diastereoselection >20:1 Me
OTs H H Ph Me Me
H Me
Cram: "Just remember Dave, old deadwood is better than young deadwood."
Ph
"A View from the Far Side. Memorable Characters and Interesting Places." Evans, D. A. Tetrahedron 1999, 55, 8589-8608.
Quotes-7 12/5/03 9:31 AM
D. A. Evans
Chem 206
OR N RO N OMe Me TFA O OR TMS OR
http://www.courses.fas.harvard.edu/~chem206/
CO2R
MeO
reversible?
O OR TMS
MeO MeO
N Me
N Me
2) 2 equiv. TFAA, 0 C
Ra +N Rc
Rb Rd
3) excess NaBH3CN
NaBH3CN
NH2
CO2R
MeO
N OMe Me
MeO MeO
N Me
Me
D. A. Evans
33-00-Cover Page 12/7/03 8:55 PM
D. A. Evans, M. Calter
Review:
Chem 206
Heimgartner, H. In "Iminium Salts in Organic Chemistry"; Bohme, H., Viehe, H., Eds.; Wiley: New York, 1979; Part 2, pp 655-732. The 3-aza-Cope Rearrangement: Neutral Variant:
R
3 2
1
Me R
1
Me N Me
250oC, 1 hr
Me
[3,3]
Exothermic as written by ~7-10kcal/mole. First Cationic Case: Elkik Compt. Rend. 1968, 267, 623.
Ammonium Variant: p. p.
R R N
[3,3]
R R
Even more exothermic than the neutral version, since enamine lacks resonance and iminium salt has stronger p-Bond than imine does.
Me + N Me
Me Me
80 oC, 2-3 hr
Me Me
Me Me
No yields given.
H2O
2-aza-Cope Rearrangement:
2
OHC
Me Me
R N
1
[3,3]
R N
In the simplest case, degenerate. Steric effects, conjugation, or selective trapping of a particular isomer, will drive equilibrium. As with the 3-aza-Cope, the cationic version proceeds under much milder conditions.
Good way to allylate aldehydes: Opitz Angew. Chem. 1960, 72, 169.
R'' N R'' H
+
OHC R
R'
-H2O
R''
N R'' R
R'
+
1-aza-Cope Rearrangement:
1
R'''
[3,3]
2
1
The 3-aza-Cope rearrangement can be driven in reverse by judicious choice of substrates(i.e., incorporating the imine into a strained ring or by making R an acyl group).
H O
R'
H 2O
R'' R''
R' N R R'''
[3,3]
R'' R''
R' N R R'''
R R'''
M. Shair, D. Evans
Chem 206
SiMe3
H 67% O N Me
CH2
Me BnO
Me
O
81%
The origin of the modest diastereoselection has not been attributed to 2-aza-Cope process.
[3,3]
SiMe3
H N O Me
CH2
29% Me
BnO OH N O OAc
NaBH4, MeOH, 83%
O Me Me N
N OAc
Me Me
Ph
BnO Me HCO2 Me N
OAc
CSA, 60oC, 1.5 hr, 79%
Ph
O O
Ph
Ph
Me
[3,3]
Me
HO
OH HO
BnO Me
OH
N Me
Homo-chiral
Ph
(-)-hastancine
Me
N O Me
racemic product
Conclusion: 2-aza-Cope rearrangements afford a low-barrier to competing processes
M. Shair, D. Evans
Chem 206
2-Aza-Cope-Mannich sequence:
OR OR
O N H HO NR2 (CH2O)n, Na2SO4 MeCN, 80C HO NR2 N [3,3] HO NR2 N HO O CH2O/HCl NHBn
Axial Attack 98 %!! Mannich Rxn O H2/Pd-C CH2O/HCl ROH2C N O NR2 steps OR O O O H
Ar
N H Bn
equivalent to
NR2 O H 67% N H N H N O H HO
strychnine Overman et al. JACS 1995, 117, 5776. Overman et al. JOC 1991, 56, 5005
O H O N steps O HO HO N O Pancracine
Pictet-Spengler cyclization
D. Evans, E. Shaughnessy
Chem 206
Prins reaction: Adams, D.R.; Bhaynagar, S. D. Synthesis 1977, 661 Prins & carbonyl ene reactions: Snider, Comprehensive Organic Synthesis, 1991, Vol. 2
Ph
Me X R2 Ph
-
>95% ee
OH
Me Me O
Ph
Me O Me
Cl4SnO Me Me
Prins
OH R1 - H+ R2
Cl4SnO Me Me
[3,3]
pinacol
O Ph
enantiopure
Ph H Cl4SnO Me Me O
Me Me
Me Me O
Me Me
>95% ee
>95% ee
If a [3,3] rearrangement were intervening, the product would be racemic. Overman, JACS 2000, 122, 8672 Overman, Org Lett 2001, 3, 1225
Pinacol Prins
Ph H Cl4SnO Me Me Me HO
Me
Cl4SnO
O Me Me
syn
Me
7:1 anti:syn
D. Evans, E. Shaughnessy
Prins-Pinacol Mechanism
Ph SnCl4 CH2Cl2 Me Me Me O O Me
-
Chem 206
Me N O (-)-Magellanine Me H OH
Ph Cl4SnO Me Me O
Me Me
Cl4SnO
Ph
[3,3]
Ph H O MeMe Me Me Aldol
pinacol O Me Me O Ph
enantiopure
The pivotal transformation O TESO SnCl4 CH(OMe)2 57% 1. OsO4, HIO4 2. Ph2CHNH3Cl NaBH3CN (-)-Magellanine Me N O H CHPh2 N O OH Me Steps H OMe H OMe
Homo-chrial
Cl4SnO
Me Me
>95% ee
Ph
OH
Ph Ph cyclization N Me Me
:OH
Ph
Ph O N Me
Ph
Me
[3,3]
Me Ph OH Me N Me Me Ph Mannich Ph O
Homo-chiral
N Me
O H OMe
O H OMe
racemic product
mixture of diastereomers
D. Evans, E. Shaughnessy
Chem 206
(-)-7-Deacetoxy-alcyoninacetate
trans-Kumausyne
Me I t-BuLi, THF, -78 C Me Me OHC Me O Me OMe Me TMS Me OHC Me OH [3,3] O Me R Me TMS Me R Me O TMS 1. TMS Et BF3OEt2 -78 C rt 73% 2. TBSCl HO H O O OTBS Et O O 1. H2, Pd-C, 88% 2. Swern, 100% OTIPS Me OH H Me BF3OEt2 (3 equiv.) CH2Cl2, -55 -20 C 79% O H OBn O O m-CPBA 72% 4:1 regioselectivity O H OBn O H PPTS, MeOH 64% OH TMS OH Felkin Control (Lecture 20-21) Me OH BnOCH2CHO RSO3H, rt OH 69% OH [3,3] O OBn O OBn OH
CHO O TMS
H CHO O H
O H
97%
D. A. Evans
Chem 206
Application to Leucasandrolide
Me OH
El SiMe3
Prins
R O El
OH
OBn
OTBS
Control of hydroxyl center: see Lecture 20-21 Let El(+) = Lewis acid activated RCHO
SiMe3 RCHO R O F 3B BF3OEt2 base O R SiMe3 O O R O BF3 R Me I BnO OTBS Myers, JACS 1997, 119, 6496 base = Me3C N CMe3 R O No (little) control over this () stereocenter HO R R BnO O TMS H O R BF3OEt2 R BnO OH O R
aldol
H SiMe3
Prins
R O
OX R
diastereoselection >20:1 Me
see Lecture 24
N. Finney, D. A. Evans
Squalene Biosynthesis
farnesyl pyrophosphate (C15)
Chem 206
Me Me Me
Enz-X
Me
Me O P P Me
Me
Me
Me Me
Me
Me Me Me
Me
Me Me
Me
Me Hb Ha Me
Me Me
Me
presqualene pyrophosphate
+
H Me
Me
H Me Me Me Me H Me
Me
squalene (C30)
33-08- Squalene, Lanosterol 12/7/03 9:03 PM
Me
Me
Me
Me
Me
lanosterol
N. Finney, D. A. Evans
Chem 206
+
H Me
Me Me H Me Me Me Me O Me Me
in vivo
O H
Me
Me HO Me H
Me
Me
X-Enz Me
squalene oxide
H O
Me Me Me Me
in vivo
Me
Me
Me stereocenter in question
Me HO Me H
Me
Me Me Me Me Me Me Me H
O Me H
Me
Me Me Me
Me
X-Enz
Me
HO Me Me Me
lanosterol
Me HO Me Me
NOT
Me HO Me H
Me
Me
O H Me H
Me
Me Me Me HO
Me
Me Me
Me
Me
+
H H Me
81 kcal/mol (MM2)
17 kcal/mol
H anti-migration Me Me Me H Me
Me
Me
anti-migration
64 kcal/mol
Me HO Me H Me
Sir John Cornforth: "That outpost of empire Australia, If you are anxious for over-exposure, to prepublication disclosure, produces some curious mammalia, to good food and good drink, the kangaroo rat, without leisure to think, the blood-sucking bat, try IUPAC symposia." and Aurthur J. Birch, inter alia."
Me
lanosterol
N. Finney, D. A. Evans
Chem 206
Me Me
Me
Me Me Me Me HO Me Me Me Me
OH
CH2 SiEt3 Me Me
CH2
O Me HO
+ Me HO O
Me
Me
96 : 4
Me
Andrew Ratz
R Me Me HN
i
CO2Me O Me N
i
Me O O
i
CO2H
Pr HN
Me
Pr Pr HN
Pr N
Me
Methyl Homodaphniphyllate
Me
HO
pyridoxal
CHO OP* Me N
H+
OP*
HO
Secodaphniphylline +
OHC Me Me Me Me CHO
Squalene Dialdehyde
Me Me
OHC R
Me CO2H
i
CO2H
Pr N
Me
pyridoxamine
R HO Me
N OP* N Me HO
Pr N
Me
HO OP* Me N H
OP* N
O Ar NH NH R R
CO2H
Pr N
Ar NH R N Ar
Pr HN
Methyl Homodaphniphyllate
Me O
N Me Me Me
formal Me [4+2] Me N
R Me Me
R Me HN
CH2O
Pr N
O Me
Daphnilactone A
Pure & Appl. Chem. 1989, 61, 289 J. Am. Chem. Soc. 1986, 108, 8274
D. A. Evans
Polyene Cyclizations
Several Comp[ex Mechanisms
Chem 206
http://www.courses.fas.harvard.edu/~chem206/
OBn OBn
1. MeNH2
Me Me Me HN
OHC
2. HOAc, NH4OAc 75%
Me
Angew. Chem. Int. Ed. Engl. 1978, 17, 476. J. Org. Chem. 1990, 57, 2544.
TIPSO
"That outpost of empire Australia, produces some curious mammalia, the kangaroo rat, the blood-sucking bat, and Aurthur J. Birch, inter alia." If you are anxious for over-exposure, to prepublication disclosure, to good food and good drink, without leisure to think, try IUPAC symposia."
D. A. Evans
33A-00-Cover Page 12/7/03 9:07 PM
D. A. Evans
Suggested Reading
Terpene Biosynthesis
Representative Terpenes
H Me Me Me Me Me HO Me H Me H Me H HO H H
Chem 206
"An Experimental Demonstration of the Stereochemistry of Enzymic Cyclization of 2,3-Oxidosqualene...." E. J. Corey, S. C. Virgil JACS, 1991, 113, 4025. "New Mechanistic and Stereochemical Insights on the Biosynthesis of Sterols from 2,3-Oxidosqualene Cyclase" E. J. Corey, et al. JACS 1991, 113, 8171. "Enzymatic Cyclization of Squalene and Oxidosqualene to Sterols and Terpenoids" Abe, et al. Chem. Rev. 1993, 93, 2189. "Isoprenoid Biosynthesis. Stereochemistry of the Cyclization of Allylic Pyrophosphates." D. E. Cane Acc. Chem. Res. 1985, 18, 220.
Me Me Me Me Me
lanosterol
cholesterol
OAc
"Biomimetic Polyene Cyclizations" W. S. Johnson Angew. Chem. Int. Ed. Engl, 1976, 15, 9. taxol
RO
Me Me Me HO BzO AcO
O Me OH
Interesting Reading Science, 1997, v277: "Structure and Function of the Squalene Cyclase", G. Shultz, p. 1811. "Structural Basis for Cyclic Terpene Biosynthesis by Tobacco 5-epi-Aristolochene", J. P. Noel, p. 1815. "Crystal Structure of Pentalene Synthase: Mechanistic Insights on Terpenoid Cyclization Reactions in Biology", D. W. Christianson, p. 1821. "The Stereochemistry of Allylic Pyrophosphate Metabolism." D. E. Cane Chem. Rev. 1980, 36, 1109. "Biosynthesis of Natural Products" P. Manitto; Wiley&Sons, NY: 1981.
HO Me Me Me
O O O O
CH2
Me O H 2C O OC OH Me CO2H Me
OH
caryophyllene
picrotoxinin
O
gibberellic acid
33A-01-terpene refs 12/8/00 9:00 AM
D. A. Evans
Chem 206
Definition: Natural products whose carbon skeletons are built up largely from isoprene subunits:
Me Me OH isoprene Me Me menthol Me (S)-carvone caraway Me (R)-carvone spearmint H Me O H Me O
Me
O OMe
Occurance: Plants, insects, higher organisms Role in plants: hormones, defense etc. example: pyrethrin insecticides Me
Me Me H Me Me H OH chrysanthemic acid O Me H Me O O Me
O Me
CHO Me OH CHO
Me
D. A. Evans
Me
head tail
Chem 206
Terpene Biosynthesis
There are two isoprene units which are used to build up terpenes: Me OX enzyme Me Me OX
2-methyl-1,3-butadiene isoprene
t h t
OH
OH OH O
ROX
R O S O
CH3
ROTs
geraniol
O O Me Me H
The basic process: alkene addition to electrophiles: Me Me OX DMAP Me Me H H Me OX -HB Me Me Me OX geranyl pyrophosphate Me OH H2O/OH-OX
-
Me Me CH2
H 2C
OX
cinnamolide antifungicide
B-carotene
natural rubber Practice: Recognize the isoprene units in the above structures.
n
Me Me
geraniol
D. A. Evans
Chem 206
-OX-
R2 CH3
R4 R1
R3 R2 CH3
geranyl pyrophosphate Me Me
Me
-OXOX Me Me Me Me
-H+
CH3 CH3
Me limonene
The precursor of bornene could also lead to camphene. Show the mechanism! camphene
Me
Me Me Me
-H+
Me
Tetrahydrocannabinol (THC)
Me OH
H+
aromatic substitution CH3
Me OH
-H+
-H+
Me Me O H
OH
C5H11
N. Finney, D. A. Evans
Cyclic Monoterpenes
Me Me OH Me
Chem 206
CO2H OH HO Me CO2H
C label
O O HO2C
HO Me OH
() MVA
-terpineol
Me Me Me H Me Me
Me
HO Me () MVA lactone
borneol
Me
+
Me Me
Me OH O P P
Me Me -pinene Me
Me
GPP
Me Me OH
H Me Me
+H
Me
Me Me Me O
carene
Me Me camphor
O -thujone
Me Me
Me
terpinolene Me
+H
CH2 OR O
Me OH Me
Me
Me
CO2CH3
secologanin
terpinenol Me
Me H
+
Irregular Monoterpenoids
Me Me Me Me Me Me Me Me 33A-05-Monoterpenes 12/8/00 8:52 AM Me Me CO2H H Me
chrysanthemic acid nezukone
Me Me O
-thujene
Me
N. Finney
Me
SesquiterpenesC15 Terpenoids
Me
Chem 206
Me Me Me
O P P (Z)-FPP Me Me
Me Me
(E)-FPP O P P
Me
Me
Me Me Me Me Me
CH3 Me
Me
+
Me
Me
Me
Me
Me
Me
Me
Me Me Me Me Me
Me Me Me
Me Me Me
CH3 Me Me
CH3 Me Me
Me
[Ox]
O O
Me Me
Me Me OH
Me
Me
Me
Me O H 2C Me
OH O
Me Me
Me Me Me
Me Me
CH2 H 3C Me Me Me
Me
cuparene picrotoxinin
widdrol
thujopsene
caryophyllene
humulene
N. Finney
Squalene Biosynthesis
farnesyl pyrophosphate (C15)
Chem 206
Me Me Me
Enz-X
Me
Me O P P Me
Me
Me
Me Me
Me
Me Me Me
Me
Me Me
Me
Me Hb Ha Me
Me Me
Me
presqualene pyrophosphate
+
H Me
Me
H Me Me Me Me H Me
Me
squalene (C30)
Me
Me
Me
Me
Me
lanosterol
N. Finney, D. A. Evans
Chem 206
+
H Me
Me Me H Me Me Me Me O Me Me
in vivo
O H
Me
Me HO Me H
Me
Me
X-Enz Me
squalene oxide
H O
Me Me Me Me
in vivo
Me
Me
Me stereocenter in question
Me HO Me H
Me
Me Me Me Me Me Me Me H
O Me H
Me
Me Me Me
Me
X-Enz
Me
HO Me Me
lanosterol
Me HO Me Me
Me HO Me H
Me
Me
Me
Me Me
Me
NOT
Me
O H Me H
81 kcal/mol (MM2)
17 kcal/mol
H anti-migration Me Me Me H Me HO Me H Me
Me
Me Me
Me
+
H H Me
64 kcal/mol
Me HO Me H Me
Me
anti-migration
Me
lanosterol
N. Finney
Chem 206
Me Me
Me
Me
Me Me Me Me HO Me Me Me Me
OH
CH2 SiEt3 Me Me
CH2
O Me HO
+ Me HO O
Me
Me
96 : 4
Me
D. A. Evans
Me Me Me O Me O Me SnCl4 C6H6, R.T. RO Ratio = 72 : 28 H Me
Chem 206
R O Me OH Me R = C8H17 O Me R O Me
H RO de = 84%
Ratio = 88 : 12 Br Ph
Ph R H O Me O Me
LiAlD4 AlCl3
CH3 O CO2Me
CH3 OH CO2Me
Br2
CH3 O CO2Me
R O Me
O MeO2C
O MeO2C
O MeO2C
G. Castaldi & Co-workers, Angew. Chem. I. E., 1986, 25, 259. ( CH2)6
94 % yield ( CH2)6
de = 86 %
Et t-Bu Ph
R Me O Me O Me
LiAlH4 AlCl3
Zn-Cu, CH2I2
R Me HO Me ratio 73:24 85:15 51:46 O Et OH Me R Ph n-C9H19 Et O Me ratio 16:1 03:1 R O Me P. Mangeney & Co-workers, Tetrahedron Lett., 1987, 28, 2363. O Me H O
PhCu
O O MOMO Me
O OMOM
Et2O,
O MOMO
O OMOM
de = >95 % R
R
R H O Me O Me
O Me
OH Me
% de 95 (R) 85 (R) 69 (S)
O Me
Me
Cu
Acetal Alkylating Product Isomer Agent (R) E/Z E E Z (1) (2) (1) 100/0 95/5 100/0
% Yield 75 70 75
D. A. Evans
C8H17 H O O TMS TiCl4 CH2Cl2, -78oC 98% yield
P. A. Bartlett & Co-workers, J. Am. Chem. Soc., 1983, 105, 2088.
Chem 206
CN Ar HO O Me
CN Ar O HO Me
Ratio = 97 : 3, 88% de
C8H17 H O Me O Me Me
W. S. Johnson & Co-workers, J. Am. Chem. Soc., 1983, 105, 2904.
H O
R O
H C6H13 COOH
Ratio = 93 : 7
S. L. Schreiber & J. Reagan Tetrahedron Lett., 1986, 27, 2945.
Temp.(oC) 0 -30
% Yield 58 90
% de 94 97
C 6H 5 H O Me O Me
W. S. Johnson & Co-workers, J. Org. Chem., 1983, 48, 2294.
C8H17 TMS C N TiCl4 CH2Cl2, -20oC 97% yield O Me C N OH Me + diastereomer Me O Ratio = 96.5 : 3.5 Me Me C8H17 OTBS O OtBu
Me Ph
c-C6H11 CH3 O Me O Me
H. Yamamoto & Co-workers, Tetrahedron Lett., 1983, 24, 4581.
CH3 OH Me
Ratio = 98 : 2
+ diastereomer
Et O Me O Me
Et OH Me O Me
Bu + diastereomer
Me2NCO
Andrew Ratz
Daphniphyllum Alkaloids
Me O
Daphniphyllum Alkaloids
O CO2Me
O Me AcO
i
Me R
*
Pr N
Daphniphylline
Pr N
i
Pr N
Pr
* *
N H Me Me
*
Methyl Homodaphniphyllate
Me O O Me O CO2Me O Me
i
Me R N H Me
BnO Me O O R O N
O O
Pr HN
Me
Pr HN
Me
Secodaphniphylline
Methyl Homosecodaphniphyllate
O N O O BnO O N
O O
O O
i
O Me
Pr N
O Me
N
Bukittinggine
Daphnilactone A
Isolated from bark and leaves of Yuzuriha tree Used to cure asthma and vermicide in the early 20th century Compounds have been known since 1909. First structure solved in 1965. 38 members in this alkaloid family
J. Org. Chem. 1992, 57, 2531-2594 Kyoto Igaku Zasshi 1909, 6, 208 Tet. Lett. 1965, 965 O Me O N
H
O CO2H + O O
O Me
O NH2
J. Org. Chem. 1992, 57, 2531 J. Am. Chem. Soc. 1975, 97, 6116 Angew. Chem. Int. Ed. Eng. 1992, 31, 665
Andrew Ratz
Daphniphyllum Alkaloids
O Me
O N
H
O O
N O
O N
1 isomer
LDA, THF
N Br S Me
4:1
BnO
73%
2. Et3N 80%
BnO Me N O
i
O O
BnO
O Me O O
8:1
LDA, THF
O
i
Pr
Me O O
74%
OBn N O O Me N
Lawesson's Reagent
OBn O O
1. LTMP, PhSeCl 2. MCPBA 60%
Pr
O Me N H O O
H O
BnO BnO Me O R S
R=iPr 10:1 46% R=Me 83:17
BnO
H2SO4, Acetone
O N O
1. H3O+ 2. HO(CH2)2OH
S
3. LDA, THF
OBn S N O
14%
N O
OBn O Me N H O H HO
NaOMe MeOH 70% 2 steps
Me O
J. Am. Chem. Soc. 1986, 108, 5650 J. Org. Chem. 1992, 57, 2531 J. Am. Chem. Soc. 1968, 90, 6177 Nouv. J. Chem. 1980, 4, 47
N O
Andrew Ratz
Daphniphyllum Alkaloids
OBn
Me N H O
O
LDA, THF
Me R O H Me O N O
H30+
Me R O H Me N O OBn Me Me Me CHO
Squalene Dialdehyde
OHC Me
Me Me
OHC R
MeCHO 100% HO
pyridoxamine
OBn
1. Me2CuLi (EtO)2POCl 83%
OBn Me
R HO Me
N OP* N
Pr N
H N O
68% + Me
(EtO)2PO2
O2P(OEt)2
Li/EtNH2 64%
N O HO
13%
OHC
OH
OH
OH O H
i
OHC
Pr H H
??
Pr H H H Pr N
+
Ar H H
1. Jones 2. MeOH, H+
NH NH
Ar NH R N Ar
1:1 ratio
R R Me N Me Me Me N Me Me Me HN R
Me Me H H N
CO2Me
Pr H H N
Me
Pure & Appl. Chem. 1989, 61, 289 J. Am. Chem. Soc. 1986, 108, 8274
Andrew Ratz
15
Me
Me14 Me 10
HO Me HN
+
Pr
OP* CO2Me
OR
OR
Me CO2H
Squalene
Pr HN
Me HN
Me H
+N
Me
Pr
+N
Me
HO OP* CO2H Me N
H+
i
CO2H OR Pr
+ N
Me
OR
Pr
+ N
Me
HO OP* Me N H Me CO2Me Me
+ HN
HO OP* Me N
H Me OR
+N
Me
Pr N OHC Me Me OR R O
+
CO2H
Methyl Homodaphniphyllate
i
OHC Me
Pr HN
Me
i
O Pr N
Daphnilactone A
O Me
Me R O
+
I Me Me
Andrew Ratz
Me MeO2C
+
N O
Me
LDA, THF -78C to 25C
Me OHC Me Me OHC Me
OBn
1. MeNH2 2. HOAc, NH4OAc 75%
Me Me Me HN
OBn N O MeO2C Me
4%
OBn
Me
Me Me
Me
Me
Me
8%
OBn
OBn
Me Me
CH3 N H Me
Me
R O O Me Me Me OBn OBn
OR
CO2Me
1. H2, Pd/C
CH3
i
+N
Me
Me H N
Me HN
2. Jones 3. MeOH, H+
Pr HN
Me
Angew. Chem. Int. Ed. Engl. 1978, 17, 476. J. Org. Chem. 1990, 57, 2544.
J. Org Chem. 1989, 54, 1215. Tet. Lett. 1986, 27, 959. Top. Stereochem. 1990, 20, 87.
Andrew Ratz
Daphniphyllum Alkaloids
Stepwise vs Concerted Cyclization
R
+
R
Stepwise
H R
R H N+
Me Me
Me
Me I
Me Me
Me OtBu O
1. LDA, Br(CH2)3CH(OMe)2 2. H3O+ 83%
Me
R R H
+N
R
Concerted
Me Me Me Me CO2tBu OH Me
70%
Me
Me
R H
+N
Me
Me tBuO2C Me Me CHO
CO2tBu R
AcOH
Me Me
R Me N
AcOH 70C 95%
OR
1. MsCl, Et3N 2. DBU 3. DIBAL 80% 1. Swern 2. NH3 3. AcOH, 80C 15%
25C 90%
Me
Me Me
Me
Me
OH
Me Me OH Me Me
Me HN
R R OHC OHC
Stepwise
R Me Me H N R Me Me HN Me Me
R H N
+
Me
Me Me
Me Me
Me Me
Concerted
Me
Other amines: Glycine (S)-(+)-Alanine (S)-(+)-Valine (+)--Phenylethyl amine 38%y 32%y 1-2%ee 13%y 20-25%ee no reaction
Me
Me Me Me HN
Andrew Ratz
Daphniphyllum Alkaloids
Synthesis of (-)-Secodaphniphylline
Me O O CO2Me O Me COX O O Me
+
i
OBn N O MeO2C Me Me
Me
OBn Pr HN N Me O
2.
CO2Me
3.
Pr HN
Me Me Me
Me
Me
O HO2C Me
Me Me 1. Weinreb O
2.
O Me O Me
Me Me LAH O
Darvon Alc. 93%
BnO O Me Me OH
92% ee KAPA 1,3-diaminoprop. 87%
OBn
Me
Li
Me HOCH2 O
1 1. RuCl3, NaIO4 2. CH2N2
CH2OH O + Me
:
Me
O
5
O Me
Me OH
Me MeO2C O O Me
+
CO2Me Me O
1. separate
COCl Me O O Me
i
MeO
OLi
O 2. KOH EtOH Me
Pr HN
90% ee
92% ee
Me Me Me MeO Me N O Li O
Interference with Li cluster ??
Me O O Me
J. Org. Chem. 1980, 45, 582 Tet. Lett. 1981, 22, 4171 J. Org. Chem. 1981, 46, 3936 iPr Tet Lett. 1967, 8, 215
Me O O
NaCN, DMSO 150C
OBn H
N Me Me O MeO2C Me
O Me MeO2C
i
O BnO Me
HN
Me
43% overall
Pr HN
Tet Lett 1986, 27, 959 J. Org. Chem. 1990, 55, 132 Topics in Stereochemistry 1989, 227
Me
99.6% ee
Andrew Ratz
Synthesis of Daphnilactone A
Br
LDA, homogeranyliodide 85%
EtO
1. LAH
Br O Br Me COBr Me Me
O O
EtO2C
2.
Pr N
O Me
Pr HN
Me
Me Me HN OEt Me CO2Et Me
Br
3. H3O+ 95%
Pr
Br O O O Me Me Me Me Me Me
LAH 90%
O O
H O O Me
OZnBr
O N
Pr HN
O Me Me Me Me
Me
Me
O HN Me
H2, Pt 100%
Pr HN
O Me
Org. React. 1975, 22, 423 Ang. Chem. Int. Ed. Eng. 1967, 6, 1 Ang. Chem. Int. Ed. Eng. 1969, 8, 535 J. Org. Chem. 1992, 57, 2585 Angew. Chem. Int. Ed. Engl. 1992, 31, 665
i
OH
HO
Pr HN
Me
Pr HN
Me
4.5
Andrew Ratz
Daphniphyllum Alkaloids
Pr HN
Me
Pr N
O Me
CO2H Oi
Pr HN
Me
O Me
+N
Pr
OH
CO2Me
Pr HN
Me
Pr HN
Me
PhNCO
CO2Me
HCO2H
i i
CO2Me
Pr N
Pr O HN Ph N
50%
Me
HOMO
LUMO
C H
H C R
C R
D. A. Evans
Chem 206
http://www.courses.fas.harvard.edu/~chem206/
Books: Modern Catalytic methods for Organic Synthesis with Diazo Compounds; M. P. Doyle, Wiley, 1998. Carbene Chemistry, 2nd ed. Academic Press, Kirmse, W., 1971.
CO2Me
H O N2
150C (71%)
H O
D. A. Evans
D. A. Evans
Suggested Reading: Doyle, Chem Rev. 1988, 86, 919. Kodadek, Science, 1992, 256, 1544.
Carbenes: An Introduction
Carbene Configuration: Triplet vs. Singlet
p
Chem 206
Energy
Recent Review Article: Chemistry of Diazocarbonyls: McKervey et al. Chem Rev. 1994, 94, 1091. Books: Modern Catalytic methods for Organic Synthesis with Diazo Compounds; M. P. Doyle, Wiley, 1998. Carbenes and Nitrenes in "Reactive Molecules: The Neutral Reactive Intermediates in Organic Chemistry", Wentrup, C. W. 1984, Wiley, p. 162. Rearrangements of Carbenes and Nitrenes in Rearrangements in Ground & Excited States, Academic Press, DeMayo ed., Jones, W. M. 1980, p. 95. Carbene Chemistry, 2nd ed. Academic Press, Kirmse, W., 1971.
S1 810 kcal/mol T1
p triplet singlet
Due to electron repulsion, there is an energy cost in pairing both electrons in the orbital. If a small energy difference between the and p orbitals exists, the electrons will remain unpaired (triplet). If a large gap exists between the and p orbitals the electrons will pair in the orbital (singlet).
1947 1957
H
133.8
H H
H
Triplet (two unpaired e-) Often has radical-like character
empty filled
Singlet (all e- paired) Often has electrophilic or nucleophilic character: A-type (Ambiphilic)
empty
Nitrene
R N
H R N
filled
1978 1982
Nitrenium ion
34-01-carbenes intro 12/10/03 7:39 AM
M. Shair, D. A. Evans
Chem 206
Me
OR
donor p orbital
Me
H N N Ts Me
Ts
Me
Me
N Me
N Ts Me
Me
N N
N2
Heteroatomsubstituted carbene
H
-donor heteroatom
Me H R1 N N R2 diazirines R1 N N R2 R1
Me
diazo compounds
C Singlet
N N
h or heat
Examples:
Cl
Singlet C6 H5
R1 C + N2 R2
Methods of Synthesis
Alkyl Halides:
Cl Cl R R Cl C H Cl C H
R2
OH
N2
ketenes
R C R C O
carbenoid
R1 R2
heat or h
R 2C
CO
R1 R2
O Rh
O Rh
M. Shair, D. A. Evans
Chem 206
"Stable Carbenes"
"Stable CarbenesIllusion or reality"? Regitz, M. Angew. Chem. Int. Ed. Engl. 1991, 30, 674 (handout) Cl
R + R
N N
N N
Arduengo et al. J. Am. Chem. Soc. 1991, 113, 361; 1992, 114, 5530. Arduengo et al. J. Am. Chem. Soc. 1994, 116, 6812, Neutron diffraction study:
N N
N N
N N R R R H 2C R ISC R H 2C R R
Arduengo argues that these resonance structures are not players based on electron distribution from neutron diffraction. These are nucleophilic carbenes which display high stability. For reviews on the subject, see: Regitz, M. Angew. Chem. Int. Ed. Engl. 1996, 35, 725. Regitz, M. Angew. Chem. Int. Ed. Engl. 1991, 30, 674.
Me N S
Me F Au F F F F Xray Structure
Simmons, H.; Smith, R. J. Am. Chem. Soc., 1958, 80, 5323. OH CH2I2 Zn(Cu) OH
>99:1 diastereoselectivity
The intermediate organometallic reagent: ICH2ZnI Zn(Cu) H. G. Raubenheimer Chem. Comm. 1990, 1722. OH CH2I2 150:1 cis : trans OH 75% yield
M. Shair, D. A. Evans
The Furakawa Simmons-Smith Variant
Chem 206
For a recent general review of the Simmons-Smith reaction see: Charette & Beauchemin, Organic Reactions, 58, 1-415 (2001) Et2Zn, CH2I2 Solvent EtZnEt + ICH2I
R3 R2 R1
66-82 % ee
OH
NHSO2R NHSO2R
Kobayashi, et al. Tetrahedron Lett. 1994, 35, 7045. For a Lewis Acid catalyzed process in which the rate of the catalyzed process is faster than the uncatalyzed, see: Charette, A. B. JACS 1995, 117, 11367.
Furukawa, J.; Kawabata, N.; Nishimura, J. Tetrahedron, 1968, 24, 53 Furukawa, J.; Kawabata, N.; Fujita, T. Tetrahedron, 1970, 26, 243 Et2Zn, PhCHI2 ether, rt 69% syn : anti 94 : 6
Applications in Synthesis
Ph O Me O MeO O
>99:1 diastereoselectivity
NH O O Me Calipeltoside A
Me
OH Me OH
Me Me H MeO Me O
Me
Me OMe
no Me diastereoselectivity
OH O O O
50:1 diastereoselectivity
>99:1 diastereoselectivity
Cl Me
Me Me O
Me
U-106305
O HO
Me OBn OBn Me
Et2Zn CH2I2
FR-900848 H R=
N O OH OH
Me
R=
NH O
N O
Me
O HO
Me OBn OBn
Charrette, A. B.; J. Am. Chem. Soc. 1996, 118, 10327.
>50 : 1 diastereoselection
Falck J. Am. Chem. Soc. 1996, 118, 6096. Barrett, JOC, 1996, 61, 3280.
D. A. Evans
Chem 206
M. Shair, D. A. Evans
Synthetic Applications
H O TBSO Me O
Cu(I)
Carbenoids: Cyclopropanation
Buchner Reaction
Chem 206
N2
H TBSO Me O H O N2
CO2Me
cat.
CO2Me CO2Me
Me
1. Br2 2. DBU
Me O
Rh2(OAc)4 (84%)
H TBSO Me O H O
Et2AlCl
1,3-shift
N2
AcO Me O Me H O
Me OTBS O
McKervey et al. JCS PTI, 1991, 2565.
Me
O O
CO2Me O N2
Cu Powder 130C, Xylenes
O CO2Me
Wolff Rearrangement
THPO OMe OMe O O2N Me N2
AgOBz H 2O
THPO O O CuLi
2 Et2O, -12C
retention CO2H
CO2Me
prostaglandins
OMe
Evans et al. J. Org. Chem. 1993, 58, 471.
(+) Macbecin
THPO
D. A. Evans
Chem 206
There is no definitive evidence for metal-catalyzed cyclopropanation and the possibility that metallacyclobutane intermediates are involved cannot be ruled out. Me3C R Cu Me3C CO2Me Ph R
Reductive Elimination
+ O N N Me Me O
For a detailed mechanistic study which provides supporting evidence for the intermediacy of a Rh carbene, see: Kodakek, Science, 1992, 256, 1544. SiMe3 N Cu N SiMe3 SiMe3 N Cu N SiMe3 spectroscopically observed "Copper(I) Carbenes: The Synthesis of Active Intermediates inCu-Catalyzed Cyclopropanation" P. Hoffmann et al, Angew. Chem. Int. Ed. 2001, 40, 1288-1290 H R
N2CHCO2R R -N2
+ O Me Me O
OTf
Me3C Me3C
CH2 CH2 N2
CO2Me Ph
Me3C Me3C
OTf
Me L* = O N
Me O N CMe3
OTf
Me3C CO2BHT Ph N2
L* CuOTf Ph
N O H N CO2Me O H nPr H H O
95% ee
nPr
Rh Rh O N2 O
Doyle et al. Tetrahedron Lett. 1995, 36, 7579.
R
+
EtO2C
CuOTf
N2
R R
ent-6b
CH2Cl2
D. A. Evans
Chem 206
Rh Rh O
variable ligand
H N
MeO2C
O Rh O N
CO2Me
CO2Me H N O H Rh N CO2Me O
27A
H N
MeO2C
O Rh O N
styrene N 2 O 1 Rh O 3 4 N Numbers designate increasing steric hindrance in each quadrant Doyle, JACS 1993, 115, 9968 H Ph 48%ee Ph CO2Me H CO2Me
27B
H 86%ee H
M. Shair, D. A. Evans
Carbene-Carbene Rearrangements
H
Carbenes: Rearrangements
Other Rearrangements
H O N2
150C (71%)
Chem 206
H O
H O
Wu, Tetrahedron Lett. 1973, 3903.
H O
H H N2 O
200C (92%) Schecter, J. Am. Chem. Soc. 1971, 93, 5940.
O O O O
Skattebol Rearrangement
C Br
Br
Vinylidenes
BuLi
Corey-Fuchs:
TIPS
TIPS
[1,2]
C13
Teoc
O O Br
Ph
Teoc
O O
(81%)
Ph Ph
Ph 2 eq. BuLi
-78C
OTBS
Br
OTBS
M. Shair, D. A. Evans
Carbene Rearrangements
Carbenes: Rearrangements
O O
OTf NaSO2Ar CH2Cl2, 20C
Chem 206
O H N2 P(OEt)2
BuLi 78 C RCHO R
OLi
SO2Ar I+Ph
I+Ph
N2
O SO2Ar N
(63%)
R C C H
O Me N2
O P(OEt)2
+
OMOM
Stang et al. J. Am. Chem. Soc. 1994, 116, 93.
MeO2C
CHO OMOM
MeO2C
(83%)
Me O H
620C
Me
Me H
Me
Me H H
H Me Me CH insertion Me O H
620C
H Me
capnellene
Me
Me H
Me O H
H Me
H Me
M. Shair, D. A. Evans
CH Insertions continued...
N2 H Me O H
Rh2(OAc)4
Carbenes: Rearrangements
NH Insertions are also possible...
O CO2Me Me
(83%)
Chem 206
HO Me
H H NH O
N2 CO2PNB
Rh2(OAc)4
HO Me
H H N O CO2PNB
CO2Me
Electrophilic carbenes are very sensitive to electronic effects Stork Tetrahedron Lett. 1988, 29, 2283.
HO Me
H H N S CO2
thienamycin
NH3
CO2Me N2 N O O
CuOTf
HO Me
CO2Me H N
(75%)
O O O
H H N O CO2PNB
R2
R1
R3
R2 A B
R1
+ +
H A B
R2
R1
H A B
O Ph O O O N2
CH2Cl2 (5 mol %)
R3
R3
N H N CO2Me H O O H
99%, 97% ee
Retention
O
Rh Rh MeO2C N2
O H Me Ph Me
Rh2(OAc)4
CO2Me Ph
Chiral DirhodiumCarboxamidates: Catalysts for Highly Enantioselective Syntheses of Lactones and Lactams, Aldrichchimica Acta. 1996, 29, 3 (handout)
M. Shair, D. A. Evans
Ring Opening
O H H N2 O
h EtOH
Carbenes: Rearrangements
Chem 206
O Me
95% yield
H R
OH CO2Et
(88% Tetrahedron Lett. 1990, 31, 6589.
O C Me H H H
Ring Contraction
N2 H S O O N CO2Me
h iPr2NH
H
carbene intermediate
O N
H H S N
O
(81%)
CO2Me
Wolff-[2+2]
N2 Me O
h
Me H
C +
Me Me Me
J. Org. Chem. 1980, 45, 2708. (74%)
Me
Me O
Me
Me O
C Me Me H
O Me
D. A. Evans
Chem 206
http://www.courses.fas.harvard.edu/~chem206/
Recent Review Article: Chemistry of Diazocarbonyls: McKervey et al. Chem Rev. 1994, 94, 1091. Books: Modern Catalytic methods for Organic Synthesis with Diazo Compounds; M. P. Doyle, Wiley, 1998. Carbenes and Nitrenes in "Reactive Molecules: The Neutral Reactive Intermediates in Organic Chemistry", Wentrup, C. W. 1984, Wiley, p. 162. Rearrangements of Carbenes and Nitrenes in Rearrangements in Ground & Excited States, Academic Press, DeMayo ed., Jones, W. M. 1980, p. 95. Carbene Chemistry, 2nd ed. Academic Press, Kirmse, W., 1971.
R R R C X R R R O R R
Rationalize
13C-labeled C10H8 is isomerized into 13C-labeled C10H8 at 1035 C L. T. Scott, JACS 1991, 113, 9692.
Corannulene 10%
D. A. Evans
Friday, December 12 , 2003 Scott, L.T., et. al., JACS 113 7082 (1991)
D. A. Evans
Chem 206
Rh Rh O
variable ligand
H N
MeO2C
O Rh O N
CO2Me
CO2Me H N O H Rh N CO2Me O
27A
H N
MeO2C
O Rh O N
styrene N 2 O 1 Rh O 3 4 N Numbers designate increasing steric hindrance in each quadrant Doyle, JACS 1993, 115, 9968 H Ph 48%ee Ph CO2Me H CO2Me
27B
H 86%ee H
M. Shair, D. A. Evans
Carbene-Carbene Rearrangements
H
Carbenes: Rearrangements
Other Rearrangements
H O N2
150C (71%)
Chem 206
H O
H O
Wu, Tetrahedron Lett. 1973, 3903.
H O
H H N2 O
200C (92%) Schecter, J. Am. Chem. Soc. 1971, 93, 5940.
O O O O
Skattebol Rearrangement
C Br
Br
Vinylidenes
BuLi
Corey-Fuchs:
TIPS
TIPS
[1,2]
C13
Teoc
O O Br
Ph
Teoc
O O
(81%)
Ph Ph
Ph 2 eq. BuLi
-78C
OTBS
Br
OTBS
M. Shair, D. A. Evans
Carbene Rearrangements
Carbenes: Rearrangements
O O
OTf NaSO2Ar CH2Cl2, 20C
Chem 206
O H N2 P(OEt)2
BuLi 78 C RCHO R
OLi
SO2Ar I+Ph
I+Ph
N2
O SO2Ar N
(63%)
R C C H
O Me N2
O P(OEt)2
+
OMOM
Stang et al. J. Am. Chem. Soc. 1994, 116, 93.
MeO2C
CHO OMOM
MeO2C
(83%)
Me O H
620C
Me
Me H
Me
Me H H
H Me Me CH insertion Me O H
620C
H Me
capnellene
Me
Me H
Me O H
H Me
H Me
M. Shair, D. A. Evans
CH Insertions continued...
N2 H Me O H
Rh2(OAc)4
Carbenes: Rearrangements
NH Insertions are also possible...
O CO2Me Me
(83%)
Chem 206
HO Me
H H NH O
N2 CO2PNB
Rh2(OAc)4
HO Me
H H N O CO2PNB
CO2Me
Electrophilic carbenes are very sensitive to electronic effects Stork Tetrahedron Lett. 1988, 29, 2283.
HO Me
H H N S CO2
thienamycin
NH3
CO2Me N2 N O O
CuOTf
HO Me
CO2Me H N
(75%)
O O O
H H N O CO2PNB
R2
R1
R3
R2 A B
R1
+ +
H A B
R2
R1
H A B
O Ph O O O N2
CH2Cl2 (5 mol %)
R3
R3
N H N CO2Me H O O H
99%, 97% ee
Retention
O
Rh Rh MeO2C N2
O H Me Ph Me
Rh2(OAc)4
CO2Me Ph
Chiral DirhodiumCarboxamidates: Catalysts for Highly Enantioselective Syntheses of Lactones and Lactams, Aldrichchimica Acta. 1996, 29, 3 (handout)
M. Shair, D. A. Evans
Ring Opening
O H H N2 O
h EtOH
Carbenes: Rearrangements
Chem 206
O Me
95% yield
H R
OH CO2Et
(88% Tetrahedron Lett. 1990, 31, 6589.
O C Me H H H
Ring Contraction
N2 H S O O N CO2Me
h iPr2NH
H
carbene intermediate
O N
H H S N
O
(81%)
CO2Me
Wolff-[2+2]
N2 Me O
h
Me H
C +
Me Me Me
J. Org. Chem. 1980, 45, 2708. (74%)
Me
Me O
Me
Me O
C Me Me H
O Me
D. A. Evans, D. Guterman
Chem 206
Rationalize
H
H
O
C-H insertion
H
H
S.M.
O
3
O
2
O
1
O
Recovery 80%
_
O O
60 87 _
O
22
18
O
2s + 2a
2s + 2a
13 _
78%
For the azulenenaphthalene Isomerization: G = 30.7 kcal/mol (298K) The Activation energy for the isomerization: G = +86 kcal/mol
54
O O
46
89%
92
8
O
90%
Option2
H H
BF
900 C
B + A 21% + 79% H H
Me 14 Torr
N2 , 1 Hr
Me O
BF H Me Me Me H H
H H
Clovene Option3
B (HBHA) = 3.4 kcal/mol (MNDO) A
D. A. Evans, D. Guterman
Chem 206
Review Articles Padwa and Krumpe Tetrahedron 1992, 48, 5385. Hoffman, R. W. Angew. Chem. Int. Ed. Engl. 1979, 18, 563.
0000 00000 00 00 00 00 00 00 000 00 00000000 00 00 00 00 00 00 0000000 00 00 00 00000000 00 00000000 00 00 00 0000000 00 00000 00 0000 00
H H H 1000 C 10-4 Torr C H H
McKervey et al. Chem. Rev. 1994, 94, 1091. Ylide Formation by the Interaction of Carbeneoids with Carbonyl Lone Pairs R Internal Ring: 6 e External Ring: 14 e
H C
R R R
R R
O R
R R
O R
Generally, the carbene precursor of choice is a diazoalkane or, more frequently, an -diazocarbonyl reagent. These can be decomposed via thermolysis or photolysis. However, the most common method involves catalytic amounts of transition metals, such as copper or rhodium. Dipolar Cycloaddition (See Lecture 18)
CH Insertion
R R
O R
R R X
O Y
R R
D. A. Evans
Chem 206
Web Problem 88. Please provide a mechanism for the following high temperature reaction that was reported by Yranzo and co-workers (J. Org. Chem. 1998, 63, 8188).
Web Problem 172. Scott has recently reported the transformation illustrated below (Tetrahedron Lett. 1997, 38, 1877) which is implemented by flash vacuum pyrolysis (FVP) at the indicated temperature.
Ph
H N N Ph
Ph flash pyrolysis
+ 820 C N2
Cl
CH2
FVP, 900 C 2 HCl
Draw a plausible mechanism for the transformation to the major product isomer. Do not invoke any radical intermediates in your answer.
Cl
CH2
Ph
H N N Ph
1,5-H shift
Ph
H N N Ph N2
Ph
thermal isomerization
H Ph
C-H insertion 700 C
Ph
Web Problem 198. Provide a mechanism for the thermal conversion of triquinacene to azulene (JACS, 1973, 2724).
Ph
1,5-H shift
Ph
1,5-H shift
Ph H
Web Problem 135. Anderson has reported the transformation illustrated below (Aust J. Chem. 1990, 43, 1137) which is implemented by flash vacuum pyrolysis (FVP). As indicated, this reaction proceeds through intermediate A.
O O O Ph
CO2 CO FVP, 900 C CO2 CO 95% yield
Web Problem 282. Hoffmann has reported the mechanistically interesting thermally induced transformation illustrated below (Chem. Ber. 1985, 634.).
NC
N
400 C
NC
Provide a mechanism for this reaction and identify intermediate A in your answer.
D. A. Evans, D. Barnes
Chem 206
R O N C CO2Et
Rh2(OAc)4
Me
COMe O
RCHO DMAD
R
Me
68%
O O Energy N N2 O O Me H Rh2(OAc)4 PhH, reflux 88% H O N O Me O O Me N2 HOMO N H H "high yield" Padwa et. al. Tetrahedron Lett. 1992, 33, 4731-4734. N H N O N O O O Me
ylide
dipolarophile
Therefore, either raising the dipolarophile HOMO (electron-donating substituents) or lowering the LUMO (electron-withdrawing) will accelerate the reaction.
O LUMO
D. A. Evans, K. Beaver
Chem 206
AcO H O
Me Me H H
(86%)
AcO
R1
R2
CO2Et O H CO2Et O H
MeN=C=O O CO2Et R1 +O Z R2 N Me O R2 R2 N Me O Z O R1
Tigilane Skeleton R
2
Me N
O O OMe
Rh2(pfb)4
OM MeO2C O N Me
(93%)
O N2 N Bz
Yields = 44-63%
N Bz
O Me N2
MeOH MeO
85% MeO2C
O Me N N
O CO2Me Et N 2 O N
O N O N O Et O CO2Me
(95%)
O Et O O N O Me MeO2C
CO2Me O N
O MeO2C Me MeOH O
CO2Me OH Me O N CO2Me
Rh2(OAc)4
Me
CO2Me
N Me
Vindoline Skeleton Padwa, A.; Hertzog, D. L.; Chinn, R. L. Tetrahedron Lett. 1989, 30, 4077-4080.
D. A. Evans, D. Barnes
Chem 206
CO2Et O Me Me
N Me
N Me
CO2CH3
CO2CH3 ~30%
H N Me O O
not observed Me
N O
rearrange
HC C CO2CH3
MeO2C O O OH
Methyl vinhaticoate
Me CO2CH3
N Me O
O H Me
N O CO2Me Me
CO2Me
The 1,3-proton shift is catalyzed by trace amounts of water. Azomethine ylide formation requires a proton at the tertiary center.
Padwa, A.; Dean, D. C.; Zhi, L. J. Am. Chem. Soc. 1989, 111, 6451-6452. Padwa, A.; Dean, D. C.; Zhi, L. J. Am. Chem. Soc. 1992, 114, 593-601.
O O EtO2C O O
O O O CH3O CO2CH3
2-methoxymethylenecholestanone-3
O 29%
D. A. Evans, D. Barnes
Chem 206
Me OH Me
Rh2(OAc)4
O OCH3
EtO O
EtO 2 O
H+ O O OEt O X O Me CO2Me Z-Enol Transition State slow O Me Me O O Me OMe PhH, , 18 hrs (75%) N O EtO Me CH2t-Bu + insertion products OH H H NH N2 O OH H H N O CO2 S HO O Me CO2Me E-Enol Transition State [3,3] fast
X = H, Rh(II) ??
X O Me CO2Me Wood, JACS 1997 9641 Wood, JACS 1999, 121, 1748 Me The opposite enantiomer is observed! O OCH3 O 47% ee
Temp (C) RT 80 RT RT 80
%1 53 50 3 1 15
%2 3 13 35 58 54
Me
O Me
HO Me
Me
O Me L4Rh2
O N CH2t-Bu H transfer Me
OH
O N CH2t-Bu
- O+
EtO H
O EtO
Doyle, M. P., et al. J. Org. Chem. 1991, 56, 820-829. Doyle, M. P.; Taunton, J.; Pho, H. Q. Tetrahedron Lett. 1989, 30, 5397.
M. Shair, K. Beaver
Chem 206
Ylide Formation
O R N2 Reviews: R 2X OEt catalyst R X R R O OEt
Methods based on sulfur ylides: (review) Vedejs, Accts. Chem. Res. 1984, 17, 358 CO2Et S N2 CO2Et CO2Et S 50%
Cu(I)
Padwa, Chem. Rev. 1991 263 Padwa, Chem. Rev. 1996 223 Barnes, Evening Seminar, March 16, 1993
2 3
KOt-Bu
TfO S
CO2Et
DBU
S Me O 72%
X is generally S, O or N and can be sp or sp hybridized Ylides often undergo sigmatropic rearrangements or cycloadditions [2,3]-Sigmatropic rearrangement:
Ph SPh O O OMe N2 Kido and Kato, JCS Perkins 1 1992 229 SPh E MeO O Cl Me O N2
Rh2(OAc)4
S EtO2C
72%
HO O Me
S E
Me O Et O
OH Methynolide has been synthesized by Vedejs using this ring-expansion methodology Me Vedejs, JACS 1989, 111, 8430
OMe O CO2Me
Rh2(OAc)4
OMe
O CO2Me
MeO Me Cl
O Me
Me
Acorenone B
OMe
O OH O
AcO Me
O O
Cl
O Me
griseofulvin
H AcO Me O O
D. A. Evans
00-Cover page 12/12/03 8:12 AM
B. Connell
Fischer Carbenes
The Use of Fischer Carbenes in Organic Synthesis
"...every synthetic chemist is well advised to follow this fascinating field with appropriate attention." - Schmalz, H.-G., ACIEE, 1994, 303.
Chem 206
Brian Connell Evans Group Seminar 2/12/99 Outline Introduction and Fundamentals Reactions Cyclopropanation Diels-Alder Cycloaddition Other Cycloadditions Dotz Reaction and Analogs Photochemistry Conjugate Additions Other Reactions
General References: Wulff,Organometallics, 1998, 3116. Wulff,Comprehensive Organic Synthesis, Vol. 5, Chap 9.2: Metal Carbene Cycloadditions, Pergamon Press, 1991. Wulff, Comprehensive Organometallic Chemistry II, Vol. 12, Chap 5.3: Transition Metal Carbene Complexes: Alkyne and Vinyl Ketene Chemistry, Pergamon Press, 1994. Hegedus, Comprehensive Organometallic Chemistry II, Vol. 12, Chap 5.4: Transition Metal Carbene Complexes: Photochemical Reactions of Carbene Complexes, Pergamon Press, 1994.
Introduction
Definition: electrophilic, heteroatom stabilized complexes having formal metal-to-carbon double bonds Group 6 metals (Cr, Mo, W) are the most common metals used. First prepared by Fischer (ACIEE, 1964, 580):
Cr(CO)6
RLi
Li
(CO)5Cr
O R
(CH3)4NBr
(CO)5Cr
N(CH3)4 can be prepared on large scale and stored R for long periods
"hard" alkylating reagents (CH3)3OBF4, CH3COBr excellent yields for all steps cheap starting materials (20-50/mmol)
(CO)5Cr R OCH3
B. Connell
Fischer Carbenes
Nitrogen Analogs
Chem 206
O O (CO)5Cr R
CH3 Br (CO)5Cr R O O
N(CH3)4
H3C
NHR2
NR2 (CO)5Cr R
O R1 NR2
OTMS
K2Cr(CO)5
TMSCl
R
1
(CO)5Cr
NR2
H3C N CH3
CH3
Bond Lengths Ccarbene - O = 1.33 Ccarbene - Cr = 2.04 Cr - COcis = 1.86 - 1.91 Cr - COtrans = 1.87 IR Frequencies vCO ~2070, 1992, 1953 cm-1 H NMR Ccarbene - CH3 = ~5
13 1
Bond Lengths Ccarbene - N = 1.31 Ccarbene - Cr = 2.16 Cr - COcis = 1.90 Cr - COtrans = 1.85 IR Frequencies vCO = ~2060, 1970, 1940 cm-1 H NMR Ccarbene - CH3 = ~3.2
13 1
H NMR
C NMR
Major Contributors
Ernst Otto Fischer
I was born in Solln, near Munich, on 10 November 1918 as the third child of the Professor of Physics at the Technical College of Munich, Dr. Karl T. Fischer (died 1953), and his wife, Valentine, ne Danzer (died 1935). After completing four years at elementary school I went on to grammar school in 1929, from which I graduated in 1937 with my Abitur. Following a subsequent period of "work service" and shortly before the end of my two years' compulsory military service, the Second World War broke out. I served in Poland, France and Russia. In the winter of 1941/2 I began to study Chemistry at the Technical College in Munich during a period of study leave. I was released by the Americans in the autumn of 1945, and resumed my study of Chemistry in Munich after the reopening of the Technical College in 1946. I graduated in 1949. I took up a position as scientific assistant to Professor Walter Hieber in the Inorganic Chemistry Department, and under his guidance I dedicated myself to working on my doctoral thesis, "The Mechanisms of Carbon Monoxide Reactions of Nickel II Salts in the Presence of Dithionites and Sulfoxylates". After receiving my doctorate in 1952, I was invited by Professor Hieber to continue my activities at the college and consequently chose to specialise in the study of transition metal and organo-metallic chemistry. I wrote my university teaching thesis on "The Metal Complexes of Cyclopentadienes and Indenes". I was appointed a lecturer at the Technical College in 1955 and in 1956 I completed a scientific sojourn of many months in the United States. In 1957 I was appointed Professor at the University of Munich. After turning down an offer of the Chair of Inorganic Chemistry at the University of Jena I was appointed Senior Professor at the University of Munich in 1959 . In 1957 I was awarded the Chemistry Prize by the Gttingen Academy of Sciences. The Society of German Chemists awarded me the Alfred Stock Memorial Prize in 1959. In 1960 I refused an appointment as Senior Professor in the Department of Inorganic Chemistry at the University of Marburg. In 1964 I took the Chair of Inorganic Chemistry at the Technical College of Munich, which had been vacated by Professor Hieber. In the same year I was elected a member of the Mathematics/Natural Science section of the Bavarian Academy of Sciences; in 1969 I was appointed a member of the German Academy of Scientists Leopoldina. In 1972 I was given an honorary doctorate by the Faculty of Chemistry and Pharmacy of the University of Munich. Lectures on my fields, particularly those on metallic complexes of cyclopentadienes and indenes, metal-pie-complex s of six-ringed aromatics, mono-, di- and oligo-olefins and most recently metalcarbonyl carbene and carbyne complexes, led me on lecture tours of the United States, Australia, Venezuela, Brazil, Israel and Lebanon, as well as numerous European countries, including the former Soviet Union. In 1969 I was Firestone Lecturer at the University of Wisconsin, Madison,Wisconsin, USA; in 1971 Visiting Professor at the University of Florida, Gainesville, USA, as well as the first Inorganic Chemistry Pacific West Coast Lecturer. In the spring of 1973 I held lectures as the Arthur D. Little Visiting Professor at the Massachusetts Institute of Technology, Cambridge, Massachusetts, USA; and that was followed by a period when I was Visiting Distinguished Lecturer at the University of Rochester, Rochester, New York, USA.
Nobel lecture: On the way to carbene and carbyne complexes. Angew. Chem. (1974), 86(18), 651-63.
Major Contributors
Claude F. Bernasconi
University of California at Santa Cruz Claude was born in Zurich, Switzerland. He received his undergraduate and Ph.D. degrees from the Swiss Federal Institute of Technology (ETH) with Heinrich Zollinger. Following a postdoctoral year with Manfred Eigen at the Max Planck Institute for Biophysical Chemistry in Gottingen, he joined the chemistry faculty at the University of California at Santa Cruz in 1967, where he has been a professor of chemistry since 1977. His main research interests are in physical organic chemistry and center on problems of mechanism, structure-reactivity relationships, intrinsic barriers of reactions, and catalysis in organic and organometallic reactions, particularly proton transfer reactions, nucleophilic addition to electrophilic alkenes, nucleophilic vinylic substitution and reactions of Fischer carbene complexes.
Charles P. Casey
University of Wisconsin-Madison Born 1942, St. Louis, MO B.S. 1963, St. Louis University Ph.D. 1968, MIT Chuck received a Ph.D. in organic chemistry from MIT in 1968, where he studied organocopper chemistry under the direction of Professor George M. Whitesides. After spending 6 months at Harvard as an NSF postdoc with Paul D. Bartlett he joined the faculty at Wisconsin. Chuck is interested in studying the mechanisms of organometallic reactions and in developing an understanding of homogeneous catalysis. In addition, he is trying to design new organometallic reagents for synthesis and new heterobimetallic catalysts.
William D. Wulff
University of Chicago Born Eau Claire, Wisconsin, 1949 B. S. 1971, University of Wisconsin-Eau Claire Ph.D. 1979, Iowa State University Professor Wulff received his Ph.D. degree from Iowa State University in 1979 with Professor Thomas Barton. After NIH postdoctoral work with Martin Semmelhack at Princeton University, he accepted a position at the University of Chicago in 1980. Professor Wulff's research interests are in the applications of organometallics in organic synthesis as both reagents and catalysts.
Jose Barluenga
University of Oviedo Jose Barluenga obtained his Ph.D. degree (solvomercuration of dienes) at the University of Zaragoza in 1966 under the direction of Professor V. Gomez-Aranda. He spent 3.5 years as a postdoctoral fellow at Max Planck Institut Fur Kohlenforschung, Mulheim, in the group of Professor Hoberg studying aluminum chemistry. In 1970 he took a position as a research associate at the University of Zaragoza, where he was promoted to Associate Professor in 1972. In 1975 he moved to the University of Oviedo as Professor of Organic Chemistry in the Department of Organometallic Chemistry. His major research interest is focused on the development of new synthetic methods in the area of heterocyclic chemistry and functionalized systems.
Louis S. Hegedus
Colorado State University Born Cleveland, Ohio, 1943 B.S, 1965, Penn State University M.A. 1966, Penn State University Ph.D., 1970, Harvard Lou was born in 1943 in Cleveland, Ohio, but grew up in rural Ohio, away from big city temptations. He did his undergraduate studies at Pennsylvania State University, where studied aqueous chromium redox chemistry with Professor Albert Haim. After Ph.D. studies at Harvard on nickel carbonyl chemistry with E. J. Corey (1970), and a NIH postdoctoral year at Stanford with J. P. Collman studying polymer-supported homogeneous catalysis, he moved to Colorado State University, where he remains today as a professor of chemistry. His research interests center on the use of transition metals in organic synthesis.
B. Connell
Fischer Carbenes
Recurring Themes Resonance
OCH3 CO OC OC CO Cr R OCH3 (CO)5Cr R (CO)5Cr R OCH3
Chem 206
The Wall of CO
CO
Rotation about heteroatom carbene bond is restricted by 14-25 kcal/mol 53Cr NMR is consistent with strong resonance contribution Hegedus and Dotz JACS, 1988, 8413. Kinetic Electrophilicity
OCH3
HOCH3
(CO)5Cr CH3
pKa = 35 (DMSO)
B. Connell
Fischer Carbenes
Sensitivity to Acid
Chem 206
pyridine
H3CO
(CO)5Crpyr
pyridine
H (CO)5Cr CH2
reductive elimination
OCH3 (CO)5Cr
pyridinium
OCH3 CH2
OCH3 (CO)5Cr Ar
CH3Li, ClCH2I
Ar CH3
OCH3 (CO)5Cr R
CH2N2
R
OCH3
OCH3 (CO)5Cr Ar
Ph3PCH2
OCH3 H2C Ar
OCH3 Ar
Cl
N2
B. Connell
Fischer Carbenes
Selected Reactions of Unsaturated Fischer Carbene Complexes
OCH3 R1 R2 OCH3 R3 (CO)5Cr R1 R2 Nu R3 R1 R4 R R
3 5
Chem 206
OH R
3
(CO)5Cr
Nu
4
OCH3
R2 = H
R2 R HN R4 R
5
O R2 R
OCH3 (CO)5M R1 R2 R3
2 3
R ,R H
R1 OCH3
H3CO
R4 R R4
R2 = NR2
R OCH3
Bu3SnH
R3 R2 R2 R1 R3 R1 OCH3 R4
OCH3 Bu3Sn O R R
3
R1
OCHR2R3 OCHR2R3
O O R
RCHO
(CO)5M XR6 R O (CO)5M CH3 R OCH3 R1 N XR (CO)5M R R3Sn XR
6 6
XR6 O
CH3
R O
R2 R2 N XR6 R1 CH3 O
B. Connell
Fischer Carbenes
Cyclopropanation
CO2CH3 OCH3 (CO)5Mo n-Bu n-Bu
Chem 206
THF, 65 C 78%
OCH3
CO2CH3
E:Z 1.9:1
OCH3 (CO)5Mo
OTBS CH3
25 C, 49%
CH3
TBSO
OCH3
>95% cis Wulff Pure Appl. Chem., 1988, 137. JACS, 1988, 2653.
OCH3 M(CO)4 R1
OCH3 M(CO)4
n-Bu
OCH3
PhH
OCH3 (CO)5Cr
reflux 97%
OCH3
B. Connell
Fischer Carbenes
Selective Cyclopropanation
Chem 206
Ph
OCH3 H O H
SiO2
Ph H
THF, 80 C, 3 h
O3
n-Bu H
OCH3 O H
Fe
Fe
Barluenga Chem. Commun., 1995, 665. JACS, 1997, 7591. Cyclopropanation Reaction with Alkynes
O
PhH
65 C, 55%
O CH3 H CO2Et
H O CH3 CO2Et
B. Connell
Fischer Carbenes
[4 + 3] Annulation
Cr(CO)5 Ph NHt-Bu Et N H Ph OCH3 NHt-Bu
Chem 206
[2 + 1]
Ph
Ph
NHt-Bu
[3,3]
HN OCH3 Et NHt-Bu H3CO N H
Et
Barluenga Chem. Commun., 1994, 321. JACS, 1995, 9419. JACS, 1996, 695. Chem. Eur. J., 1996, 88.
Diels-Alder Cycloaddition
25 C, 7 mo 54%
H3C
70:30 regioselectivity
H3CO OCH3
CH3
(CO)5Cr
(CO)5Cr
25 C, 3 h 70%
H3C
92:8 regioselectivity
B. Connell
Fischer Carbenes
Diels-Alder Cycloadditions
(OC)5Cr CH3 H3CO
Chem 206
Me
25 C, 2 h 85%
H3CO
Cr(CO)5
O CH3 H3CO
Me O H3CO
170 C, 1 h 22%
120 C, 48 h
H3CO O
addition of LA causes decomp
25 C, 2 h 100%
H3CO W(CO)5
Diels-Alder Cycloadditions
CH3 Me Cr(CO)5
+ 25 C, 2 h
H3CO Cr(CO)5
87%
9:1
+ 25 C, 2 h 88%
H3CO Me Cr(CO)5
Me Cr(CO)5 OCH3
8.5:1.5
B. Connell
Fischer Carbenes
Asymmetric Exo-Selective Diels-Alder Reaction
CH3 N O N Ph OCH3 CH3 TBSO O N (CO)4Cr H3CO OTBS O H3C OCH3 O HC M C N O Ph H3C NCH3 O C C Ph CH3 CH3 N CH3
Chem 206
25 C, 12 h, 80%
exo:endo >96:4
[2 + 2] Cycloaddition
DMSO
10 min 95%
25 C, 6 h 97%
CH3 CH3
CH3
O H3CO O O
H3C O O CO2CH3
+ 180 C, 16 h
O OCH3 H3CO O CO2CH3
36%
24%
B. Connell
Fischer Carbenes
[3 + 2] Cycloaddition
Chem 206
OCH3 CH3
TMSCHN2
25 C, 2 h 76 - 87%
CH3
(OC)5M HN N
CAN
97% 30 min
O HN N
CH3
>300:1 regioselection
H3CO
OCH3
TMSCHN2
70 C, 5 d
CH3
O HN N
+
HN N
25%
48% Wulff, JACS, 1986, 6726. Barluenga TL, 1998, 4887. Barluenga JCS Perkin I, 1997, 2267.
Dotz Reaction Thermal Reaction of Unsaturated Carbene Complexes "...one of the most utilized reactions in natural product synthesis involving an organometallic process."
OH OCH3 (CO)5Cr RL RS
RL
CO
(CO)3Cr OCH3
RS
Observed Connectivity:
O RL
RS H3CO (CO)5Cr
Dotz ACIEE, 1975, 644. New J. Chem., 1990, 433. ACIEE, 1984, 587.
B. Connell
Fischer Carbenes
Dotz Proposed Reaction Mechanism
OCH3 OCH3
Chem 206
CO
(CO)4Cr
OCH3
RL
RS
(CO)4Cr RL RS
(CO)5Cr
OCH3
RL
RL
RS
800 psi CO
HO
OCH3 RL RS
Cr(CO)6
or FeCl3
HO
OCH3 RL RS Cr(CO)3
(NH4)2Ce(NO3)6 H2O
RL
RS
(NH4)2Ce(NO3)6
O
OCH3 OCH3 RL RS
CH3OH
B. Connell
Fischer Carbenes
Dotz: Nitrogen Analog
Chem 206
N N (CO)5Cr CO2Et H Ph
THF, 60 C
then SiO2 95%
Ph OH CO2Et
OCH3 (CO)5Cr Ph
1.5 equiv.
n-Bu
OAc n-Bu
THF, reflux, 45-60 min 1.1 equiv. Ac2O 1.1 equiv. NEt3 0.16 equiv. DMAP 400 g scale 68% Biaryl Synthesis
OCH3
OCH3
2 equiv.
(CO)5Cr R2
H R3
R1
R1
OCH3 R1 R1 HO R
2 3OH
R3
R2 OCH3 R
The concept works, in moderate to low yield, but the reactions must be run stepwise. Occasionally CO insertion is suppressed and five-membered rings are formed.
B. Connell
Fischer Carbenes
Intercepted Intermediates
Chem 206
(CO)6Cr H3CO
CH3 Et Et Et
O H3C
37%
H3C OH Et
CH3 OCH3
via
CH3 O CH3
HO
OCH3 Et Et Cr(CO)3
Synthetic Uses
CH3CN, 45 C, 24 h
66%
OCH3 OCH3
CO2CH3
O OCH3 CH3
OH
OCH3
B. Connell
Fischer Carbenes
Synthetic Uses 1)
Ot-Bu O OCH3 AcO
Chem 206
AcO
OTf
CH2Cl2, 45 C, 24 h
H3CO Cr(CO)4
H O disaccaride R OH OH O
OCH3 OH OH O CH3
trisaccaride
8 equiv. OTMS
TMS (CO)5Cr
OTMS
(CO)5Cr H3CO
1.5 equiv.
50 C, THF, 3 d ~25%
OCH3
OH
O CH3 OH
O O OTMS OTMS
OCH3 O
OH
OH OCH3
Daunomycinone
B. Connell
Fischer Carbenes
Dihydrofluorene Synthesis
OCH3 H3CO H3C W(CO)5 H3C
Chem 206
-20 C to rt +
N O Ph
12 h >95%
O
N O
N O
Alkyne-Alkene Reactions 1)
CH3 OCH3 (OC)5Cr CH3 H3C H3C O O
CH3CN, 70 C, 3 h 83% 2) H+
CH3
H+
B. Connell
Fischer Carbenes
Ketene Cyclizations
Chem 206
OCH3 Cr(CO)5
OCH3
h 60 - 90%
OH
Via:
CH3O Cr(CO)4 O
"Asymmetric" Benzopentaannulation
R *O
Ph
R *O
H3C W(CO)5 Ph
OR* (CO)5W Ph
R *O
Ph
R *O
[1,3]
MeOTf
Ph
H3C W(CO)5
(CO)5W Ph
Ph
B. Connell
Fischer Carbenes
Furan Synthesis
Chem 206
R3
1)
O R1 R2 R4 (CO)5Cr
OCH3 CH3
CH3 O R4
66 - 84%
R1 R2
2) H3O
H3O+
R4
R2 R1
R4
R2 R1
R2 R1 R4 O R3
O (CO)4Cr H3C
O R3 (CO)4Cr H3C R3
OCH3
H3C OCH3
OCH3
99:1 dioxane:H2O 8 h,
40 - 90%
RS OCH3
O OCH3 (CO)5W RL
OCH3 RS OCH3
Cr0, H2O
RL
RS
OCH3
RS
Herndon JACS, 1988, 3334. TL, 1989, 295. JOC, 1990, 786. JACS, 1991, 7808. JACS, 1992, 8394.
B. Connell
Fischer Carbenes
Photochemistry
Chem 206
Electronic absorption consists of three low-lying bands: ~500 nm: spin-forbidden M carbene * charge transfer transition 360-450 nm: spin allowed M carbene * charge transfer transition (visible) 300-350 nm: ligand field transition In addition, all carbene complexes absorb strongly below 300 nm.
H3CO (CO)4Cr O
CH3
B. Connell
Fischer Carbenes
Ketene [2 + 2]
S OCH3 (CO)5Cr CH3 N H3C H3CO O H S N
Chem 206
h 81%
Ph (CO)5Cr N O O
Ph
N O
MCPBA
92%
Ph C8H17 H3CO N O O O O
h 84%, 97% de
Hegedus JOC, 1995, 3787. JOC, 1996, 6121. Organometallics, 1997, 2313. JOC, 1998, 4691 & 8012.
H2N
TBAF 90%
H3CO C8H17
1) NaOCl 30%
C8H17 O
2) NH3 100%
O
2 equiv. NaH
O N O O
88%
O O N (CO)4Cr CH3 Ph
PhONa
O N (CO)4Cr CH2 Ph
PhOH
O N (CO)4Cr H CH2 Ph
B. Connell
Fischer Carbenes
Amino Acid Synthesis
H3C H3C (CO)5Cr CH2R O
Chem 206
h, t-BuOH
N Ph
R Ph N
60-80% 97% de
Mutiply-labeled amino acids are readily prepared from (13CO)6CO and CH3OD:
O
13
R Ph
13
C Ot-Bu
C D CH3 CH3
Hegedus JACS, 1990, 2264. JACS, 1992, 5602. JACS, 1993, 87. Acc. Chem. Res., 1995, 299. JOC 1995, 5831. JACS, 1995, 3697. JOC 1997, 7704.
Peptide Synthesis
H3C
h
H3C (CO)5Cr CH3 N Ph H3C NH2 CO2t-Bu Ph
H3C N
Solid Support Merrifield Resin: Acc. Chem. Res., 1995, 299. PEG: JOC 1995, 5831; JOC 1997, 7704.
Reactions have been performed and do work, but are not as practical because the failure to achieve 100% yields and high diastereoselectivity limit this method. hard to work with because the polymer "sticks to everything, making quantitative transfer difficult". Acc. Chem. Res., 1995, 299.
B. Connell
Fischer Carbenes
Aryl Glycines
Ph Ph HN Ar H N Ph
Chem 206
h
OH (CO)5Cr HO Ph O
Ar
H N
Ph
(CO)5Cr Ar
Ph
H2, PdCl2
Aryl glycines cannot be made via the previous route due to instability of the required carbenes:
H3C H3C (CO)5Cr Ar
H3N Ar
COO
N Ph
O N
Ph O N O
H3C
O N O CH3O2C
Ph R O H
O N
Ph R O N O O O Ph N O N O
HCl, CH3OH
B. Connell
Fischer Carbenes
Zwitterionic Aza Cope Rearrangement
OCH3 (CO)5Cr CH3 N Bn Bn N O OCH3 CH3
Chem 206
h 71%
91:8
81:19
H3CO (CO)4Cr O Bn
CH3
H3CO
CH3
[3,3]
N O Bn N
Michael Reaction
(CO)4 Cr N N NCH3 O NCH3
(CO)4Cr
O OLi
-40 C R Ph CH3 Yield 81% 92% syn:anti 99.5:0.5 98.3:1.7 Wulff, JACS, 1993, 4602.
a) n-BuLi b)
O (CO)5Cr (CH3)2N
DMSO
71%
(CH3)2N
B. Connell
Fischer Carbenes
Asymmetric Michael Addition
OLi Ph H3C O CH3
(CO)4 Cr
Chem 206
O N NCH3 CH3
(CO)4Cr
N H3C
O NCH3
-20 C
Ph CH3
90% 3:1diastereoselection
O R1 R2 R2
(CO)4 Cr
Ph
(CO)4Cr
H3C N
O NCH3
a) n-BuLi b) O
R1
O N NCH3
Ph
CH3
Ph
CH3
O R1
CH3
O O
1) CAN
N NCH3
CH3
O OCH3
2) NaOCH3
Ph CH3
R1
Ph
74%, 84% de
Ph H3C O (CO)5Cr Ph CH3 CH3
OLi H3C Ph
OR* (CO)5Cr
Ph
O Ph CH3
B. Connell
Fischer Carbenes
Michael Reactions: Selectivity
Chem 206
R1 O
O OC Cr H CO C R H
2
Ph
Pyridine Synthesis
H EtO W(CO)5 H3C HN O N CH3 CH3 O
then HBF4
Ph
CH3 Ph
75%
HBF4
EtO
W(OC)5 HN CH3
EtO
W(OC)5 HN CH3
CH3
H O H3C H3C
B. Connell
Fischer Carbenes
Alkylation
OCH3 (CO)5Cr CH3
Chem 206
OCH3
OCH3
OCH3
+
CH3
7:3
a) n-BuLi b)
OTf (CO)5Cr
OCH3
80%
N (CO)5Cr CH3
N CH3
"Aldol" Reaction
OCH3 (CO)5Cr CH3
a) n-BuLi
(CO)5Cr
OCH3 OH
Ph
a) n-BuLi
N (CO)5Cr CH3 N
(CO)5Cr
OH
Ph
Ketones work as well.
(CO)4Cr
H3C N
O NCH3
OH H3C CH3
O
N
O NCH3
Ph
CH3
B. Connell
Fischer Carbenes
Ene Reaction
Chem 206
OCH3 CH3
+
CH3
1)
O O
80 C, 3 d
O (CO)5Cr CH3
24:1 trans:cis
CH3 H3C
H3C CH3 H3C CH3 O (CO)5Cr CH3 OCH3 OCH3 (CO)5Cr CH3 OCH3 H O OCH3 H3C
CH3
B. Connell
Fischer Carbenes
Vinylsilane Synthesis
Chem 206
RCH2Li or RCH2MgX
CeCl3
-78 C, cold quench
OCH3 (CO)5Mo SiPh2CH3 H3CPh2Si
R = i-Pr, 94%, 96:4 E:Z R = Bu, 86%, 96:4 E:Z R = i-Bu, 85%, 97:3 E:Z
RCH2Li or RCH2MgX
CeCl3, HMPA
-78 C to rt
H3CPh2Si R
R = i-Pr, 76%, 92:8 Z:E R = Bu, 79%, 97:3 Z:E R = i-Bu, 61%, 97:3 Z:E
n-BuLi
Li (CO)5Mo
OCH3
H2O
-78 C
H (CO)5Mo
OCH3
n-Bu
SiPh2CH3
n-Bu
SiPh2CH3
warm LiOCH3
HOCH3
n-Bu
Li (CO)5Mo SiPh2CH3
CH3OLi
(CO)5Mo SiPh2CH3
hydrogen migration
B. Connell
Fischer Carbenes
Allyl Stannane Synthesis
Chem 206
W(CO)5
SnBu3
Bu3SnH, pyr
H3C OCH3
73%
H3C
OCH3
Ph H3CO
Cr(CO)5 OCH3
Bu3SnH, pyr
69%
H3CO
Ph
SnBu3 OCH3
Bu3SnH, pyr
88%
Bu3Sn TMS
OCH3
E:Z 1:1
W(CO)5
Bu3SnH, pyr
MOM Me
Bu3Sn Me
OMOM
66%
Halban-White Cyclizations
O Ph Ph O OPh O Ph OPhO Ph PhO Ph Ph O O O O Ph
Ph
PhCO
COPh
PhCO
COPh
Ph
Andres, A. Dissertation, Strasbourg, 1911. van Halban, Helv. Chim. Acta, 1948, 1899.
O OCH3 (CO)5M R4 R6 R5 R1 R2 O R1 O
R2
R6 R5 R4 R3
O O
6 R2 R
R5
R4 R H3CO
1
D. A. Evans
Chem 206
http://www.courses.fas.harvard.edu/~chem206/
CMe3
OH Bu3Sn OMe
THF, -78 C 94%
OTBS
OMe Me
The C=O addition illustrated in eq 1 proceeds while the carbon analogue (eq 2) does not. Explain TMS O RO P OR O R H Me O RO P OR fails! R R O SiR3 O P RO OR Me O P RO OR R OTMS O (1) P R RO OR
OMe P O (2)
RO OR
Provide a mechanism for the indicated transformation OLi H O X Takeda, Org. Lett, 2000, 2, 903-1905 Me H X O OSiMe3
Me3Si
D. A. Evans
D. A. Evans
Chem 206
CC 83
CSi 76
SiSi 53
CF 116
SiF 135
CO 86 CH 83
Ph3SiF2 NR4
CC 1.54
C C
CSi 1.87
CO 1.43
SiO 1.66
FSiMe3
C CC
better than
Si
Si
CSi
OSiMe3 KOCMe3
Si-SP3
O THF 20 2h
K Me3SiOCMe3
C-SP3 CC
C-SP3
C-SP3 CSi
Li Me3SiMe
This trend is even more dramatic with pi-bonds: CC = 65 kcal/mol CSi = 36 kcal/mol
+
SiSi = 23 kcal/mol
K. Scheidt, D. A. Evans
Chem 206
1.647 CF3 F Ph F Si F Ph
D. A. Evans
Bonding Considerations: Carbon vs Silicon Carbonyl addition Reactions The prospect of catalysis was investigated
Me3Si CN
+
Chem 206
1970 DAE Objective: Develop a reagent that will transform aldehydes into protected cyanohydrins in one step
O
+
ZnI2
1-5 min
OSiMe3 C5H11 CN H
O H
CN
SiR3 G R
OSiR3 G H
LiNR2
OSiR3 R Li G
Me
1-5 min
G = carbanion-stabilizing FG
Principle established that normally inaccessible cyanohydrin derivatives may now be accessed
Me Me Me OTMS Me Me
92% yield only 1,2-addition (ZnI2 catalysis)
TMSO CN Me
O
>95% yield only 1,2-addition (CN catalysis)
R3Si R3Si
G CN
Candidates
CN
>95% yield (ZnI2 catalysis)
TMSO
CN
with Truesdale, Carroll, Chem Commun. 1973, 55; J. Org. Chem.. 1974, 39, 914 Tetrahedron Lett 1973, 4929 (first discussion of Nu catalysis)
R3Si
OSO2Ar
R H
SO2Ar OSiR3
"The Silicon Advantage" From the preceding case, it is clear that HSi is more exothermic than HH
O R + R X CN R R OX CN
R3Si
OPR2
R H
POR2
HSi > HH
O R R R C N
O R CN Me3Si CN
O H
50 C 2-5 hr
OSiMe3 C4H9 H
Me
OTMS C N + R CN R
D. A. Evans
Chem 206
OH
1-4 addition
CN OH O
Organosilanes undergo carbonyl addition processes in direct analogy with their proton counterparts but with an attendant greater exothermicity. Organosilanes undergo a range of thermal rearrangements processes in direct analogy with their proton counterparts.
X X H A. J. Ashe III, JACS 1970. 92, 1233 rt H
1-2 addition
C N TMSO CN
SR R1 SR R2
O ZnI2 R1 Me3Si
+
RS R2 SR
OSiMe3 R1 SR R2 Me
heat Me Me O R
with Truesdale, Grimm, Nesbitt, JACS 1975, 97, 3229 JACS 1977, 99, 5009 O R H O Me3Si N2 OEt CN or F
1-5 min
SiR3 N SiR3
G* 15-22kcal/mol
Si transfer is intramolecular
SiR3
Non-catalyzed processes may also occur if a proper geometry for atom transfer can be achieved
TMS O H
+
Me3Si C N OTMS O P R RO OR
O R
O R
SiR3 O P
Organosilicon hydrides undergo transition metal catalyzed hydrosilylation processes in direct analogy with normal hydrogenation reactions
Me HSiR3 R Rh(I) catalysis Rh(I) catalysis Me HH R Me H
RO P OR O R
RO OR R RO TMSO O P OR
OTMS RO RO P O R
SiR3
"Hydrosilylation of CC Bonds". T. Hayashi In Comprehensive Asymmetric Catalysis, Jacobsen, E. N.; Pfaltz, A.; and Yamamoto, H. Editors; Springer Verlag: Heidelberg, 1999; Vol I, 319-332.
D. A. Evans
Chem 206
Et2NH DMSO
Y = C; X = O
Me Np Si Ph Ph O Me Ph Si Np Me O Ph 110 C Np Si Ph Ph O
Et2NH
Ea ~ 8-11 kcal/mol
SiR3
R3Si Ph C Ph O H N Et Et Et H Ph Ph
C H N
O H Et
Brook has documented that retention at Silicon & inversion at Carbon occur.
Y = C; X = C
Me Np Si Ph
Acylsilanes
O R Cl Li SiR3 Cu(I) R O R2BH SiR3 [Ox] R SiR3
Np H 2C
Theoretical calculations lead to the conclusion that the concerted [1,3] sigmatropic rearrangement with retention of Si-configuration should represent the lower energy pathway. Yamabe, JACS 1997, 119, 808 At the present time these rearrangements are not well studied,
SiR3
Li
El(+)
Li
O R
[1,2] Si R3Si R
Li R El(+)
R R3Si
D. A. Evans
Chem 206
Li
O R
[1,2] Si R3Si R
Li R El(+) PhS O El R
OSiMe3
R R3Si
OH R
R3Si
s-BuLi R3Si
Li O R
El(+) R3Si
LiO
SiR3 [1,2] Si
OSiMe3
PhS Li O SiR3 O R O R
PhS
Takeda JACS 1993, 115, 9351; Synlett 1994, 178; SynLett 1997, 255
CH2()
O SiR3 PhS
OLi Me3Si R R
OSiMe3
"Metalated Allylic Ethers as Homoenolate Anion Equivalents". Evans, D. A.; Andrews, G. C.; Buckwalter, B. JACS 1974, 96, 5560. SiVariant: Still & MacDonald JACS 1974, 96, 5561
OLi
Brook Equilibrium
Me3Si Ph Ph Me3Si Ph H C C
Reich JACS 1980, 102, 1423 (see footnote 8) THF OLi Ph Ph C Li THF OLi Ph H C Li SiMe3 O R SiMe3 O PhS O LiO SiR3 [1,2] Si PhS R O PhS OSiMe3
[3,3] OSiMe3
OLi
D. A. Evans
The natural product target:
RO H Me CHO
Chem 206
Me
C Si
N P
Pr
Anti Elimination
Pr
OH KH
Me3Si
OM R R
M Me3Si O R R Me3Si H Pr
Syn Elimination
Pr Colvin chapter 12, pp 141
Magnesium alkoxides: Stable O Me3Si CH2MgCl R R Me3Si R R R Me3Si OK (Na) OMgCl R these adducts are quite stable H Me3Si
O H Pr
R3Si R2CuLi H R
OH H Pr
KH
H R
H Pr
D. A. Evans
Chem 206
Miyakolide (+)-1
Evans et al. JACS 1999, 121, 6816-6826.
O Me
H2C Me
OH H Me O Xp
1
OMe O O OMe Xp Me
1
Me OMe
O Me3Si OEt
O
LiN(TMS)2
TMS
OMe
OEt O
O O OPMB
Conditions 78 C
9
OPMB 19-E
CO2Me
Me3Si
t-BuLi MgBr2
entry 1 2 3 4
E:Z 73 : 27 18 : 82 66 : 33 66 : 33
O CMe3
BF3OEt2
OH Me3Si n-Hexyl
OH CMe3
KH
OH
KH
Me3Si n-Hexyl
R
Hudrlik, JACS 1981, 103, 6251
OH CMe3
D. A. Evans
OTMS Me Me OTMS O TMSO O Me KN(TMS)2 OTMS Me Me OTMS O TMSO O Me N O Me3Si N
Chem 206
2 Me3Si
CH2M
M = Li M = CeCl2
O N
Me H O
OH
OBn
OTBS
SiMe3 87%
J. Leighton, D. A. Evans
Chem 206
Et Et Si OR Et
triethylsilyl (TES)
Me t-Bu Si OR Me
tert-butyldimethylsilyl (TBS or TBDMS) TES ~102 times more stable to acidic hydrolysis than TMS TBS ~104 times more stable to acidic hydrolysis than TMS
t-Bu Ph t-Bu Si OR Ph
tert-butyldiphenylsilyl (TBDPS)
t-Bu Si O
Me
OSiR3
1% HCl in EtOH 22.5 C SiR3 Half-life < 1 min 18 min 244 min
Me
OH
O R
di-tert-butyldimethylsilylene (DTBS)
Me
OSiR3
Me
OH
Formation:
By far the two most common methods:
R OH
R OSiR3 OSiR3
2 equiv TBAF THF, 22.5 C
2 equiv of imidazole are required relative to R3SiCl. Corey, E. J.; Venkateswarlu, A. J. Am. Chem. Soc. 1972, 94, 6190.
OH
R OH
R OSiR3
J. Leighton, D. A. Evans
Selective Protection:
Chem 206
OH Me Me Me
OH Me Me
OTBDPS
TBSOTf, 2,6-lutidine
OTBS Me
Me
Me
Me
CO2Me OTBS Me
71%
O MeO
OH
OH Me OTIPS
TESCl, DMAP CH2Cl2, 0 C 77%
O MeO
OTESOH Me OTIPS
Me
HO CO2Me Me HO Me OH HO CO2Me OH H
Yankee, E. W.; Bundy, G. L. J. Am. Chem. Soc. 1972, 94, 3651. TMS-NEt2 acetone, -45 C
Me OH H
TBSOTf, 2,6-lutidine CH2Cl2, -78 C 91%
Me
Me TMSO Me OH
OH OTMS
OTBS OTMS
TMS-NEt2 has been reported to selectively protect equatorial alcohols in the presence of axial alcohols: Weisz, I. et al. Acta. Chim. Acad. Sci. Hung. 1968, 58, 189.
Askin, D.; Angst, D.; Danishefsky, S. J. Org. Chem. 1987, 52, 622.
OH
OH
O N
O
TBSOTf, 2,6-lutidine
HO SO2Ph
TBSCl, imid. DMF, RT 80%
HO SO2Ph Me Me Me
CH2Cl2, 0 C
92%
Bn TBSO
Evans, Ng JACS 1993, 115, 11446
OTBSOH
O N
O O
HO
Me
Me
Me
J. Leighton, D. A. Evans
Selective Protection:
OH Me Me Me Me Bn
Evans, Ng JACS 1993, 115, 11446
Chem 206
OH
O N
Me
> 80%
Me
OMe O
Calter, M. A. Ph. D. Thesis, Harvard University, 1993
CH2Cl2, 0 C
TMSO O Me O O
OTBSOH Me Me Me Me
O N Bn
OTMS Me OMe Me Me
K2CO3
Me
OMe O
OH Me Me Me
OH
O N
O
TBSOTf, 2,6-lutidine
TMSO Me O
CH2Cl2, -10 C
OH Me OMe Me
Me Bn OH Me Me Me
OTBSO N Me Bn
Me O
OH Me Me Me TESCl, imidazole
DMAP
Me H
Me H Me
H O HO MeO OTES Me Me
CH2Cl2, -78 C
Me H
Me H
Me H O HO MeO O
98%
(NCCH2CH2O)2P
HFpyr, pyridine THF 94%
Me Me O O
Me OTBS
PivO
OMe
J. Leighton, D. A. Evans
Chem 206
Selective Deprotection:
OH Me OTBDPS
Me
Me O
Me
Me
Me O
Me
Me CO2Me
Me
OH
Mulzer, J.; Schollhorn, B. Angew. Chem., Int. Ed. Eng. 1990, 29, 431-432.
TBSO Me
O Me
N3 Me
O Me
OTBS
1,3-Migration:
OTBSOH
TBAF, THF RT 90%
OH
KHMDS THF, -78 C 94%
OTBS
Bu3Sn OMe Me
Bu3Sn OMe Me
Me
Me O
Me
Me
Me O
Me
Me CO2Me
HO Me
O Me
N3 Me
O Me
OTBS OTBS H O
66%
OH OPiv
?
OTBS
Nakaba, T.; Fukui, M.; Oishi, T. Tetrahedron Lett. 1988, 29, 2219, 2223.
Bu3Sn OMe Me
TESO
TESO CO2H
4 AcOH:THF:H2O (8:8:1) 4 h, 20 C 76%
CO2H
4
OTBS OH
Bu3Sn OH Me
4:1
C5H11 HO H OTBS
OMe Me
Hart, T. W.; Metcalfe, D. A.; Scheinmann, F. J. Chem. Soc., Chem. ommun. 1979, 156.
J. Leighton, D. A. Evans
Principle Methods for Benzylation of Alcohols:
1.
R OH
Chem 115
1. Hydrogenation
R OBn
10% Pd on C, H2 EtOH/EtOAc/AcOH
OH
2.
R OH O
CCl3
R R
OBn PMB
Ar = Ph:
2. Transfer Hydrogenation
R OBn
OH
Synthesis 1981, 396. J. Org. Chem. 1978, 43, 4194. J. Org. Chem. 1979, 44, 3442. Tetrahedron Lett. 1986, 27, 2497
Cruzado, C.; Bernabe, M.; Martin-Lomas, M. J. Org. Chem. 1989, 54, 465. Review: David, S.; Hanessian, S. Tetrahedron, 1985, 41, 643-663. 4.
R OH
OBn
3. Lewis Acids
R OBn R OH
Ref. Tetrahedron Lett. 1989, 30, 5713. J. Am. Chem. Soc. 1989, 111, 1923. Chem. Pharm. Bull. 1987, 35, 3880.
R2
J. Leighton, D. A. Evans
PMB Deprotection:
OMe O
Chem 115
ROH + ArCHO
Me Me
-1 e
styryl
OMe OMe O OH OPMB
O H
+
O Cl CN CN O OMe R
DDQ =
-H+
Cl
H 2O
OMe O
H O OMe
Selective Benzylation:
-1 eBr Me Br Me
H Ar
OH R
OPMB
H O OH OH
H OBn
Other Oxidants: NBS, Br2, CAN ((NH4)2Ce(NO3)6). Acta Chem. Scand. Ser. B, 1984, B38, 419. J. Chem. Soc., Perkin Trans. I, 1984, 2371.
HO
OH O
1. (Bu3Sn)2O, PhMe,
OH
BnO
OH O
OBn
Cruzado, C.; Bernabe, M.; Martin-Lomas, M. J. Org. Chem. 1989, 54, 465.
J. Leighton, D. A. Evans
Me O Me 33 OH
H H H H
Chem 115
OH
17
OH O
8
O
11
OH
8
OH
CO2H
1
O
H
O O 25 Me
I Me Me OH
Me Me O
Me
Me
Me
Me
20
11
Me
17 14
OH X Me Me
OR
10
O H Me
8
OH
4
CO2R'
1
Et
HO
Me Me
Me
Me
Me
17
C9-C17 Subunit
C1-C8 Subunit
O Me Me 33 OH
H H H H
Ph O
10
14
H OH O
10
O
H
Me OH O 25 Me O N Me Me Bn O O O Xq Me Me Me
Spiroketal Fragment
14
Ph
(Xq)
Et 20
B(OH)2
OH
17
O
11
OH
8
OH
CO2H
1 14
OH Ph
OH
10
O Xq
I Me Me
Me
Me
Me
Me
Me
Me
Me
Polypropionate Fragment
J. Leighton, D. A. Evans
OH
14
Chem 115
OH
10
O Xq Me
Ph Me Me Me
Me 33
H H
O
H H H
Me OTES O 25 Me Me
OTBS O
8
TBSO PMBO
O
10
?
Ph
14
TBSO
99%
Me O
11
OTBS
Me
Me
Me HO
1
Me
20
Et
TBSO
Me Me
17 5
Me 33 OH
14
H H
OH
10
O Xq
OH
OH
10
OH TBSO
O
H H
Me OH O 25
H
OTBS O
8
Ph Me Me Me
14
Me Me O
Ph Me OMe OMe Me Me
Me
OTBS
20
11
Me
Et
TBSO
Me Me
PMP TBSO
14
MeO OH O
17
O
10
O
10
14
Ph Me Me Me
Me
Me
Me
Me O O
H
Me OH O O Me O OH
OH
H H
Me Me O HO
TBSO PMBO
14 10
OH
TBSO PMBO
O
10
Ph Me Me Me
Me Me Me
14
Ph
Et
Rutamycin B
J. Leighton, D. A. Evans
OH
37
Chem 115
Me O N H
30
MeO Me2N
TBSO N
25 26
O OMe
OH
No Reaction
(+) Calyculin A
O N C1 Me
8
Me
(HO)2 P O 17 Me
13
Me Me O O
OH
O OMe OH
Me
Me
OH
OH
OMe
Evans, D. A.; Gage, J. R.; Leighton, J. L. J. Am. Chem. Soc. 1992, 114, 9434-9453.
After protonation of the amine, coulombic repulsion insulates against formation of another cationic site in the vicinity.
70%
OTBS
N C1 Me
8
Me
Me
PMBO 17
13
Me Me O O
Me
21 OTBS
TESO
37
O
33
Me O N H
30
Me
Me
MeO Me2N
OTES
N
25
26
O N C1 Me
8
(PMBO)2P Me Me
13
O 17
Me Me O O
Me Me Me O O Me
21 OTBS
Me
13
RO 17
Me
Me
21 OTBS
R = PMB R=H
94%
J. Leighton, D. A. Evans
Me H Me OH H Me H H H O H OH
Chem 115
Rapamycin
OH
H Me O OH Me O OMe Me Me OH OMe
Cytovaricin
Evans, D. A.; Kaldor, S. W.; Jones, T. K.; Clardy, J.; Stout, T. J. J. Am. Chem. Soc. 1990, 112, 7001-7031.
Romo, D.; Meyer, S. D.; Johnson, D. D.; Schreiber, S. L. J. Am. Chem. Soc. 1993, 115, 7906-7907. 30% overall
O
2. Dess-Martin Periodinane
i-Pr
DEIPS =
Si Et
O Me Me OTBS H Me DEIPSO Me TBSO O Me TESO H H O H H H H O H O O O Me Me OTES Me O Si O t-Bu Me OAloc ODEIPS Me OTES Me OMe Me Me Me OAloc OTIPS O H OMe Me OMe O H O N OAloc
TESO
t-Bu H H MeO
J. Leighton, D. A. Evans
Chem 115
1. DDQ, t-BuOH-CH2Cl2; Ac2O, DMAP, pyr. 2. aq. HClO4, THF, 8 days 3. LiOH, H2O/MeOH/THF, RT, 20 h 4. TBAF, THF/DMF, RT, 90 h 5. AcOH, H2O, RT, 36 h 35%
OH
HO
OH OH
OH O HO OH Me Me O OH Me OH Me HO HO OH OH OH HO O Me HO OH O OH OH
O HO
OH O Me OH O OH
OH OH
O O H N O Me3Si(CH2)2O TBSO OTBS OTBS O Me OTBS OAc OTBS OTBS OPMB O MeO OAc Me Me O OAc Me Me PMBO OTBS
PMBO
HO OH
OH
OH
OH
OTBS
OTBS OTBS
O PMBO
OTBS OTBS
OAc