SELECTIVITY SELECTIVITY Science 1983, 219, 245 Chemoselectivity preferential reactivity of one functional group (FG) over another - Chemoselective

reduction of C=C over C=O:
O H2, Pd/C O

1

- Chemoselective reduction of C=O over C=C:
O NaBH4 OH O

+

O

NaBH4, CeCl3

OH only

- Epoxidation:
MCPBA

+
OH O OH (2 : 1) VO(acac)2, tBuOOH OH O OH exclusively O OH

Regioselectivity - Hydration of C=C:
1) B2H6 2) H2O2, NaOH R OH

R R 1) Hg(OAc)2, H2O 2) NaBH4

OH

- Friedel-Crafts Reaction:
O RCOCl, AlCl3 R

+
O

R

O SiMe3 RCOCl, AlCl3 R

SELECTIVITY - Diels-Alder Reaction:
R O R O R

2

+

+
O major O R minor O R

R

+
O major

+

minor

O

O

+
O H O OAc OAc O H O OAc O Raney Ni, H2 OAc

O

O

OAc

+
O H O SPh O H O SPh O H O

Change in mechanism:
SPh PhSH, H+ R

R SPh

R PhSH, (PhCO2)2

Stereochemistry: Relative stereochemistry: Stereochemical relationship between two or more stereogenic centers within a molecule

H HO cholesterol

H enantiomers same relative stereochemistry

H

H OH

syn: on the same side ( cis) anti: on the opposite side (trans) - differences in relative stereochemistry lead to diastereomers. Diastereomers= stereoisomers which are not mirror images; usually have different physical properties

SELECTIVITY Absolute Stereochemistry: Absolute stereochemical assignment of each stereocenter (R vs S) Cahn-Ingold-Prelog Convention (sequence rules) - differences in absolute stereochemistry (of all stereocenters within the molecule) leads to enantiomers. - Reactions can "create" stereocenters
O Ph H MeMgBr HO Ph CH3 H

3

MeMgBr

H 3C Ph

OH H enantiomers (racemic product)

O Ph H HO Ph MeMgBr CH3 H

Diastereomeric transition states- not necessarily equal in energy
Me N O Zn CH3 CH3 Zn H 3C H H 3C Me O Ph O Me N Zn CH3 CH3 Zn Ph Me O H

HO Ph

CH3 H

HO H

CH3 Ph

Diastereoselectivity
CH3MgBr Ph CHO Ph HO syn CH3 H

+

Ph anti

CH3 H OH

Diastereomers

Cram Model (Cram's Rule): empirical
O O M R L R L H Ph S M S Nu CH3MgBr H 3C O H CH3MgBr favored

SELECTIVITY Felkin-Ahn Model
O M L S Nu R Nu M R disfavored S O L

4

favored

Chelation Control Mode
M OR O R S OR M CH3MgBr favored S R M O HO CH3MgBr Nu R M S

OR

HO TBSO H O OBn O MgBr TBSO H O OBn relative stereochemical control

Stereospecific Stereochemictry of the product is related to the reactant in a mechanistically defined manner; no other stereochemical outcome is mechanistically possible. i.e.; SN2 reaction- inversion of configuration is required
Br2 H 3C Br H Br H CH3 meso

Br2

H Br

CH3 Br H CH3

Br

+

CH3 H CH3 Br

H

enantiomers (racemic)

Stereoselective When more than one stereochemical outcome is possible, but one is formed in excess (even if that excess is 100:0).
H2, Pd/C CH3 H H H α-pinene
O N S O LDA, CH3I O N S (96 : 4) Diasteromers O O

H

H CH3 H

+

only isomer
O

not observed
O O N S O

+

Diastereoselective Enantiospecific

OXIDATIONS Oxidations Carey & Sundberg: Chapter 12 problems: 1a,c,e,g,n,o,q; 2a,b,c,f,g,j,k; 5; 9 a,c,d,e,f,l,m,n; 13 Smith: Chapter 3 March: Chapter 19 I. Metal Based Reagents 1. Chromium Reagents 2. Manganese Rgts. 3. Silver 4. Ruthenium 5. other metals II Non-Metal Based Reagents 1. Activated DMSO 2. Peroxides and Peracids 3. Oxygen/ ozone 4. others III. Epoxidations Metal Based Reagents Chromium Reagents - Cr(VI) based - exact stucture depends on solvent and pH - Mechanism: formation of chromate ester intermediate Westheimer et al. Chem Rev. 1949, 45, 419 JACS 1951, 73, 65.
HO R2CH-OH HCrO4 H+
-

5

R R

C O H + H2O

Cr

OO-

R R

O

+ HCrO3- +

H+

Jones Reagent (H 2CrO4, H2Cr2O7, K2Cr2O7) J. Chem. Soc. 1946 39 Org. Syn. Col. Vol. V, 1973, 310. - CrO3 + H2O → H2CrO4 (aqueous solution) K2Cr2O7 + K2SO4 - Cr(VI) → Cr(III)
(black) (green)

- 2°- alcohols are oxidized to ketones
Jones reagent R2CH-OH acetone R R O

- saturated 1° alcohols are oxidized to carboxylic acids.
Jones reagent RCH2-OH acetone R O H hydration HO OH R H Jones reagent acetone R O OH

- Acidic media!! Not a good method for H+ sensitive groups and compounds

OXIDATIONS
SePh OH Me 3Si H17C 8 O OH Jones O O acetone O O JACS 1975, 97, 2870 1) Jones, acetone 2) CH2N2 Me 3Si JACS 1982, 104, 5558 H17C 8 O O SePh CO 2CH 3

6

Collins Oxidation (CrO3•2pyridine) TL 1969, 3363 - CrO3 (anhydrous) + pyridine (anhydrous) → CrO 3•2pyridine↓ - 1° and 2° alcohols are oxidized to aldehydes and ketones in non-aqueous solution (CH 2Cl2) without over-oxidation - Collins reagent can be prepared and isolated or generated in situ. Isolation of the reagent often leads to improved yields. - Useful for the oxidation of H+ sensitive cmpds. - not particularly basic or acidic - must use a large excess of the rgt.

CrO3•(C 5H5N)2 OH ArO O O CH 2Cl 2 ArO O

H O O JACS 1969, 91, 44318.

CrO3 catalyzed (1-2 mol % oxidation with NaIO6 (2.5 equiv) as the reozidant in wet aceteonitrile. oxidized primary alcohols to carboxylic acids. Tetrahedron Lett. 1998, 39, 5323. Pyridinium Chlorochromate (PCC, Corey-Suggs Oxidation) TL 1975 2647 Synthesis 1982, 245 (review) CrO3 + 6M HCl + pyridine → pyH+CrO3 Cl- ↓ - Reagent can be used in close to stoichiometric amounts w/ substrate - PCC is slighly acidic but can be buffered w/ NaOAc
PCC, CH 2Cl 2 OHC HO O O OH O PCC, CH 2Cl 2 O CHO TL, 1975, 2647 JACS 1977, 99, 3864.

OXIDATIONS - Oxidative Rearrangements
Me OH Me PCC, CH 2Cl 2 O
Me PCC, CH 2Cl 2 OH O Me JOC 1976, 41, 380

7

JOC 1977, 42, 682

- Oxidation of Active Methylene Groups
PCC, CH 2Cl 2 O PCC, CH 2Cl 2 O O O O O

JOC 1984, 49, 1647

- PCC/Pyrazole PCC/ 3,5-Dimethylpyrazole JOC 1984, 49, 550.
NH N N NH

- selective oxidation of allylic alcohols
OH OH PCC, CH 2Cl 2 H HO H 3,5-dimethyl pyrazole O H H (87%)

Pyridinium Dichromate (PDC, Corey-Schmidt Oxidation) TL 1979, 399 - Na2Cr2O7•2H2O + HCl + pyridine → (C5H5N)2CrO7 ↓
PDC CHO CH 2Cl 2 OH PDC DMF CO 2H

1° alcohol

-allylic alcohols are oxidized to α,β-unsaturated aldehydes

OXIDATIONS - Supported Reagents Comprehensive Organic Synthesis 1991, 7, 839. PCC on alumina : Synthesis 1980, 223. - improved yields due to simplified work-up. PCC on polyvinylpyridine : JOC, 1978, 43, 2618.
CH 2 CH cross-link N N CrO3, HCl N Cr(VI)O3 •HCl N Cr(III) CH 2 CH R2CH-OH R2C=O CH 2 CH

8

partially spent reagent

to remove Cr(III) 1) HCl wash 2) KOH wash 3) H2O wash

CrO3/Et2O/CH2Cl2/Celite Synthesis 1979, 815. - CrO3 in non-aqueous media does not oxidized alcohols - CrO3 in 1:3 Et2O/CH2Cl2/celite will oxidized alcohols to ketone and aldehydes
C 8H17 CrO3 Et2O/CH 2Cl 2/celite (69%) HO O Synthesis 1979, 815 C 8H17

H2CrO7 on Silica - 10% CrO3 to SiO2 - 2-3g H2CrO3/SiO2 to mole of R-OH - ether is the solvent of choice Manganese Reagents Potassium Permanganate KMnO4/18-Crown-6 JACS 1972 94, 4024.
O O K+ O O O O MnO 4-

(purple benzene)

- 1° alcohols and aldehydes are oxidized to carboxylic acids - 1:1 dicyclohexyl-18-C-6 and KMnO4 in benzene at 25°C gives a clear purple solution as high as 0.06M in KMnO4.
O JACS 1972, 94, 4024 CO 2H CHO Synthesis 1984, 43 CL 1979, 443 CHO

OXIDATIONS Sodium Permanganate TL 1981, 1655 - heterogeneous reaction in benzene - 1° alcohols are oxidized to acids - 2° alcohols are oxidized to ketones - multiple bonds are not oxidized Barium Permanganate (BaMnO4) TL 1978, 839. - Oxidation if 1° and 2° alcohols to aldehydes and ketones- No over oxidation - Multiple bonds are not oxidized - similar in reactivity to MnO2 Barium Manganate BCSJ 1983, 56, 914

9

Manganese Dioxide Review: Synthesis 1976, 65, 133 - Selective oxidation of α,β-unsatutrated (allylic, benzylic, acetylenic) alcohols. - Activity of MnO2 depends on method of preparation and choice of solvent - cis & trans allylic alcohols are oxidized at the same rate without isomerization of the double bond.
OH HO MnO 2, CHCl3 (62%) HO O J. Chem. Soc. 1953, 2189 JACS 1955, 77, 4145. OH HO

- oxidation of 1° allylic alcohols to α,β-unsaturated esters
OH MnO2, ROH, NaCN CO 2R

OH MnO 2, Hexanes MeOH, NaCN

CO 2Me

JACS1968, 90, 5616. 5618

Manganese (III) Acetate α-hydroxylation of enones Synthesis 1990, 1119 TL 1984 25, 5839
O Mn(OAc)3, AcOH AcO O

Ruthenium Reagents Ruthenium Tetroxide - effective for the conversion of 1° alcohols to RCO2H and 2° alcohols to ketones - oxidizes multiple bonds and 1,2-diols.

OXIDATIONS
Ph O OH Ph H CH 3 OH 96% ee OH RuO4, NaIO4 CCl 4, H2O, CH3CN RuO4, NaIO4 CCl 4, H2O, CH3CN Ph O JOC 1981, 46, 3936 CO 2H

10

Ph H

CO 2H CH 3 94%ee

HO RuO2, NaIO4 O O CCl 4, H2O O O O TL 1970, 4003

Tetra-n-propylammonium Perruthenate (TPAP, nPr4N+ RuO4-) Aldrichimica Acta 1990, 23, 13. Synthesis 1994, 639 - mild oxidation of alcohols to ketones and aldehydes without over oxidation
OH TPAP MeO 2C MeO 2C OSiMe 2tBu O N+ -O Me OSiMe 2tBu O

TL 1989, 30, 433

(Ph3P)4RuO2Cl3 RuO2(bipy)Cl2 - oxidizes a wide range of 1°- and 2°-alcohols to aldehydes and ketones without oxidation of multiple bonds.
OH OH H H CHO CHO JCS P1 1984, 681.

Ba[Ru(OH)2O3] -oxidizes only the most reactive alcohols (benzylic and allylic) (Ph3P)3RuCl2 + Me3SiO-OSiMe3 - oxidation of benzylic and allylic alcohols TL 1983, 24, 2185. Silver Reagents Ag2CO3 ( Fetizon Oxidation) also Ag2CO3/celite - oxidation of only the most reactive hydroxyl
O OH OH Ag 2CO 3 O O OH O O O OH OH Ag 2CO 3, C 6H6 O O O JACS 1981, 103, 1864. mechanism: TL 1972, 4445.

Synthesis 1979, 401

OXIDATIONS - Oxidation of 2° alcohol over a 1° alcohol
OH OH Ag2CO3, Celite (80%) O OH JCS,CC 1969, 1102

11

Silver Oxide (AgO2) - mild oxidation of aldehyde to carboxylic acids AgO 2, NaOH RCHO

RCO 2H
CO 2H

CHO

AgO 2

JACS 1982, 104, 5557 Ph Ph

Prevost Reaction Ag(PhCO2)2, I2
Ag(PhCO 2)2, I2 AcOH AcO OAc

Ag(PhCO 2)2, I2 AcOH, H 2O

AcO

OH

Other Metal Based Oxidations Osmium Tetroxide OsO 4 review: Chem. Rev. 1980, 80, 187. -cis hydroxylation of olefins old mechanism:
OsO 4, NMO O O OH OH cis stereochemistry

Os O O osmate ester intermediate

- use of R 3N-O as a reoxidant TL 1976, 1973.
O O OH OH TL 1983, 24, 2943, 3947 Stereoselectivity: R2 RO H OsO 4 R3 R4 OsO 4, NMO HO H R2 HO R3 RO H R4 OsO 4, NMO O O OH OH

OXIDATIONS - new mechanism: reaction is accelerated in the presences of an 3° amine
R1 O Os O O O R2 [2+2] O O O Os O [O] [3+2] O Os O O R1 R2 O O hydrolysis R1 HO R2 OsO2 [O] R1 R2 R3N O O O Os O NR3 R1 R2

12

+
OH

OsO4

- Oxidative cleavage of olefins to carboxylic acids. JOC 1956, 21, 478. - Oxidative cleavage of olefins to ketones & aldehydes.
OH OH OsO 4, NMO O O OAc O O OAc OH NaIO4 O O OAc CHO CHO O O O O

H2O

JACS 1984, 105, 6755.

Substrate directed hydroxylations: -by hydroxyl groups
O HO OsO4, pyridine

Chem. Rev. 1993, 93, 1307
HO HO O HO 3:1 HO HO

+

HO O HO

O TMSO

OsO4, pyridine

HO O TMSO

HO

CH3 OsO4, Et2O

HO

CH3 OH OH CH3

HO

CH3 OH OH CH3

+
(86 : 14)

CH3

- by amides
AcO MeS HN OsO4 O OAc MeS OH HN O OAc AcO OH

OXIDATIONS - by sulfoxides
••

13

O S

OMe OsO4

••

O S

OMe OH

OH
••
S HN O O 1) OsO4 2) Ac2O AcO OAc

(2 : 1)

••
S

O

HN

O (20 : 1)

- by sulfoximines
O Ph S MeN OH OsO4, R3NO O Ph S MeN OH OH OH CH3 Raney nickel H 3C OH OH OH CH3 ∆ O OH OH

- By nitro groups
PhO2S N O2N N N O O N N HO N N N NHR N O O N HO N NHR N NHR 1) OsO4 2) acetone, H
+

PhO2S N O2N

N NHR N N

- OsO4 bis-hydroxylation favors electon rich C=C.
OsO4 X OH OH X

+
OH OH

X

- Ligand effect:
OH

X= OH = OMe = OAc = NHSO2R
OsO4 K3Fe(CN)6, K2CO3 MeSO2NH2, tBuOH/H2O OH OH X

80 : 20 98 : 2 99 : 1 60 : 40
+

(directing effect ?) (directing effect ?)

OH OH

OH

OsO4 (no ligand) Quinuclidine DHQD-PHAL

4:1 9:1 > 49 : 1

Sharpless Asymmetric Dihydroxylation (AD) - Ligand pair are really diastereomers!!
dihydroquinidine ester

OXIDATIONS Chem. Rev. 1994, 94, 2483.

14

N
"HO OH"

Ar H OR'

H R3 OH R1 OH R2
80-95 % yield 20-80 % ee

R3

R2

0.2-0.4% OsO4 acetone, H 2O, MNO

R1 H OR'
"HO OH"

Ar N
Ar =

MeO N
R'= p-chlorobenzoyl

dihydroquinine ester

Mechanism of AD:
L HO OH

O O H 2O O Os O O

O O O Os O O [O] O Os O L

O O Os L

First Cycle (high enantioselectivity)
O O

Second Cycle (low enantioselectivity)
O O

[O]

O O O O R 3N HO OH H 2O, L Os O O

- K3Fe(CN)6 as a reoxidant gives higher ee's- eliminates second cycle TL 1990, 31, 2999. - Sulfonamide effect: addition of MeSO2NH2 enhances hydrolysis of Os(VI) glycolate (accelerates reaction) - New phthalazine (PHAL) ligand's give higher ee's
N Et H MeO N (DHQD)2-PHAL JOC 1992, 57, 2768. N N (DHQ)2-PHAL N O N N O Et N H OMe MeO H Et N O N N O H OMe N Et

OXIDATIONS - Other second generation ligands
N Et H MeO N O N Ph PYR N N IND Ph O Et N H OMe N O N O Et N H OMe

15

Proposed catalyst structure:
O O O N H O H N N O N
N

H O

MeO

N
N

Os

Os

Asymmetric Binding Cleft

"Bystander quinoline (side wall)

N

OMe

Phthalazine Floor

OMe O Corey Model: JACS 1996, 118, 319 Enzyme like binding pocket; [3+2] addition of OsO4 to olefin. O O Os O N O O N O N N

OMe

N O

H N

DHQL

Rs

RM H

RL large and flat, i.e Aromatics work particularly well

RL

DHQ

OXIDATIONS
Olefin Preferred Ligand PYR, PHAL R2 R1 PHAL 70 - 97 % ee's 30 - 97 %

16

R1

R1 R2

IND

20 - 80 %

R1

R2

PHAL

90 - 99.8 %

R2 R1 H R2 R1 R4 R3 PHAL, PYR + MeSO2NH2 20 - 97 % R3 PHAL 90 - 99 %

"AD-mixes" commercially available pre-mix solutions of Os, ligand and reoxidant AD-mix α (DHQ)2PHAL, K 3Fe(CN)6, K2CO3, K2OsO4 (0.4 MOL % Os to C=C) AD-mix β (DHQD)2PHAL, K 3Fe(CN)6, K2CO3, K2OsO4
O HO O N N O OMe N O OMe AD (DHQD)2PYR 94 % ee OH N O OH OH N OMe O O Campthothecin

- Kinetic resolution (not as good as Sharpless asymmetric epoxidation)
H Ph tBu H Ph AD mix α 30% conversion tBu tBu OH OH H Ph tBu H Ph Ph H tBu (4 : 1) tBu enriched OH OH Ph H olefins with axial dissymmetry

+

+

OXIDATIONS 17 Asymmetric Aminohydroxylation TL 1998, 39, 2507; ACIEE 1996, 25, 2818, 2813, preparation of α-aminoalcohols from olefin. Syn addition as with the dihydroxylation regiochemistry can be a problem
O Ph Ph CO2Me O N Na Cl Ph O Ph NH CO2Me OH Ligand= PHAL AQN 4:1 1:4 + Ph N O O OH CO2Me O Ph

K2OsO6H4 (cat) Ligand

Molybdenum Reagents MoOPH [MoO5•pyridine (HMPA)] JOC 1978, 43, 188. - α-hydroxylation of ketone, ester and lactone enolates.
OR R' O O Mo O L L O O THF, -78°C R O R' OH

+

Palladium Reagents Pd(0) catalyzed Dehydrogenation (oxidation) of Allyl Carbonates Tetrahedron 1986, 42, 4361
R H R OH O 2 CO Pd(OAc) 2, CH 3CN, 80° C O R H R O O Pd(0) - CO 2

(Tsuji Oxidation)
R H R O Pd R O

-

R

TL 1984, 25, 2791 Tetrahedron 1987, 43, 3903

HO

H OH OH O
2

CO

HO

H OH JACS 1989, 111, 8039. H O O

H

O

Pd2(DBA) 3•CHCl 3, CH 3CN, 80° C

Oxidation of silylenol ethers and enol carbonates to enones
O OTMS Pd(OAc) 2, CH 3CN O

O O O Pd(OAc) 2, CH 3CN O

OTIPS Ph

(NH 4)2Ce(NO 3)6 DMF, 0°C

O Ph TL 1995, 36, 3985

Oppenauer Oxidation
+O Al

Synthesis 1994, 1007
OiPr OiPr R1R2CHOH (CH3)2C=O H R1 R2 OiPr +O Al O OiPr

OXIDATIONS Organic reactions 1951, 6, 207
O R1 R2

18

+ Al(OiPr)3

Nickel Peroxide Chem Rev. 1975, 75, 491 Thallium Nitrate (TNN, Tl(NO 3)3•3H2O Pure Appl. Chem. 1875, 43, 463. Lead Tetraacetrate Pb(OAc)4 Oxidations in Organic Chemistry (D), 1982, pp 1-145. Non-Metal Based Reagents Activated DMSO Review: Synthesis 1981, 165; 1990, 857.
Me S+ Me O+ E Me Me S+ O E Nu:

Organic Reactions 1990, 39, 297
Me Nu S
+

+ E-O Me

E= (CF3CO)2O, SOCl2, (COCl)2, Cl2, (CH3CO)2O, TsCl, MeCl, SO3/pyridine, F 3CSO2H, PO5, H3PO4, Br2 Nu:= R-OH, Ph-OH, R-NH2, RC=NOH, enols Swern Oxidation - trifluoroacetic anhydride can be used as the activating agent for DMSO
O Me S + OMe (COCl) 2 CH 2Cl 2, -78°C Me S+ O Me O Cl Cl -CO, -CO 2 Me S + Cl Me

R2CH-OH Me Me

S+ O H

R R

Et3N:

R O R +

Me S Me

B:

O Cl DMSO, (COCl) 2 OH CH 2Cl 2, Et3N

O TL 1988, 29, 49. O
Me R R H B:
CHO

Moffatt Oxidation (DMSO/DCC)
Me S + OMe + C 6H11 N C N C 6H11 CF 3CO 2H, Pyridine Me S Me

JACS 1965, 87, 5661, 5670.
C 6H11 NH
+

O C N C 6H11

R2CH-OH

S+ O Me

R O R

OH CO 2Me O S

DCC/ DMSO CF 3CO 2H, Pyridine CO 2Me O S JACS 1978, 100, 5565

SO3/Pyridine
HO

JACS 1967, 89, 5505.
CO 2Me H OH CONH 2 H OH SO 3, pyridine, DMSO, CH 2Cl 2 H HO O HO CO 2Me H CONH 2 JACS 1989, 111, 8039.

OXIDATIONS Corey-Kim Oxidation (DMS/NCS)
Me S: Me O N-Chlorosuccinimide (NCS)

19

JACS 1972, 94, 7586.
O Me N Cl Me S + Cl

+

Oxygen & Ozone Singlet Oxygen

Acc. Chem. Res. 1980, 13, 419
•• •• •O O • •• •• triplet hν

Tetrahedron 1981, 37, 1825
••
H O O Tetrahedron 1981, 1825 singlet

H O O

"ene" reaction

Ph3P: OH

1) O2, hν, Ph2CO 2) reduction

HO

Ozone

Comprehensive Organic Synthesis 1991, 7, 541
O 3, CH 2Cl 2 -78°C O O O O O O Ph3P: NaBH 4 H Jones OH O + O

RCOOH

Other Oxidations Mukaiyama Oxidation
R

BCSJ 1977, 50, 2773
O PrMgBr CH OH R
OH

R CH O MgBr R

N

N

N O

••
N R O R
OHC O Cl

O O

••

••

THF

Cl MeO

CH 3 NH

O O O SEt SEt MeO OEt N

O N N

O N O MeO

CH 3 NH

O tBuMgBr, THF (70%) MeO JACS 1979, 101, 7104 SEt SEt

OEt

OXIDATIONS
OH O tBuMgBr, THF O N O N N O N O

20

Dess-Martin Periodinane JOC 1983, 48, 4155. - oxidation conducted in CHCl3, CH3CN or CH2Cl2 - excellent reagent for hindered alcohols - very mild
AcO OAc I OAc R2CH-OH R O R O +
••

JACS 1992, 113, 7277.

OAc I O O + 2 AcOH

O

HO RO

Dess-Martin (99%) RO

O JOC 1991, 56, 6264

Chlorite Ion -oxidation of α,β-unsaturated aldehydes to α,β−unsaturated acids. Tetrahedron 1981, 37, 2091
NaClO 2, NaH2PO 4 OBn CHO
-O-Cl-O

- HClO2 OBn OH H OBn CO 2H

tBuOH, H 2O

Selenium Dioxide - Similar to singlet oxygen (allylic oxidation)
1) SeO2 2) NaBH 4 OAc OH OAc

Phenyl Selenium Chloride
OLi PhSeCl THF H O SePh H2O 2 O Ph Se O- PhSeOH O

- PhS-SPh will do similar chemistry however a sulfoxide elimination is less facile than a selenoxide elinimation. Peroxides & Peracids - R3N: → R3N-O - sulfides → sulfoxides → sulfones -Baeyer-Villiger Oxidation- oxidation of ketones to esters and lactones via oxygen insertion Organic Reactions 1993, 43, 251 Comprehensive Organic Synthesis 1991, vol 7, 671.

OXIDATIONS m-Chloroperbenzoic Acid, Peracetic Acid, Hydrogen peroxide
O O H O O 2N O O H O

21

Cl

NO 2

O R1 R2 O O Ar O R1 O HO

O O Ar

H O R1 O R2

C R2

+

ArCO2H

- Concerted R-migration and O-O bond breaking. No loss of stereochemistry - Migratory aptitude roughly follows the ability of the group to stabilize positive charge: 3° > 2° > benzyl = phenyl > 1° >> methyl
JACS 1971, 93, 1491 O O mCPBA O O O O O HO HO CHO CO2H HO

O CO2H

OH PGE1

O O CH3 CH3 mCPBA (80 %) CH3 O CH3 Tetrahedron Lett. 1977, 2173 Tetrahedron Lett. 1978, 1385

Oxone (postassium peroxymonosulfate)
RCHO

oxone

Tetrahedron 1997, 54, 401
RCOOH

acetone (aq)

Oxaziridines reviews: Tetrahedron 1989, 45, 5703; Chem. Rev. 1992, 92, 919
O N C R R3 R2
O R R' O PhSO2 O R _ R' N Ph O Ph O R By-product supresed by using bulkier oxaziradine such as camphor oxaziradine R' _ NSO2Ph O R HO R'

- hydroxylation of enolates
O R R' Base O R _

+ PhSO2N=CHPh

+ PhSO2N=CHPh
Ph

R' NHSO2Ph

OXIDATIONS Asymmetric hydroxylations
O MeO 2C OMe N Ar MeO O CO2Me KN(SiMe3)2 SO 2 O MeO O NaN(SiMe3)2, THF HO MeO 2C OMe (67% ee) OH CO2Me O OH O Tetrahedron 1991, 47, 173 O

22

OH OH

MeO

N SO2 O

MeO (>95% ee)

MeO

O

OH

OH

- hydroxylation of organometallics R-Li or R-Mg → R-OH

JACS 1979, 101, 1044

- Asymmetric oxidation of sulfides to chiral sulfoxides. JACS 1987, 109, 3370. Synlett, 1990, 643. Remote Oxidation (functionalization) Barton Reaction
NOCl, CH2Cl2 pyridine OH O NO

Comprehensive Organic Synthesis 1991, 7, 39.

hν - NO • H O • • OH

•NO OH NO ketone oxidation state N HO OH N C5H11

JACS 1975, 97, 430

perhydrohistricotoxin

Epoxidations Peroxides & Peracids - olefins → epoxides Tetrahedron 1976, 32, 2855 - α,β-unsaturated ketones, aldehydes and ester → α,β-epoxy- ketones, aldehydes and esters (under basic conditions).
O tBuOOH triton B, C6H6 O JACS 1958, 80, 3845

(CH 2)n

O (CH 2)n

OXIDATIONS
CO 2Me mCPBA, NaHPO3 TL 1988, 23, 2793 O O H O O H O CO 2Me

23

Henbest Epoxidation- epoxidation directed by a polar group
OH mCPBA O OH OH

+

O

OAc mCPBA

OAc O

10:1 diastereoselection OH

+

O

1:4 diastereoselection
O Ph NH mCPBA O Ph O NH "highly selective"

Ar O H H O H O O proposed transition state: -OH directs the epoxidation

- for acyclic systems, the Henbest epoxidation is often less selective Rubottom Oxidation:
O LDA, TMSCl

JOC 1978, 43, 1588
OTMS mCPBA TMSO O H2O O OH

Sharpless Epoxidation tBuOOH w/ VO(acac)2, Mo(CO)6 or Ti(OR) 4 Reviews: Comprehensive Organic Synthesis 1991, vol 7, 389-438 Asymmetric Synthesis 1985, vol. 15, 247-308 Synthesis, 1986, 89. Org. React. 1996, 48, 1-299. Aldrichimica Acta 1979, 12, 63 review on transition mediated epoxidations: Chem. Rev. 1989, 89, 431. - Regioselective epoxidation of allylic and homo-allylic alcohols - will not epoxidize isolated double bonds - epoxidation occurs stereoselectively w/ respect to the alcohol.

OXIDATIONS - Catalysts: VO(acac)2; Mo(CO)6; Ti(OiPr)4 - Oxidant: tBuOOH; PhC(CH3)2OOH
OH

24

VO(acac)2 tBuOOH O OH

OH

OH

(CH2)n

(CH2)n

O

ring size 5 6 7 8 9 Acyclic Systems:
L 1,3-interaction R3 A1,2-strain R1 R2 M O O O

VO(acac)2 >99% >99 >99 97 91
tBu

MoO2(acac)2 -98 95 42 3

mCPBA 84 95 61 <1 <1

R1 L Rt Rc L R2 O M R3 Rt Rc O O L

A1,3-strain

Major influences: A1,2-Strain between Rg and R1 A1,3 -strain between R2 and Rc 1,3-interactions between L and R1
VO(acac)2, tBuOOH O OH

(Rg and R2) (R1 and Rc) (L and R2)
+
OH (4 : 1)

O

OH

CH3 H L O M O O L

tBu H H L H 3C H O L M O H H O

tBu

OXIDATIONS
VO(acac)2, tBuOOH O OH OH (19 : 1)

25

+

O

OH

tBu L H 3C H L O M O O H H CH3
SiMe3 SiMe3 O OH

H 3C H 3C L

H O M O

H H O L tBu

VO(acac)2, tBuOOH

SiMe3

+
OH (> 99 : 1)

O

OH

- Careful conformational analysis of acyclic systems is needed. Homoallylic Systems
L L O OH OH O V O OtBu

dominent stereocontrol element

Titanium Catalyst structure:
RO2C OR RO Ti O O CO2R O O O OR
CO2R O CO2R O O O tBu OR Disfavored OR Favored Ti O O CO2R RO Ti O O CO2R O Ti O O tBu O CO2R

OR O OR OR

Ti

OR RO Ti O O

OR CO2R O O

OXIDATIONS Asymmetric Epoxidation tBuOOH, Ti(OiPr), (+) or (-) Diethyl Tartrate, 3Å molecular sieves Empirical Rule
R1 R3 R2 OH (+)- DET epoxidation from the bottom (-)- DET epoxidation from the top

26

Catalytic system: addition of molecular sieves to "soak" up any water with 3A sieves, 5-10 mol % catalyst is used. Preparation of Allylic Alcohols:
R R CHO R CO2R' [(CH3)2CHCH2]2AlH R OH H2, Lindlar's Catalyst CO2R' [(CH3)2CHCH2]2AlH (DIBAL) R OH Na (MeOCH2CH2O)2AlH2 (REDAL) R C C CH2OH

"In situ" derivatization of water soluble epoxy-alcohol
(-)-DIPT O OH water soluble O (+)-DIPT OH

(R)-glycidol OH

O

O OH

(S)-glycidol O
O S O NO2 organic soluble

Alkoxide opening of epoxy-alcohol product reduced by use of Ti(OtBu)4 and catalytic conditions
OO R OH from Ti(OiPr)4 O OH OH R

Stoicheometric vs Catalytic epoxidation:
(+)-DET Ti(OiPr)4 tBuOOH OH O

OH

stoicheometric: catalytic (6-7 mol %) in situ deriv. with PNB

85% ee 47% yield >95% ee 78% yield 92 % ee >98 %ee after 1 recrystallization
R OH (+)-DET Ti(OiPr)4 tBuOOH R O OH

yields: 50 - 100 % ee: > 95%

OXIDATIONS Ring Opening of Epoxy-Alcohols
REDAL R AE R OH R O OH R OH 1,2-Diol OH 1,3-Diol OH OH

27

DIBAL

Two dimensional amplification
OH (+)-DIPT, Ti(OiPr)4, tBuOOH, 3A sieves (90 % ee) O OH OH OH

+

OH

O 95 : 5

OH

major major minor 95 : 5 O OH major

minor minor 95 : 5 O OH

O

OH

O

OH

O

OH

O

OH

90 % (>99.5 % ee)

meso 9.75%

0.25 %

Kinetic Resolution of Allylic Alcohols
OH R (+)-DIPT, Ti(OiPr)4, tBuOOH, 3A sieves R OH

+

O R

OH

OR RO Ti O O CO2R O O

CO2R O Ti O O tBu

H O CO2R

OR

OXIDATIONS
R3 R2 R1 R4 OH kinetic resolution -20 °C, 0.5 - 6 days R3 R2 R1 40 - 50 % yield > 99 % ee R4 OH R3 R4 O R2 R1 40 - 50 % yield high ee OH

28

+

Reiterative Approach to the Synthesis of Carbohydrate
OR OR CHO (MeO)2P(O)CH2CO2Me NaH CO2Me OR O OH PhS HO-

OR DIBAL OH OR

(+)-DET, Ti(OiPr)4, tBuOOH, 3A sieves

OR OH O

OR OH acetone, H+ O SPh SPh OR CHO O O O O CHO HO HO HO HO H H H H CH2OH L-glucose O mCPBA, Ac2O Pummerer

HO PhS-

OR O O OAc SPh DIBAL

OR O O CHO

Jacobsen Aysmmetric Epoxidation JACS 1990, 112, 2801; JACS 1991, 113, 7063; JOC 1991, 56, 2296. - Reaction works best for cis C=C conjugated to an aromatic ring
H N Mn O Cl O tBu tBu O tBu N H NaOCl H N Mn O O tBu N H

O

5 mol % Cat. ,NaOCl, H2O, CH2Cl2

O (98% ee)

O

86% ee O

Methyltrioxoruthenium (MTO) Ru(VII) Sharpless et al. JACS 1997, 117, 7863, 11536.
Ph 0.5 mol % MTO Ru (VII), pyridine, CH2Cl2 1.5 eq. 30% H2O2 (aq.) Ph O

OXIDATIONS Oxaziridines - Asymmetric epoxidation of olefins
Ph

29

Tetrahedron 1989 45 5703
CH3

*
Ph

O2 O N S N

*

*

C6F5

Dioxiranes

(Murray's Reagent)

Reviews: Chem. Rev. 1989, 89, 1187; ACR 1989, 27, 205 Org. Syn. 1996, 74, 91
O KHSO 5 "oxone" O O

- epoxidation of olefins
OTBS TBSO TBSO O O O CH 2Cl 2, acetone (100%) TBSO TBSO OTBS O O JOC 1990, 55, 2411

-

Asymmetric epoxidation JACS 1996, 118, 491. oxidation of sulfides to sulfoxides and sulfones oxidation of amines to amine-N-oxides oxidation of aldehydes to carboxylic acids hydroxylation of enolates
1) LDA 2) Cp 2TiCl2 O 3) O O O OH H JOC 1994, 59, 2358

- bis-trifluoromethyldioxirane, much more reactive JACS 1991, 113, 2205.
F3C F3C O O

- oxidation of alcohols to carbonyl compounds. 1° alcohols give a mixture of aldehydes and carboxylic acids. - Insertion into 3° C-H bonds to give R3C-OH DCC-H2O2 JOC 1998, 63, 2564
R R N C N R H2O2, MeOH H N R N C O H O R R O + H N R O C N R H

REDUCTIONS Carey & Sundberg Chapter 5 problems: 1a,b,c,d,f,h,j; 2; 3a-g, n,o; 4b,j,k,l; 9; 11; Smith: Chapter 4 March: Chapter 19 Reductions 1. Hydrogenation 2. Boron Reagents 3. Aluminium Reagents 4. Tin Hydrides 5. Silanes 6. Dissolving Metal Reductions Hydrogenations Heterogeneous Catalytic Hydrogenation Transition metals absorbed onto a solid support metal: Pd, Pt, Ni, Rh support: Carbon, alumina, silica solvent: EtOH, EtOAc, Et2O, hexanes, etc. Reduction of olefins & acetylenes to saturated hydrocarbons. Sensitive to steric effects and choice of solvent Polar functional groups, i.e. hydroxyls, can sometimes direct the delivery of H2. Cis addition of H2.
R1 R2 R1 R2 H2, Pd/C R1 H R2 H R1 R2

30

- Catalyst can be "poisoned" - Directed heterogeneous hydrogenation
O H2, Pd/C O MeO OH O O MeO CO2Me MeO H2, Pd/C MeO H H O O OH O O CO2M2 (86 : 14)

Lindlar Catalyst ( Pd/ BaSO4/ quinoline)- partially poisoned to reduce activity; will only reduce the most reactive functional groups. acetylenes + H2, Pd/BaSO4/ quinoline → cis olefins Acid Chlorides + H2, Pd/BaSO4 → Aldehydes
H2, Pd/BaSO4, Quinoline R O H2, Pd/BaSO4, pyridine CO 2Me CO 2Me JOC 1982, 47, 4254 O

(Lindlar Reduction) (Rosemund Reduction) Org. Rxn. 1948, 4, 362
SiMe 3 TL 1976, 1539

R

SiMe 3

REDUCTIONS
HO OH H2, Lindlar Catalyst CH 2Cl 2: MeOH: Quinoline (90:9.5:0.5) 8π econrotatory 6π edisrotatory HO OH HO H H H OH

31

JACS 1982, 104, 5555

HO

OH

Ease of Reduction: (taken from H.O. House Modern Synthetic Reactions, 2nd edition)
R COCl R NO 2 R R' R CHO R CH CH O R Ar R' O R R' R CHO R NH 2 R R'

R CH 2-OH R CH 2 CH 2 R' HO H R Ar R' CH 3 + HO R

R C N

R CH 2 NH 2

O R CH 2-OH R O R' R N R' R OR' CH 2 R' N R' requires high temperature & pressure + HO R'

R CO 2- Na+

no reaction

Raney Nickel Desulfuriztion , Reviews: Org. Rxn. 1962, 12, 356; Chem. Rev. 1962, 62, 347.
R O R R S R S (CH 2)n R H Raney Nickel R H

REDUCTIONS
O O HO Raney Nickel S S H EtOH (74%) JOC 1987, 52, 3346 H O HO O O O

32

Homogeneous Catalytic Hydrogenation - catalyst is soluble in the reaction medium - catalyst not "poisoned" by sulfur - very sensitive to steric effects - terminal olefins faster than internal; cis olefins faster than trans
R R R

>
R

>

R

R

>

R

R

R

>
R

R

>>

R R

R

- (Ph3P)3RhCl (Wilkinson's Catalyst); [R3P Ir(COD)py]+ PF6- (Crabtree's Catalyst)
(Ph3P)3RhCl, H2 C 6H6 (92%)

OH

OH

JOC 1992, 57, 2767

Directed Hydrogenation Review: Angew. Chem. Int. Ed. Engl. 1987, 26 , 190 - Diasterocontrolled hydrogenation of allylic alcohols directed by the -OH group
O K
+

(Ph3P)3RhCl, H2

PPh3 O PPh3 Rh H H H

O- K+

MeO

MeO

Ph Ph P Rh+ P Ph Ph Brown's Catalyst

BF4-

Ir +

P(C 6H11)3 N PF6 -

(Crabtree's Ctalyst) JACS 1983, 105 , 1072

Regioselective Hydrogenation- allylic and homoallylic alcohols are hydrogenated faster than isolated double bonds
MeO2C OH MeO2C OH

REDUCTIONS mechanism:
L L lose reductive elimination OH HO H L M L S migratory insertion H H L M L O H + + M H2 L L + M OH S S + L L M O H

33

H H

H2 (oxidative addition)

Diastereoselective Hydrogenation: since -OH directs the H2, there is a possibility for control of stereochemistry - sensitive to: H2 pressure catalyst conc. substrate conc. solvent. Regioselective Hydrogenation- allylic and homoallylic alcohols are hydrogenated faster than isolated double bonds
HO "Ir" (20 mol %) O H HO

O

(24 : 1)

Brown's Catalyst OH H2 (640 psi), CH2Cl 2 H OH

JACS 1984, 106, 3866

OMe

OMe Me O OH Brown's Catalyst H2 (1000 psi)

OMe

OMe H Me O OH

TL 1987, 28 , 3659

Selectivity is often higher with lower catalyst concentration:
OH OH 20 mol % Catalyst 50 : 1 OH OH 2.5 mol % Catalyst 150 : 1

33 : 1

52 : 1

REDUCTIONS Olefin Isomerization:
CH3 (3 : 1) OH olefin isomerization OH

34

OH

O

major product

- Conducting the hydrogenation at high H 2 pressures supresses olefin isomerization and often gives higher diastereoselectivity. Other Lewis basic groups can direct the hydrogenation. (Ir seems to be superior to Rh for these cases)
OMe Ir
+

OMe 99 : 1

CO2Me

CO2Me Ir+ Rh+ > 99 : 1 32 : 1

O

O

CO2H > 99 : 1

CO2H Ir+ 7 : 1 Rh+ 1 : 1

O O O

O N O N O

1:1

130 : 1

Acyclic Examples
OH Me Rh+ (2 mol %) H2 (15 psi) Me CH 3 JCSCC 1982, 348 OH (97:3)

L L M H H

H O OH Ph Ph

H 3C

H

anti

H H L

H

CH3 Ph

1,2-strain Ph

OH syn

M L

O H

REDUCTIONS
L L R3 H OH R3 R2 R3 H L H R1 R2 M L O H disfavored 1,2-strain R3 R2 OH R1 anti R1 M H O R2 R1 H favored R3 R2 OH R1 syn

35

- Supression of olefin isomerization is critical for acyclic stereocontrol !
L OH R2 CH3 olefin isomerization OH R2 R1 L H H R1 L M OH H O CH2R2 H R2 R2 R1 syn R1 L R2 H M H O OH CH3 R1 H R2 R2 R1 anti

- Rh+ catalyst is more selective than Ir + for acyclic stereoselection. Acyclic homoallylic systems:
HO R1 R2 relative stereochemistry is critical R3

A E R2 O H M R3 L L E 1,2-strain R2

A

1,3-strain R3 O H M L L

REDUCTIONS
OH OBz TBSO Rh+ (20 mol %) H2 (15 psi) OBz TBSO TBSO TBSO Rh+ (20 mol %) OH OBz 32 : 1 Tetrahedron Lett. 1985, 26, 6005 OH OH OBz 8:1 H2 (15 psi)

36

Asymmetric Homogeneous Hydrogenation - Chiral ligands for homogeneous hydrogenation of olefins and ketones
H P MeO P OMe O O H DIOP DIPAMP PPh2 PPh2 PPh2 PPh2 PPh2 NORPHOS CAMPHOS X PPh2 X= CH2 DPCP X= N-R PYRPHOS N CO2tBu BPPM PPPFA PPh2 Ph2P PPh2 Fe PPh2 NMe2 PPh2 PPh2 PPh2 PPh2 CHIRAPHOS PPh2 PPh2 R= -CH3 PROPHOS = -Ph PHENPHOS = -C6H11 CYCPHOS PPh2 PPh2

DBPP

P P

PPh2 PPh2

PPh2 PPh2

DUPHOS

DIPHEMP
CO 2H HN O CO 2Me NHAc O O HO Ph Rh (I) L*, H2

BINAP
CO 2H HN (95% ee) O CO 2H NH 2 OH L-DOPA Ph ACR 1983, 16, 106.

Ph

Ph

DIOP DIPAMP PPPFA BINAP NORPHOS BPPM

85% ee 96% ee 93% ee 100% ee 95% ee 91% ee

REDUCTIONS 37 General Mechanism: J. Halpern Science 1982, 217, 401 Asymmetric Synthesis 1985, vol 5, 41.
Ph P P S Rh S CO2Me NHAc (fast equilibrium) P P Rh Ph NH O CO2Me CH3 CO2Me NHAc Ph P P S H Rh O CO2Me NH CH3 CH3
P S Rh S CO2Me NHAc

Ph

rate limiting

H2 (slow)

H S (fast) P P O Rh

Ph CO2Me H NH

Detailed Mechanism:
*

+

Ph

P

MeO2C P

NH Ph O CH3 H 3C

HN Ph O

CO2Me P Rh

*

Rh P

*
P

major complex H2 (slow) MeO2C H H P Rh

minor complex H2 (slow) CO2Me H Rh O P * S H P

NH Ph

NH Ph CH3 H 3C

* P

O

S

CH3 O P NH CO2Me Ph HN MeO2C Ph

CH3 O S Rh P P H

*

Rh P

S

*

H

H 3C O

H N

CO2Me Ph

MeO2C Ph

H N O

CH3

(R) Minor product

(S) Major product

REDUCTIONS

38

MeO2C H H Rh P P O

+
NH Ph CH3

*

Free Energy

NH Ph HN Ph H 3C O minor complex CO2Me P Rh P

CO2Me H H Rh O P P *

+

+
*

H 3C

MeO2C P

NH Ph O CH3

+

*

Rh P

major complex

Reaction Coordinate

Ph Ph O O P Ru O P O Ph Ph BINAP

ACR 1990, 23, 345.

O O (BINAP)RuAc2, H2 (100 atm) 50 °C, CH2Cl 2

O O (94 % ee)

O R O

O (BINAP)RuAc2, H2 (100 atm) 50 °C, CH2Cl 2 R O (95 - 98 % ee)

CO 2H MeO

Ru(AcO)2(BINAP), H2 (135 atm), MeOH (97% ee) MeO (S)-naproxen

CO 2H 97 % ee

MeO MeO NAc OMe OMe (BINAP)RuAc2, H2 (4 atm)

MeO MeO NAc OMe (95 - 100 % ee) OMe

MeO MeO NH OMe OMe Tetrahydropapaverine

Directed Asymmetric Hydrogenation
(BINAP)Ru (II), H2 OH (96 - 99 % ee) OH CHO

OH HO

OH

J. Am. Chem. Soc. 1987, 109, 1596 O Vitamin E

REDUCTIONS Kinetic Resolution by Directed Hydrogenation

39

MeO Ph P

Rh+ P Ph OMe

CF 3SO 3-

MeO 2C R

CO 2Me

H2 (15 psi), L*Rh+ 0 °C (~60% conversion) MeO 2C R

CO 2Me

R=

Et Ph OMe

> 96 % ee 82 % 93 %

Hydrogenation of Carbonyls 1,3-diketones:
O R1 O R2 R1 OH O R2 R1 O OH R2

O R1

O R2

Ru (II) H2 (700 psi) R1

OH

OH

OH

OH R2

+
R2 R1

R1=

-CH3 -CH3 -CH2CH3 -CH2CH3
O O R2
M O R2

R2=

-CH3 -CH2CH3 -iPr -CH2CH3
O R1

anti

syn

anti : syn=

99 : 1 16 : 1 (90 % ee) 32 : 1 49 : 1
OH R1 OH R2

H2

OH R2
H

Directed Reduction

R1

H O R1 H M O

R2 R1 O H

anti
Ru2Cl 4(BINAP) Et3N, H2 (100 atm) (98% ee) OH MeO 2C

syn

O MeO 2C

JACS 1988, 110 , 6210

Decarbonylations
O R H (Ph3P)3RhCl R H - CO R Cl O (Ph3P)3RhCl R Cl - CO

REDUCTIONS
OHC

40

(Ph3P)3RhCl Fe Fe PhCH 3, ∆ Fe Fe JOC 1990, 55, 3688

Diimide HN=NH Review: Organic Reactions 1991, 40J. Chem. Ed. 1965, 254 - Only reduces double bonds - Syn addition of H 2 - will selectivley reduce the more strained double bond - Unstable reagent which is generated in situ K+O2C-N=N-CO2K+ + AcOH → H-N=N-H H2N-NH2 + Cu2+ + H2O2 → H-N=N-H
HN=NH ACIEE 1965, 271 (76%) O CO 2MeK NO 2
+-

O O 2C N N CO 2- K+ AcOH, MeOH (95%) CO 2Me NO 2 JACS 1986, 108 , 5908

O HN HN S O O S N N H H hν, 16 hr (96%) O TL 1993, 34, 4137 hν (254 nm) NH NH

+ COS + CO

Metal Hydrides Review on Metal Hydride Selectivity:

Chem Soc Rev. 1976, 5 , 23 Comprehensive Organic Synthesis 1991, vol 8, 1. Boron Hydrides Review: Chem. Rev. 1986, 86 , 763. NaBH4 reduces ketones and aldehydes LiBH4 reduces ketones, aldehydes, esters and epoxides. THF soluble LiBH4/TMSCl stronger reducing agent. ACIEE 1989, 28, 218. Zn(BH4)2 reduces ketones and aldehydes R4N BH4 organic soluble (CH2Cl2) borohydrides. Synth Commun. 1990, 20, 907 LiEt3BH reduces ketones, aldehydes, esters, epoxides and R-X Li s-Bu3BH reduces ketones, aldehydes, esters and epoxides (hindered borohydride) Na(CN)NH3 reduces iminium ions, ketones and aldehydes Na(AcO)3BH reduces ketones and aldehydes (less reactive) NaBH2S3 reduces ketones and aldehydes

REDUCTIONS Sodium Borohydride NaBH4 - reduces aldehydes and ketones to alcohols - does not react with acids, esters, lactones, epoxides or nitriles. - Additives can increase reactivity.

41

Sodium Cyanoborohydride Na (CN)BH3 Reviews: Synthesis 1975, 136; OPPI 1979, 11 , 201 - less reactive than NaBH4 - used in reductive aminations (Borch Reduction) Na(CN)BH3 reduces iminium ions much more quickly than ketones or aldehydes
R O R O CHO N R"-2NH, MeOH, AcO - NH4+ , pH~ 8 R N+ R R' R' Na(CN)BH3 R H R' R N R' JACS 1971, 93 , 2897 N H N

R"-2NH, MeOH, AcO- NH4+ Na(CN)BH3

- Related to Eschweiler-Clark Reaction
H2CO, HCO 2H R NH 2 or H2CO, H2/Pd R N H Me

- Reduction of tosylhydrazones gives saturated hydrocarbon
O H 1) TsNHNH 2, H+ 2) Na(CN)BH3 H (90%) H TL 1978, 1991 H

HO O 1) TsNHNH 2, H+ 2) Na(CN)BH3 (100%)

HO

JOC 1977, 42 , 3157

- migration of the olefin occurs w/ α,β-unsaturated ketones
O JACS 1978, 100 , 7352 (75%)

- Epoxide opening
O OH NaBH3CN, BF3•OEt2, THF HO OH JOC 1994, 59, 4004

NaBH2S3

Lalancette Reduction

REDUCTIONS Synthesis 1972, 526 Can. J. Chem. 1970, 48 , 735.

42

NaBH4/ NiCl 2 Chem. Pharm. Bull. 1981, 29 , 1159; Chem. Ber. 1984, 117 , 856. Ar-NO2 → Ar-NH2 Ar-NO → Ar- NH2 R2C=N-OH → R2CH-NH2 NaBH4 / TiCl 4 Synthesis 1980, 695. R-COOH → R-CH2-OH R-COOR' → R-CH2-OH R-CN → R-CH2-NH2 R-CONH2 → R-CH2-NH2 R2C=N-OH → R2CH-NH2 R-SO2-R' → R-S-R' NaBH4 / CeCl 3 Luche Reduction reduced α,β-unsaturated ketones in a 1,2-fashion
OH R R O CO 2Me C 5H11 OH NaBH 4/ CeCl3 MeOH C 5H11 OH R NaBH 4/ CeCl3 R R R O NaBH 4 R R R OH + R R H R JCSCC 1978, 601 JACS 1978, 100 , 2226 OH CO 2Me O

- selective reduction of ketones in the presence of aldehydes.
O CO 2Me CHO O CeCl 3 H2O R OH OH
O CHO NaBH 4/ CeCl3 EtOH, H2O (78%) OH CHO

OH NaBH 4/ CeCl3 EtOH, H2O CHO 1) NaBH 4, CeCl3 2) work-up JACS 1979, 101 , 5848 CO 2Me

REDUCTIONS Zinc Borohydride Zn(BH4)2 Synlett 1993, 885. ZnCl2 (ether) + NaBH 4 → Zn(BH4)2 - Ether solution of Zn(BH4)2 is neutral- good for base sensitive compounds - Chelation contol model
Zn O R1 R2 R1 R2 OR RO O H H H H B H R1 R2 OH OR

43

OH O

Zn(BH4)2, Et2O, 0°C OH H Me R H-

OH

TL 1983, 24 , 2653, 2657, 2661 O O Zn

Na + (AcO)3BH , Me4N + (AcO)3BH Review: OPPI 1985, 17 , 317 - used in Borch reductive amination TL 1990, 31 , 5595; Synlett 1990, 537 - selective reduction of aldehydes in the presence of ketones
O CHO (77%) TL 1983, 24 , 4287 AcO O Ph CHO Bu4N (AcO) 3BH C 6H6, ↑↓ Ph H O B O Ph OH OH OAc Bu4N (AcO) 3BH C 6H6, ↑↓ O OH

-hydroxyl-directed reduction of ketones TL 1983, 24 , 273; TL 1984, 25 , 5449
OH O O N Me Me O O Me Ph Me4N (AcO) 3BH, CH 3CN, AcOH, −40°C Me Me O (98:2) H O R R major O H O minor OAc B OAc R H R O H OAc B OAc OH OH O N O Me Ph TL 1986, 27 , 5939 JACS 1988, 110 , 3560

OH

O Na+ BH(OAc)3

OH

OH

50 : 1

REDUCTIONS
OH O O CO2R Na+ BH(OAc)3 OH OH O CO2R Na+ BH(OAc)3 OH OH OH

44
CO2R

HO BnO OBn OBn Me4N (AcO) 3BH, CH 3CN, AcOH, −40°C Me MeO Me O O OH Me OH MeO O Me OH N O HO Me FK-506 O O OH BnO OBn MeO OBn O O Me OH OH Me O

TL 1989, 30 , 1037

(Ph3P)2Cu BH4 reduction of acid chlorides to aldehydes reduction of alkyl and aryl azides to amines

JOC 1989, 45, 3449 J. Chem. Res. (S) 1981, 17

R4N BH4 organic soluble borohydride (CH2Cl2) R4N= BnEt3N or Bu4N Heterocylces 1980, 14, 1437, 1441 reduction of amides to amines reduction of nitriles to amines BnEt3N BH4 / Me 3SiCl reduction of carbolxylic acids to alcohols LiBH4/ Me 3SiCl Alkyl Borohydrides Selectrides
M + HB 3 M + = Li (L-selectride) K (K-selectride) Li + HB LS-selectride 3

Synth. Commun. 1990, 20, 907

ACIEE 1989, 28, 218.

- hindered reducing agent increased selectivity based on steric considerations
O CO 2H L-selectride THF R HO OH HO OH OH CO 2H

JACS 1971, 93, 1491 R

REDUCTIONS - selective 1,4-reductions of α,β-unsaturated carbonyl cmpds. JOC 1975, 40 , 146; JOC 1976, 41 , 2194
O K-selectride, THF (99%) O

45

- 1,4-reduction generates an enolate which can be subsequently alkylated.
O a) K-selectride, THF b) Br O

K+ HBPh3 Syn. Comm. 1988, 18 , 89. - even greater 1,4-selectivity Li + HBEt3 (Super Hydride) - very reactive hydride source - reduces ketones, aldehydes, esters, epoxides and C-X (alkyl halides and sulfonates)
O HO

Li Et3BH, THF

HCA 1983, 66 , 760

HO

H HO OH 1) TsCl, pyridine 2) Li Et3BH, THF

HO

H HO CH 3 HCA 1988, 71 , 872

HO

HO H

H

Boranes Hydroboration
B 2H6 B B 2H6 R B B 2H6 H H R' H3O + H2O 2, NaOH HO H R H R' H

R

R'

R H

R

H

B

H2O 2, NaOH

R-CH 2CHO

- BH3 reduces carboxylic acids to 1° alcohols in the presence of esters, nitro and cyano groups. - BH3 reduces amides to amines
HO 2C O O BH 3•SMe 2 THF HO O O

- Boranes also reduce ketones and aldehydes to the corresponding alcohols.

REDUCTIONS Hindered Boranes
Disiamyl Borane (Sia2BH) B H

46

Thexyl Borane

B H

H B 9-BNN B H = B H O Catecholborane O
BH Pinylborane 2 2 BH

BH

Alpine Borane

B H

B

BCl IPC 2BCl (DIP-Cl) 2
B Borolane H Ph Oxazaborolidine Ph O

BCl

2

N B H

Asymmetric Reduction of Unsymmetrical Ketones Using Chiral Boron Reagents Review: Synthesis 1992, 605. Alpine Borane Midland Reduction JACS 1979, 111 , 2352; JACS 1980, 112 , 867 review: Chem. Rev. 1989, 89 , 1553.
O alpine-borane THF, 0°C OH Tetrahedron 1984, 40 , 1371 (94% ee)

REDUCTIONS
B H 9-BBN α-pinene 9-BBN = B B

47

B

Mechanism:

B H Rs

OH O RL Rs RL

- works best for aryl- and acetylenic ketones - because of steric hindrance, alpine-borane is fairly unreactive Chloro Diisopinylcamphenylborane (DIP-Cl, Ipc2BCl) H.C. Brown Review: ACR 1992, 25 , 16. Aldrichimica Acta 1994, 27 (2), 43
BCl

- Cl increases the Lewis acidity of boron making it a more reactive reagent - saturated ketones are reduced to chiral alcohols with varying degrees of ee.
O I PrO OMe CO2tBu Ipc2B-Cl, THF I PrO OMe (90 % ee) OH CO2tBu JOC 1992, 57, 7044

2

Borolane (Masamune's Reagent) JACS 1986, 108 , 7404; JACS 1985, 107, 4549
B H
B O H MeSO 3H, pentane OH (80% ee)

Asymmetric Hydroboration:
a) B H b) H2O 2, NaOH OH (99.5% ee) (99.5% ee)

REDUCTIONS Oxazaborolidine (Corey) JACS 1987, 109 , 7925; TL 1990, 31, 611l ; TL 1992, 33 , 4141
Ph Ph O Ph Ph O + BH3

48

N B H

N B

CH 3 Catalytic

O R

OH R > 90 % ee OH 92 % ee

O

O I O I OH

OH

86 % ee

93 % ee

Ph Ph O O N B Me BH 3•THF, -0°C (90% ee) CF 3 O Cl 94 % ee Fluoxetine (Prozac) OH Cl O N H CH 3 OH

TL 1988, 29 , 6409

• HCl

O O O

O

90 : 10 BzO BzO

O

OH

Aluminium Hydrides 1. LiAlH 4 2. AlH3 3. Li (tBuO)3AlH 4. (iBu)2AlH DIBAL-H 5. Na (MeOCH2CH2O)2AlH2

REDAL

Lithium Aluminium Hydride LiAlH4 (LAH) - very powerful reducing agent - used as a suspension in ether or THF - Reduces carbonyl, carboxylic acids and esters to alcohols - Reduces nitrile, amides and aryl nitro groups to amines - opens epoxides - reduces C-X bonds to C-H - reduces acetylenic alcohols trans-allylic alcohols
OH R LAH R

REDUCTIONS 49 Chem. Rev. 1986, 86, 763 Org. Rxn. 1951, 6, 469.

OH

H2N

N H

LAH, THF NH 2 (62%) Lindlar/ H2

H2N

N H

NH 2 NH 2

H2N
O CO 2Me LAH, THF, ↑↓ (100%) O O H O O H HO

N H
OH TL 1988, 29 , 2793.

BINAL-H (Noyori) - Chiral aluminium hydride for the asymmetric reduction of prochiral ketones
1) LiAlH4 2) ROH R= Me, Et, CF 3CH 2H Al O OR

OH OH

O

Li +

BINOL

BINAL-H

O O O BINAL-H,THF -100 to -78°C HO (94% ee) Tetrahedron 1990, 46 , 4809

Intermediate for 3-Component Coupling Strategy to Prostaglandins
I O Li+ O CO 2Me

RO

Li+ RCu OTBS

RO

OTBS O CO 2H

O

CO 2Me

HO RO OTBS

OH PGE 2

REDUCTIONS Alane

50

AlH3 LiAlH 4 + AlCl3 → AlH3 - superior to LAH for the 1,2-reduction of α,β-unsaturated carbonyls to allylic alcohols
OMe Ph O O Me O O O 1) AlH3, ether, 0°C 2) H3O + HO Me OH O JACS 1989, 111 , 6649

Diisobutyl Aluminium Hydride

DIBAL or DIBAL-H
Al H

- Reduces ketones and aldehydes to alcohols - reduces lactones to hemi-acetals
O DIBAL O (CH 2)n (CH 2)n (stable complex) O O Al work up CHO OH (CH 2)n (CH 2)n lactol OH O

- reduces esters to alcohols - under carefully controlled reactions conditions, will partially reduce an ester to an aldehyde
O R CO 2Me DIBAL H if complex is stable R CHO
O O HO HO OH OBn O OBn O OBn

Al

if complex is unstable R CHO

R C OMe

fast

R CH 2 OH

O O

DIBAL, CH 2Cl 2

HO HO

O

H

OH OH

OBn

JACS 1990, 112 , 9648 OBn iPrO2C CO 2iPr OBn
O R OH O R OSiMe3

OBn DIBAL, CH 2Cl 2 OHC CHO OBn

TMS-Cl, Et3N CH2Cl2

DiBAl-H CH2Cl2, -78°C R

O TL 1998, 39, 909 H

Reduction of O-Methyl hydroxamic acids
O R R' R'-M R O OMe N Me DIBAL or LAH R H O TL 1981, 22 , 3815

REDUCTIONS Sodium Bis(2-Methoxyethoxy)Aluminium Hydride REDAL Organic Reactions 1988, 36, 249 Organic Reactions 1985, 36, 1.
MeO MeO Na+ O O H Al H

51

- "Chelation" directed opening fo allylic epoxides
OH REDAL R 1,3-diol
Sharpless epoxidation Ph OH Ph O OH REDAL DME Ph

O R OH

DIBAL-H

R OH 1,2-diol OH

OH

TL 1982, 23 , 2719

OH

JOC 1988, 53 , 4081 OH

O LiAlH4 AlH3 O BnO OH

OH

+ 2 : 98 95 : 5

OH

OH BnO OH REDAL DIBAL 150 : 1 1 : 13
O OH OH O OH Me HO Me OH Me O O Me Erythromycin A O OH Me O sugar

OH

+

BnO

OH

OH Me HO Me O O Me OH OH OH

O Amphotericin B HO

O NH 2

Me OH

sugar

Lithium Tri(t-Butoxy)aluminium Hydride - hindered aluminium hydride, will only react with the most reactive FG's
O R Cl H Me N+ R-CO 2H Me R pyridine, -30°C O O H Me N+ Me Li(tBuO)3AlH CuI (cat), -78°C R O H TL 1983, 24 , 1543 Cl Li(tBuO)3AlH R O H

Li+ (tBuO)3AlH

Meerwein-Ponndorf-Verley Reduction: opposite of Oppenauer oxidation Synthesis 1994, 1007 Organic Reactions 1944, 2, 178
O H Al(O-Pr)3, iPrOH O O AcHN O O O AcHN OH O H

REDUCTIONS Asymmetric M-P-V Reduction
Ph Bn N O Sm I O Ph

52

X

O

X

OH JACS 1993, 115, 9800 X= H, Cl, OMe yield: 83-100 % 96% ee

iPrOH, THF

Dissolving Metal Reductions Birch Reductions reduction of aromatic rings Organic Reactions 1976, 23, 1. Tetrahedron 1986, 42, 6354. Comprehensice Organic Synthesis 1991, vol. 8, 107. - Li, Na or K metal in liquid ammonia
H H M, NH3 R R H H

_ • •
R R H H H

- position of the double bond in the final product is dependent of the nature of the substituent
R R= ERG R R= EWG R

- ketones and nitro groups are also reduced but esters and nitrile are not. - α,β-unsaturated carbonyl cmpds are reduced in a 1,4-fashion to give an enolate which can be subsequently used to trap electrophiles
Me HO O O Me
O O a) Li, NH3, tBuOH b) CH 2O O HO

Me Me O

K, NH3, MeOH, -78°C (92%)

Me HO

O O Me
O O

Me Me JOC 1991, 56 , 6255 OH

JOC 1984, 59 , 3685

O

Other Metals - Mg
Mg, MeOH X H Mg, MeOH EtO2C (98%) TL 1987, 28 , 5287 EtO2C X X- CN, CO2R, CONR'2 H

- Zn reduction of α-halocarbonyls
O Br O Zn, PhH, DMSO, MeI Me JACS 1967, 89, 5727

REDUCTIONS
Cl R O O Zn R-OH R R' X Y Zn, AcOH R X= Cl, Br, I Y= X, OH CH CH R'

53

"Copper Hydrides" LAH or DIBAL-H + MeCu → "CuH" - selective 1,4-reduction of α,β-unsaturated ketones (even hindered enones)
O 1) MeCu, DIBAL, HMPA, THF, -50°C 2) MeLi 3) Br O JOC 1987,52 , 439

O

O MeCu, DIBAL, HMPA THF, -50°C

JOC 1986,51 , 537 H H

H O

H

(85%) O H

[(Ph3P)CuH]6 Stryker Reagent JACS 1988, 110 , 291 ; TL 1988, 29 , 3749 - 1,4-reduction of α,β-unsaturated ketones and esters; saturated ketones are not reduced - halides and sulfonates are not reduced - 1,4-reduction gives an intermediate enolate which can be trapped with electrophiles.
O Br [(Ph3P)CuH] 6, THF O TL 1990, 31 , 3237

Silyl Hydrides - Hydrosilylation Et3SiH + (Ph3P)3RhCl (cat) - selective 1,4-reduction of enones, 1,2-reduction of saturated ketones to alchohols.
O Et3SiH, (Ph3P)3RhCl (cat) O SiEt3 H3O + O TL 1972, 5085 J. Organomet. Chem. 1975, 94 , 449

O O O

iPr3SiH, Et2O Si O
2 Pt 2

OSi(iPr)3 O JOC 1994, 59, 2287 O (87%)

- Buchwald Reduction JACS 1991, 113 , 5093 - catalytic reagent prepared from Cp2TiCl2 + nBuLi and stoichometric (Et)3SiH in THF will reduce ester, ketones and aldehydes to alcohols under very mild conditions. - α,b− unsaturated esters are reduced to allylic alcohols - free hydroxyl groups, aliphatic halides and epoxides are not reduced

REDUCTIONS Clemmensen Reduction Organic Reactions 1975, 22, 401 Comprehensive Organic Synthesis 1991, vol 8, 307. - reduction of ketones to saturated hydrocarbons
Zn(Hg), HCl O H H

54

Wolff-Kishner Reduction

Organic Reactions 1948, 4, 378 Comprehensive Organic Synthesis 1991, vol. 8, 327.

- reduction of ketones to saturated hydrocarbons
H2N-NH2, KOH O H H

Radical Deoxygenation Review: Tetrahedron 1983, 39 , 2609 Chem. Rev. 1989, 89, 1413. Comprehensive Organic Synthesis 1991, vol. 8, 811 Tetrahedron 1992, 48, 2529 W. B. Motherwell, D. Crich Free Radical Chain Reactions in Organic Synthesis (Academic Press: 1992) - free radical reduction of halide, thio ethers, xanthates, thionocarbanates by a radical chain mechanism.
nBu3Sn-H, AIBN Ph-CH3 ↑↓ R3C-X S X= -Cl, -Br, -I, -SPh, O Ph , O R3C-H S SMe , O S N N CN AIBN N N CN

Barton-McCombie Reduction JCS P1 1975, 1574 R3C-X → R3C-H
O O HO O O O

X= -OC(=S)-SMe, -OC(=S)-Im, -OC(=S)Ph
O NaH, imidazole, THF, CS2, MeI O O S Xanthate O O SMe O nBu3SnH, AIBN PhCH3, reflux (85%) O O O O O

R a) Ph

Cl NMe2 , THF
+

R nBu3SnH, AIBN PhCH3, reflux (73%) Ph O Thionobenzoates

R

S

b) H2S, pyridine HO (90%) S Ph O O O HO AcHN OBn N N (CH2Cl)2 59% N N N N Ph O O O O AcHN OBn S

nBu3SnH, AIBN PhCH3, reflux (57%)

Ph

O O AcHN

O OBn

Thiocarbonyl Imidazolides

REDUCTIONS - Cyclic Thionocarbonates: deoxygenation of 1,2- and 1,3-diols to alcohols
S OH HO MeO MeO O OMe N N N N S O O MeO MeO O OMe nBu3SnH, AIBN PhCH3, reflux (61%) HO MeO MeO OMe O

55

JCS P1 1977, 1718

- Thionocarbonate Modification (Robbins) JACS 1981, 103 , 932; JACS 1983, 105 , 4059.
iPr iPr Si O Si O iPr iPr OH O O B PhOC(S)Cl, pyridine, DMAP > 90% iPr iPr Si O Si O iPr iPr O S OPh O O B nBu3SnH, AIBN PhCH3, reflux (58-78%) iPr iPr Si O Si O iPr iPr O O B

S OAr O O O O Ar= 2,4,6-trichlorophenyl, 4-fluorophenyl Best method for deoxygenation of primary alcohols O O nBu3SnH, AIBN, PhCH3 88-91% O O O O CH3 O Tetrahedron 1991, 47, 8969

- N-Phenyl Thionocarbamates
iPr iPr Si O Si O iPr iPr O NHPh O O U S PhNCS NaH, THF (78%)

Tetrahedron 1994, 34, 10193.
iPr iPr Si O Si O iPr iPr O NHPh O O U S (TMS)3SiH, AIBN PhH, reflux (93%) iPr iPr Si O Si O iPr iPr O O U

Thiocarbamates

- Methyl oxylates
O OC HO CO2Me MeO2C O Methyl Oxylate Esters OAc O MeO2CCOCl THF O CO2Me OC OAc nBu3SnH, AIBN PhCH3, reflux OC CO2Me O OAc

- Water Soluble Tin Hydride: [MeO(CH2)2O(CH2)3]3SnH / 4,4'-Azo(bis-4-cyanovaleric acid) TL 1990, 31 , 2957 - Silyl Hydride Radical Reducing Agents - replacement for nBu3SnH (Me3Si)3SiH Chem Rev. 1995, 95, 1229. JOC 1991, 56 , 678; JOC 1988, 53 , 3641; JACS 1987, 109 , 5267 Ph2SiH2 / Et3B / Air TL 1990, 31 , 4681; TL 1991, 32 , 2569 - hypophosphorous acid as radical chain carrier JOC 1993, 58, 6838

REDUCTIONS - Photosensitized electron transfer deoxygenation of m-trifluoromethylbenzoates JACS 1986, 108, 3115, JOC 1996, 61, 6092, JOC 1997, 62, 8257
iPr iPr Si O Si O iPr iPr O O CF3 O O U N-methylcarbazole, hν, iPrOH, H2O (85%) iPr iPr Si O Si O iPr iPr O O U

56

Dissolving Metal : JACS 1972, 94, 5098
O OH nBuLi, (Me2N)2P(O)Cl O O H O H P(NMe2)2 O Li, EtNH2, THF, tBuOH O O H CH3

O

Radical Decarboxylation: Barton esters Aldrichimica Acta 1987, 20 (2), 35
N S R hn or ∆ N S O O R nBu3SnH, ∆ - CO2 R H

Radical Deamination Comprehensive Organic Synthesis 1991, vol. 8, 811 Reduction of Nitroalkanes
O O

JOC 1998, 63, 5296
NO2 Bu3SnH, PhSiH3 initiator, PhCH3 (reflux) (75%) O O

PROTECTING GROUPS Carey & Sundberg Chapter 13.1 problems # 1; 2; 3a, b, c ; Smith: Chapter 7

57

Protecting Groups T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis (2nd edition) J. Wiley & Sons, 1991. P. J. Kocienski, Protecting Groups, Georg Thieme Verlag, 1994 1. 2 3. 4. Hydroxyl groups Ketones and aldehydes Amines Carboxylic Acids - Protect functional groups which may be incompatible with a set of reaction conditions - 2 step process- must be efficient - Selectivity a. selective protection b. selective deprotection Hydroxyl Protecting Groups Ethers Methyl ethers R-OH → R-OMe Formation: Cleavage: O

difficult to remove except for on phenols

CH2N2, silica or HBF4 NaH, MeI, THF AlBr3, EtSH PhSe Ph2P Me3SiI
OMe AlBr3, EtSH O OBz O OBz O OH TL 1987, 28 , 3659

Methoxymethyl ether MOM R-OH → R-OCH2OMe

stable to base and mild acid

Formation: - MeOCH2Cl, NaH, THF - MeOCH2Cl, CH2Cl2, iPr2EtN Cleavage - Me2BBr2 TL 1983, 24 , 3969

PROTECTING GROUPS Methoxyethoxymethyl ethers (MEM) R-OH → R-OCH2OCH2CH2OMe stable to base and mild acid TL 1976, 809

58

Formation: - MeOCH2CH2OCH2Cl, NaH, THF - MeOCH2CH2OCH2Cl, CH2Cl2, iPr2EtN Cleavage - Lewis acids such as ZnBr2, TiCl4, Me2BBr2
S MEM-O C5H11 O-Si(Ph)2tBu B Cl S O HO C5H11 O

TL 1983, 24 , 3965, 3969 O-Si(Ph)2tBu

- can also be cleaved in the presence of THP ethers Methyl Thiomethyl Ethers (MTM) R-OH → R-OCH2SMe

Stable to base and mild acid

Formation: - MeSCH2Cl, NaH, THF Cleavage: - HgCl2, CH3CN/H2O - AgNO3, THF, H2O, base Benzyloxymethyl Ethers (BOM) R-OH → R-OCH2OCH2Ph

Stable to acid and base

Formation: - PhOCH2CH2Cl, CH2Cl2, iPr2EtN Cleavage: - H2/ PtO2 - Na/ NH3, EtOH Tetrahydropyranyl Ether
O H
+

(THP)

R-OH

, PhH

R

O

O

Stable to base, acid labile

Formation Cleavage:

- DHP (dihydropyran), pTSA, PhH - AcOH, THF, H2O - Amberlyst H-15, MeOH

Ethoxyethyl ethers (EE) JACS 1979, 101 , 7104; JACS 1974, 96 , 4745.
R-OH O H+ R O O

(R-OEE)

base stable, acid labile

Benzyl Ethers (R-OBn) R-OH → R-OCH2Ph Formation: Cleavage:

stable to acid and base JCS P1 1985, 2247

- KH, THF, PhCH2Cl - PhCH2OC(=NH)CCl3, F3CSO3H - H2 / PtO2 - Li / NH3

PROTECTING GROUPS 2-Napthylmethyl Ethers (NAP) JOC 1998, 63, 4172 formation: 2-chloromethylnapthalene, KH cleavage: hydrogenolysis
OH BnO O ONAP H2, Pd/C (86%) BnO OH O OH

59

p- Methoxybenzyl Ethers (PMB) Formation: - KH, THF, p-MeOPhCH2Cl - p-MeOPhCH2OC(=NH)CCl3, F3CSO3H Cleavage: H2 / PtO2 Li / NH3 DDQ Ce(NH4)2(NO3)6 (CAN) e-

TL 1988, 29 , 4139

o-Nitrobenzyl ethers Review: Synthesis 1980, 1; Organic Photochemistry, 1987, 9 , 225
NaH, THF R-OH Cl NO 2 R O O 2N

Cleavage:
HO HO HO O O

- photolysis at 320 nm
NO 2 hν, 320 nm, pyrex, H2O HO HO HO O OH JOC 1972, 37 , 2281, 2282. OH

OH

p-Nitrobenzyl Ether TL 1990, 31 , 389 -selective removal with DDQ, hydrogenolysis or elctrochemically 9-Phenylxanthyl- (pixyl, px)
Formation:

TL 1998, 39, 1653
Ph Cl pyridine Ph OR

ROH

+
O O Ph hν (300 nm) OH

Removal:

Ph

OR

ROH
O CH3CN,H 2O

+
O

Trityl Ethers -CPh3 = Tr R-OH → R-OCPh3 - selective for 1° alcohols - removed with mild acid; base stable formation: - Ph3C-Cl, pyridine, DMAP - Ph3C + BF4Cleavage: - mild acid

PROTECTING GROUPS Methoxytrityl Ethers JACS 1962, 84 , 430 - methoxy group(s) make it easier to remove
R1 (p-Methoxyphenyl)diphenylmethyl ether 4'-methoxytrityl MMTr-OR R2 C O R Di-(p-methoxyphenyl)phenylmethyl ether 4',4'-dimethoxytrityl DMTr-OR Tri-(p-methoxyphenyl)methyl ether 4',4',4'-trimethoxytrityl TMTr-OR R3

60

Tr-OR < MMTr-OR < DMTr-OR << TMTr-OR
O HN R O O O HO OH R = Tr 48 hr. R= MMTr 2 hr. R= DMTr 15 min. R= TMTr 1 min. N 80% AcOH (aq) 20°C HO HN O O HO OH N O

(too labile to be useful)

Oligonucleotide Synthesis (phosphoramidite method - Lessinger) Review: Tetrahedron 1992, 48 , 2223
S I L I C A OH OH OH S I L I C A O O O DMTrO S I L I C A DMTrO O O P O coupling S DMTrO O I2, H2O O OOB O S O S O Cl 3CCOOH O B' O HO O OO B O Repeat Cycle B' N (iPr)2 CN O B' O O O O O Si (CH 2)3 N C (CH 2)2 C O H O Cl 3CCOOH S O B HO O B Si (CH 2)3 NH 2 S I L I C A O O O O O Si (CH 2)3 N C (CH 2)2 C OH H

DMTrO O

B'

DMTrO O

B'

P O

O

CN B O

Base

O

P O

O

-

B O

S

O

P O

P O

PROTECTING GROUPS Silyl Ethers Synthesis 1985, 817 Synthesis 1993, 11 Synthesis 1996, 1031 R-OH → R-O-SiR3 formation: - R3Si-Cl, pyridine, DMAP - R3Si-Cl, CH2Cl2 (DMF, CH3CN), imidazole, DMAP - R3Si-OTf, iPr2EtN, CH2Cl2 Trimethylsilyl ethers Me3Si-OR TMS-OR - very acid and water labile - useful for transiant protection

61

Triethylsilyl ethers Et3Si-OR TES-OR - considerably more stable that TMS - can be selectively removed in the presence of more robust silyl ethers with with F - or mild acid
O TESO OTBS H2O/ACOH/THF (3:5:11), 15 hr (97%) OH O OTBS Liebigs Ann. Chem. 1986, 1281

Triisopropylsilyl ethers iPr3Si-OR TIPS-OR - more stabile to hydrolysis than TMS Phenyldimethylsilyl ethers J. Org. Chem. 1987, 52 , 165 t-Butyldimethylsilyl Ether tBuMe 2Si-OR TBS-OR TBDMS-OR JACS 1972, 94 , 6190 - Stable to base and mild acid - under controlled condition is selective for 1° alcohols t-butyldimethylsilyl triflate tBuMe 2Si-OTf TL 1981, 22 , 3455 - very reactive silylating reagent, will silylate 2° alcohols cleavage: - acid - F- (HF, nBu4NF, CsF, KF)
TBSO HO CO2Me HF, CH3CN (70%) O OTBS O HO JCS Perkin Trans. 1 1981, 2055 CO2Me

t-Butyldiphenylsilyl Ether tBuPh2Si-OR TBDPS-OR ∑-OR - stable to acid and base - selective for 1° alcohols - Me3Si- and iPr 3Si groups can be selectively removed in the presence of TBS or TBDPS groups. - TBS can be selectively removed in the presence of TBDPS by acid hydrolysis. TL 1989, 30 , 19

PROTECTING GROUPS cleavage - F- Fluoride sources: Me O Si tBu Me AcOH / THF/ H2O Ph O Si tBu Ph Me tBu Si Me Me O OTHP PPTS / EtOH tBu Me Si O OH JACS 1984, 106 , 3748 O Si Ph tBu Ph JOC 1981, 46 ,1506 TL 1989, 30 , 19.

62

nBu 4NF (basic reagent) HF / H2O /CH3CN HF•pyridine SiF4. CH2Cl2
OH

TL 1979, 3981. Synthesis 1986, 453 TL 1992, 33 , 2289

Esters R-OH → R-O2CR' Formation: - "activated acid", base, solvent, (DMAP) Activated Acids Chem. Soc. Rev. 1983, 12, 129 Angew. Chem. Int. Ed. Engl. 1978, 17, 569. RCO2H → "activated acid" → carboxylic acid derivative (ester, amide, etc.) Acid Chlorides
O O R OH R O Cl N acyl pyridinium ion (more reactive) N N R + N R O N + N

1. SOCl2 2. PCl5 3. (COCl)2 Anhydrides
O 2 R OH P2O 5 R O O O R

Activating Agents: Carbonyl Diimidazole
O O R OH O N N R N NH + CO + N N N

+

N Acyl Imidazole

PROTECTING GROUPS Dicyclohexylcarbodiimide
O O R OH C 6H11 NH O C N C 6H11 Nu: R O Nu

63

O

+

N C N

R

+C 6H11

N H

N H

C 6H11

Ketene formation is a common side reaction- scambling of chiral centers
O R H O C N C 6H11 C 6H11 NH R C O

"ketene"

Hydroxybenzotriazole (HOBT) - reduces ketene formation
O R O C N C 6H11 C 6H11 NH N O N N OH N R O N N

+

N-Hydroxysuccinimide (NHS)
O R O C N C 6H11 C 6H11 NH O O O O N O

+

HO

N R O

2,2'-Dipyridyl Disulfide (Aldrithiol, Corey Reagent) Aldrichimica Acta 1971, 4 , 33
O R OH Ph3P: N S S N R O S N

+

+
N SH

+

Ph3P=O

Mukaiyama's Reagent (2-Chloro-1-methyl pyridinium Iodide or 2-Fluoro-1methyl pyridinium p-toulenesulfonate) Aldrichimica Acta 1987, 20 , 54 Chem. Lett. 1975, 1045; 1159; 1976, 49; 1977, 575
O TsO R O O + N Me I-

+
R OH

F

+ N Me

Acetates R-OH → R-O2CCH3 - stable to acid and mild base - not compatable with strong base or strong nucleophiles such as organometallic reagents Formation: - acetic anhydride, pyridine - acetyl chloride, pyridine

PROTECTING GROUPS Cleavage: K2CO3, MeOH, reflux KCN, EtOH, reflux NH3, MeOH LiOH, THF, H2O enzymatic hydrolysis (Lipase)
OAc Porcine Pancreatic Lipase OAc TL 1988, 30 , 6189 OH (96% ee)

64

Org. Rxns. 1989, 37, 1.

OAc

Chloroacetates - can be selectively cleaved with Zn dust or thiourea.
O Me Cl AcO Me OAc Cl O O O O OR O H2NNHCOSH Me O OR HO O AcO Me OAc O O Cl HO O JCS CC 1987, 1026 O

OH

Trifluoroacetates Formation: - with trifluoroacetic anhydride or trifluoroacetyl chloride Cleavage: - K2CO3, MeOH Pivaloate (t-butyl ester) - Fairly selective for primary alcohols Formation: - tbutylacetyl chloride or t-butylacetic anhydride Cleavage: - removed with mild base Benzoate (Bz) - more stable to hydrolysis than acetates. Formation: - benzoyl chloride, benzoic anhydride, benzoyl cyanide (TL 1971, 185) , benzoyl tetrazole (TL 1997, 38, 8811) Cleavage: - mild base - KCN, MeOH, reflux 1,2 and 1,3- Diols Synthesis 1981, 501
R2 OH R R1 OH O R3 H+ , -H2O R2 O R R3 O R1

Chem. Rev. 1974, 74, 581

Isopropylidenes

(acetonides)
OH R R1 OH H+ acetone or OMe MeO OMe or Me O R Me O R1

- in competition between 1,2- and 1,3-diols, 1,2-acetonide formation is usually favored - cleaved with mild aqueous acid

PROTECTING GROUPS Cycloalkylidene Ketals - Cyclopentylidene are slightly easier to cleave than acetonides - Cyclohexylidenes are slightly harder to cleave than acetonides
O OH R R1 OH H+ , -H2O MeO OMe (CH 2)n O R (CH 2)n O R1 (CH 2)n -or-

65

Benzylidene Acetals
OH R R1 OH PhCHO -orPhCH(OMe)2 H , -H2O
+

Ph O R O R1

- in competition between 1,2- and 1,3-diols, 1,3-benzylidene formation for is usually favored - benzylidenes can be removed by acid hydrolysis or hydrogenolysis - benzylidene are usually hydrogenolyzed more slowly than benzyl ethers or olefins. p-Methoxybenzylidenes - hydrolyzed about 10X faster than regular benzylidenes - Can be oxidatively removed with Ce(NH 4)2(NO3)6 (CAN)
OBn BnO MeO O O O OMe Ce(NH 4)2(NO3)6 CH 3CN, H2O (95%) MeO O BnO OBn OH OH

Other Reactions of Benzylidenes - Reaction with NBS (Hanessian Reaction)
H Ph O O HO O O HO OMe NBS, CCl 4 Ph O HO O HO OMe Br Org. Syn. 1987, 65, 243

- if benzylidene of a 1° alcohol, then 1° bromide - Reductive Cleavage
Ph O MeO 2C
O

O CO 2Me

Na(CN)BH3, TiCl4,CH 3CN MeO 2C

OH CO 2Me OBn Synthesis 1988, 373.

O O O

Ph

TMS-CN BF3•OEt2 MeO

O

OH Tetrahedron 1985, 41, 3867 O O H Ph CN

MeO

PROTECTING GROUPS
Ph O O DIBAL-H TL 1988, 29 , 4085 O O BnO OH

66

OMe

OMe

Carbonates
OH R R1 OH (Im)2CO O R O O R1

- stable to acid; removed with base - more difficult to hydrolyze than esters Di-t-Butylsilylene (DTBS) TL 1981, 22 , 4999 - used for 1,3- and 1,4-diols; 1,2-diols are rapidly hydrolyzed - cleaved with fluoride (HF, CH 3CN -or- Bu4NF -or- HF•pyridine) - will not fuctionalize a 3°-alcohol
OH OH (t-Bu)2SiCl 2, Et3N CH 3CN, HOBT O Si O tBu tBu

1,3-(1,1,3,3)-tetraisopropyldisiloxanylidene (TIPDS) - specific for 1,3- and 1,4-diols - cleaved with fluoride or TMS-I
O HN HO O O HO OH N iPr2Si(Cl)-O-Si(Cl)iPr2 pyridine

TL 1988, 29 , 1561

O HN O Si O Si O OH O O N

Ketones and Aldehydes - ketones and aldehydes are protected as cyclic and acyclic ketals and acetals - Stable to base; removed with H3O+
R O R1 (CH 2OH)2, H+ PhH, -H2O -or(CH2OSiMe 3)2, TMS-OTf, CH2Cl 2 CH 2(CH 2OH)2, H+ , PhH, -H2O MeOH, H+ R OMe OMe R1

R

O TL 1980, 21 , 1357

R1 O 1,3-dioxolanes R O R1 O 1,3-dioxanes

PROTECTING GROUPS Cleavage rate of substituted 1,3-dioxanes: Chem. Rev. 1967, 67 , 427.
R O > R1 O R1 O R O >> R1 O R O

67

- Ketal formation of α,β-unsaturated carbonyls are usually slower than for the saturated case.
O CH 2(CH 2OH)2, H+ , PhH, -H2O O
O O O O LiBF4 O (88%) Me3Si O

O O

O

Fluoride cleavable ketal:
O

TL 1997, 38, 1873

Base cleavable ketal:
O R1 R2 HO OH O pTSA, C6H6 R1 O R2 R1 R2 SO2Ph SO2Ph DBU, CH2Cl 2 O

TL 1998, 39, 2401

Carboxylic Acids Tetrahedron 1980, 36, 2409. Tetrahedron 1993, 49, 3691 Nucelophilic Ester Cleavage: Organic Reactions 1976, 24, 187. Esters Alkyl Esters formation: - Fisher esterification (RCOOH +R'OH + H+) - Acid Chloride + R-OH, pyridine - t-butyl esters: isobutylene and acid - methyl esters: diazomethane Cleavage: - LiOH, THF, H2O - enzymatic hydrolysis Org. Rxns. 1989, 37, 1. - t-butyl esters are cleaved with aqueous acid - Bu 2SnO, PhH, reflux (TL 1991, 32, 4239)
OH MeO 2C CO 2Me Pig Liver Esterase pH 6.8 buffer OH MeO 2C CO 2H

O R OR'

Bu2SnO, PhH, ↑↓ R R= Me, Et, tBu

O OH TL 1991, 32, 4239

9-Fluorenylmethyl Esters (Fm) TL 1983, 24 , 281 - cleaved with mild base (Et2NH, piperidine)
DCC RCO 2H + OH R O O

PROTECTING GROUPS 2-Trimethylsilyl)ethoxymethyl Ester (SEM) HCA 1977, 60 , 2711. - Cleaved with Bu 4NF in DMF
DCC RCO 2H + HO O SiMe 3 R O O O SiMe 3

68

- Cleaved with MgBr2•OEt2 TL 1991, 32, 3099. 2-(Trimethylsilyl)ethyl Esters JACS 1984, 106 , 3030 - cleaved with Fluoride ion
DCC RCO 2H + HO SiMe 3 O R O SiMe 3

Haloesters

- cleaved with Zn(0) dust or electrochemically
DCC RCO 2H + HO CCl 3 R O O CCl 3

Benzyl Esters RCO2H + PhCH2OH → RCO2Bn Formation: Cleavage: Diphenylmethyl Esters
DCC RCO 2H + HO CHPh 2 O R O CHPh 2

DCC Acid chloride and benzyl alcohol Hydrogenolysis Na, NH3

Cleavage:

- mild H3O+ - H2, Pd/C - BF3•OEt2

o-Nitrobenzyl Esters - selective removed by photolysis Orthoesters Synthesis 1974, 153 TL 1983, 24 , 5571
O RCOCl + R OH

Chem. Soc. Rev. 1987, 75
O O O

BF 3•OEt2 R

O O O

- Stable to base; cleaved with mild acid

PROTECTING GROUPS

69

Amines Carbamates 9-Fluorenylmethyl Carbamate (Fmoc) Acc. Chem. Res. 1987, 20 , 401 - Cleaved with mild base such as piperidine, morpholine or dicyclohexylamine
NaHCO 3 H2O, dioxane O Cl O R2N O O

R2NH

+

2,2,2-Trichloroethyl Carbamate
O Cl 3C O Cl O R2NH, pyridine Cl 3C O N R R

- Cleaved with zinc dust or electrochemically.
O N EtO2C S O CCl 3 S Te Te S NaBH 4 EtO2C S NH TL 1986, 27 , 4687

2-Trimethylsilylethyl Carbamate (Teoc) - cleaved with fluoride ion.
O Me 3Si O O O N O
SiMe 3 OH Cl MeO O N O O CH 3 H O SEt SEt JACS 1979, 101 7104 OEt OTBS Bu4NF, THF (100%) MeO Cl H N O CH 3 H O SEt SEt OEt

O + R2NH Me 3Si O N R R

t-Butyl Carbamate

(BOC)
O R2NH tBuO O O O OtBu R2N OtBu

Cleavage:

- with strong protic acid (3M HCl, CF3COOH) - TMS-I
O B Cl

Allyl Carbamate (Alloc)

O

TL 1985, 26 , 1411 TL 1986, 27 , 3753

PROTECTING GROUPS
O R2NH O O O O R2N O O

70

- removed with Pd(0) and a reducing agent (Bu3SnH, Et 3SiH, HCO2H)
O HN O CO 2Me 1) Pd(OAc) 2, Et3N, Et3SiH 2) H3O + NH 2 CO 2Me TL 1986, 27 , 3753

Benzyl Carbanate

(Cbz)
O BnO R2NH Cl R2N O O Ph

Cleavage:

-

Hydrogenolysis PdCl 2, Et3SiH TMS-I BBr3 hν (254 nm) Na/ NH3

m-Nitrophenyl Carbamate JOC 1974, 39 , 192
O R2N O NO 2

- removed by photolysis Amides Formamides - removed with strong acid
R2NH

+

HCO 2Et R2N

O H

Acetamides - removed with strong acid
R2NH

+

Ac2O R2N

O CH 3

Trifluoroacetamides Cleavage: - base (K2CO3, MeOH, reflux) - NH3, MeOH
R2NH

+

(CF3CO) 2O R2N

O CF 3

Sulfonamides p-Toluenesulfonyl

(Ts)
R2NH pTsCl, pyridine R2N SO 2

PROTECTING GROUPS Cleavage: - Strong acid - sodium Naphthalide - Na(Hg)

71

Ts

N

N

Ts

Na(Hg), MeOH Na2HPO 4 (65%)

H

N

N

H JOC 1989, 54 , 2992

N Ts

N H

Trifluoromethanesulfonyl
Tf N N Tf

Na, NH3

NH

HN

JOC 1992, 33, 5505
NH HN

N Tf

N Tf

Trimethylsilylethanesulfonamide (SES) TL 1986, 54 , 2990; JOC 1988, 53, 4143 - removed with CsF, DMF, 95°C
R2NH Me 3Si SO 2Cl R2N O S O SiMe 3

Et3N, DMF

tert-Butylsulfonyl (Bus) JOC 1997, 62, 8604
tBuSOCl, Et3N, CH2Cl2 R 2N O S tBu mCPBA -orRuCl3, NaIO4 CF3SO3H, CH2Cl2, anisole R-NH2

R-NH2

R2N SO2tBu

C-C BOND FORMATION

72

Carbon- Carbon Bond Formation 1. Alkylation of enolates, enamines and hydrazones C&S: Chapt. 1, 2.1, 2.2 problems Ch 1: 1; 2; 3, 7; 8a-d; 9; 14 Ch. 2: 1; 2; 4) Smith: Chapt. 9 2. Alkylation of heteroatom stabilized anions C&S :Chapt. 2.4 - 2.6) 3. Umpolung Smith: Chapt. 8.6 4. Organometallic Reagents C&S: Chapt. 7, 8, 9 problems ch 7: 1; 2; 3, 6; 13 Ch. 8: 1; 2 Smith: Chapt. 8 5. Sigmatropic Rearrangements . C&S Chapt. 6.5, 6.6, 6.7 # 1e,f,h,op Smith Chapt. 11.12, 11.13 Enolates Comprehensive Organic Synthesis 1991, vol. 2, 99. - α-deprotonation of a ketone, aldehyde or ester by treatment with a strong nonnucleophillic base. - carbonyl group stabilizes the resulting negative charge.
O H H H R B: O H H R H H OR

- Base is chosen so as to favor enolate formation. Acidity of C-H bond must be greater (lower pKa value) than that of the conjugate acid of the base (C&S table 1.1, pg 3)
O H 3C O H 3C CH3 O CH2 OEt

pKa = 20

MeO- pKa = 15 tBuO- pKa = 19

unfavorable enolate concentration more favorable enolate concentration

pKa = 10

- Common bases: NaH, EtONa, tBuOK, NaNH2, LiNiPr2, M N(SiMe3)2, Na CH2S(O)CH3 Enolate Formation: - H+ Catalyzed (thermodynamic)
O H+ OH

- Base induced (thermodynamic or kinetic)
O H

:B

O-

+

B:H

Regioselective Enolate Formation Tetrahedron 1976, 32, 2979. - Kinetic enolate- deprotonation of the most accessable proton (relative rates of deprotonation). Reaction done under essentially irreversible conditions.
O LDA, THF, -78°C O - Li+

C-C BOND FORMATION typical conditions: strong hindered (non-nucleophilic) base such as LDA R2NH pKa= ~30
N Li

73

Ester Enolates- Esters are susceptible to substitution by the base, even LDA can be problematic. Use very hindered non-nucleophillic base (Li isopropylcyclohexyl amide)
O OR' R LDA, THF, -78°C E+ N R O- Li+ OR' R N Li THF, -78°C R OR' O

O

- Thermodynamic Enolate- Reversible deprotonation to give the most stable enolate: more highly substituted C=C of the enol form
O - K+ O tBuO- K+, tBuOH O - K+

kinetic

thermodynamic

typical conditions: RO- M+ in ROH , protic solvent allows reversible enolate formation. Enolate in small concentration (pKa of ROH= 15-18 range) - note: the kinetic and thermodynamic enolate in some cases may be the same - for α,β-unsaturated ketones
thermodynamic site O kinetic site

Trapping of Kinetic Enolates - enol acetates
Ph O 1) NaH, DME 2) Ac2O kinetic Ph O O isolatable separate & purify

+

Ph O O

CH3Li, THF

CH3Li, THF

Regiochemically pure enolates

Ph O- Li+

Ph O- Li+

- silyl enolethers
Ph O

Synthesis 1977, 91.
1) LDA 2) Me3SiCl kinetic Ph

C-C BOND FORMATION Acc. Chem. Res. 1985, 18, 181.
+
OTMS isolatable separate & purify CH3Li, THF -orBu4NF -or- TiCl4 CH3Li, THF Ph OTMS

74

Geometrically pure enolates

Ph O- M+

Ph O- M+

- tetraalkylammonium enolates- "naked" enolates - TMS silyl enol ethers are labile: can also use Et3Si-, iPr3Si- etc. - Silyl enol ether formation with R 3SiCl+ Et3N gives thermodyanamic silyl enol ether - From Enones
1) Li, NH3 2) TMS-Cl O TMSO 1) MeLi 2) E+ O H
O TMS-Cl, Et3N TMS-OTf Et3N O Li, NH3, tBuOH TMS-Cl OSiMe3

E

H

OSiMe3

OSiMe3

- From conjugate (1,4-) additions
O (CH3)2CuLi O- Li+ E+ O E

Trap or use directly

- From reduction of α-halo carbonyls
O Br Zn or Mg O- M+

Alkylation of Enolates (condensation of enolates with alkyl halides and epoxides) Comprehensive Organic Synthesis 1991, vol. 3, 1. 1° alkyl halides, allylic and benzylic halides work well 2° alkyl halides can be troublesome 3° alkyl halides don't work

C-C BOND FORMATION
O a) LDA, THF, -78°C b) MeI O Me

75

- Rate of alkylation is increased in more polar solvents (or addition of additive)
O (Me2N)3P HMPA O R NMe2 R= H DMF R-CH3 DMA H 3C O S CH3 CH3N O CH3N O NCH3 Me2N TMEDA NMe2

DMSO

Mechanism of Enolate Alkylation: SN2 reaction, inversion of electrophile stereochemistry
X C

180 °
M+ -O

Alkylation of 4-t-butylcyclohexanone:
O R O E R

equitorial anchor H E tBu R B E B tBu E R O- M+ H O Twist Boat Chair O

E H tBu R A

A favored

on cyclohexanone enolates, the electrophile approaches from an "axial" trajectory. This approach leads directly into a chair-like product. "Equitorial apprach leads to a higher energy twist-boat conformation. Alkylation of α,β-unsaturated carbonyls
O- M+ R1 O R1 H H R1 H Thermodynamic R2 O- M+ R2 E R1 H E O R2 Kinetic H R2 E R1 E H O R2

C-C BOND FORMATION Stork-Danheiser Enone Transposition: - overall γ-alkylation of an α,β-unsaturated ketone
O LDA PhCH2OCH2Cl OMe O PhO OMe CH3Li PhO OMe J. Org. Chem. 1995, 60, 7837. HO CH3 H3O
+

76

CH3 PhO O

Chiral enolates- Chiral auxilaries. D.A. Evans JACS 1982, 104 , 1737; Aldrichimica Acta 1982,15 , 23. Asymmetric Synthesis 1984, 3, 1. - N-Acyl oxazolidinones
O R N Me O R N O H 2N O OH O H 2N O Me Ph Ph norephedrine OH

valinol
O R N Me O N O LDA, THF Et-I R O O Ph LDA, THF Et-I Me Ph major product (96:4) O O N O LiOH, H2O, THF R R O N O O LiOH, H2O, THF R O OH

Complimentary Methods for enantiospecific alkylations
O OH

O R

Diastereoselectivity: 92 - 98 % for most alkyl halides

major product (96:4)

Enolate Oxidation Chem. Rev. 1992, 92, 919.
O R N O O NaN(SiMe3)2, THF, -78°C O Ph N SO2Ph O LDA, THF O tBuO N N O OtBu R Boc N HN Boc N O O R OH (88 - 98 % de) 1) HO2) CH2N2 3) TFA 4) Raney Ni O N O O

O R NH2 OMe

(94 - 98 % de)

C-C BOND FORMATION
O R N O O Bu2BOTf, Et3N R Bu B O N O O NBS R Br Ph O R NH2 Ph D- amino acids OH Bu O N O O N3-

77

Ph O R N3 N O O Ph 1) LiOH 2) H2, Pd/C

O R N

O O KN(SiMe3)2, THF SO2N3 Ph R N3

O N

O O

Ph

Oppolzer Camphor based auxillaries Tetrahedron, 1987, 43, 1969. diastereoselectivities on the order of 50 : 1
SO2Ph N O O R
H O O SO2N(C6H11)2 Et2Cu•BF3 LDA, NBS O O SO2N(C6H11)2 O Br O SO2N(C6H11)2

Ar Ar R O N O SO2Ph O

R R N S O2 O

O SO2N(C6H11)2

H HO

H

NH2 O

Asymmetric Acetate Aldol
O N S O 1) Br O H Br 85 %, 19:1 de TIPSO O NH2

Sn(OTf)2, CH2Cl 2, R3N, -40°C 2) TIPS-OTf, pyridine 3) NH3

J. Am. Chem. Soc. 1998, 120, 591 J. Org. Chem. 1986, 51, 2391

Chiral lithium amide basess
CH3 MeO CO2Et OMe Ph N Li THF, -78°C (CH3)2C=O OMe MeO O OMe O (72% ee) CH3

C-C BOND FORMATION
H O N N Ph N Li But O H N Li N (97 % ee) N Me tBu Ph OTMS

78

tBu

THF, HMPA TMSCl

Lewis Acid Mediated Alkylation of Silyl Enolethers- SN1 like alkylations
OTMS tBu-Cl, TiCl4, CH2Cl2, -40°C (79%) SPh R Cl O O CH3 C(CH3)3

note: alkylation with a 3° alkyl halide
ACIEE1978, 17, 48 TL 1979, 1427 R

OTMS

SPh R Raney Ni (95 %)

O

TiCl4, CH2Cl2, -40°C (78%)

Enamines Gilbert Stork Tetrahedron 1982, 38, 1975, 3363. - Advantages: mono-alkylation, usually gives product from kinetic enolization
O N O N can not become coplanar

"Kinetic"
O •• N

"Thermodynamic"
O + N R O E

O O N H H+, (-H2O)

R-I

H2O

enamine

-Chiral enamines
N O E

Imines
Ph N

Isoelectronic with ketones
Me O OMe LDA, THF, -20°C Li N Ph 1) E 2) H3O+ O E E = -CH3, -Et, Pr, PhCH2-, allylee 87 - 99 %

Hydrazones

C-C BOND FORMATION isoelectronic with ketones Comprehensive Organic Synthesis 1991, 2, 503
O Me2N-NH2 H , (-H2O)
+

79

N

N N LDA, THF

N

-N -

N

E+

N

N hydrolysis E

O E

- Hydrazone anions are more reactive than the corresponding ketone or aldehyde enolate. - Drawback: can be difficult to hydrolyze. - Chiral hydrazones for asymmetric alkylations (RAMP/SAMP hydrazones- D. Enders "Asymmetric Synthesis" vol 3, chapt 4, Academic Press; 1983)
OMe N NH2 SAMP MeO N H 2N RAMP

N N OMe I

LDA OTBS

N N OMe

O3

O H

(95 % de) TBSO

TBSO

N

N

1) LDA 2) Ts-CH3, THF -95 - -20 °C OMe 3) MeI, 2N HCl

O CH3 (100 % ee)

Me O Li R1 E (C,C) R2 H
••

MeO R1 R2 E H N N

N N Z (C,N)

E

Aldol Condensation
O H R

Comprehensive Organic Synthesis 1991, 2, 133, 181.
a) LDA, THF, -78°C b R'CHO H R O OH R' β-hydroxyl aldehyde (aldol)

- The effects of the counterion on the reactivity of the enolates can be important Reactivity Li+ < Na+ < K+ < R4N+ addition of crown ethers

C-C BOND FORMATION - The aldol reaction is an equilibrium which can be "driven" to completion.
O- M+ R R' + RCHO H R M O O R' work-up H R O OH R'

80

In the case of hindered enolates, the equillibrium favors reactants. Mg2+ and Zn2+ counterions will stabilize the intermediate β-alkoxycarbonyl and push the equillibrium towards products. (JACS 1973, 95, 3310)
O- M+ PhCHO, THF O OH Ph M= Li M= MgBr 16% yield 93% yield

- Dehydration of the intermediate β-alkoxy- or β-hydroxy ketone can also serve to drive the reaction to the right.
O O O

tBuO- Na +, tBuOH O O H O O H

JACS 1979, 101 , 1330

Enolate Geometry - two possible enolate geometries
O LDA, THF, -78°C O - Li+ H O - Li+

+
H Z - enolate

E - enolate

- enolate geometry plays a major role in stereoselection.
Z -enolate
R
1

OM R2 H

R3CHO
R

O
1

OH R R2
3

erythro (syn)

E -enolate
R
1

OM H R2

R3CHO
R
1

O

OH R R
2 3

threo (anti)

- Zimmerman-Traxler Transition State : Ivanov condensation JACS 1957, 79 , 1920.
+

O
-

MgBr
- +

H O Ph Ph H Mg

Br O

Ph

H

+

PHCHCO2 MgBr

OMgBr

"pericyclic" T.S.

C-C BOND FORMATION Analysis of Z-enolate stereoselectivity
R2 R3 O H H R1 M O R3 R2 O R2 M O H H R1 H H R1 R3 O M O R1 R2 O OH R3

81

erythro (syn) favored
R2 H O H R3 M R1 O O H R3 R1 R3 H R2 O M H R2 O H R1 M O R1 R2 O OH R3

threo (anti) disfavored

Analysis of E-enolate stereoselectivity
H R3 O R2 H M R1 O O R2 H R1 H R3 H H O M R
3

O R2

M R1

O R1

O

OH R3 R2

threo (anti) favored
H

H H O R R3
2

M R1

O

H

H

O

M O

H

O R2 R3

M R1

O O R1 R2 OH R3

R2

R3 R1

erthro (syn) disfavored

Analysis of Boat Transition State for Z-Enolates
R2 O R3 H H R1 Favored Chair M R1 R2 H Boat H R2 O H H R3 R1 Disfavored Chair O M R1 R2 O HO R3 staggered R3 R2 R1 H Boat: R1-R2 1,3-interaction is gone O O M R1 O R3 O HO H R3 R2 O O M

C-C BOND FORMATION Analysis of Boat Transition State for E-Enolates
H O R3 R2 H Favored Chair H O H R2 R3 R1 R1 R2 R3 staggered M O O HO R3 H R2 R1 O M O O R1 R1 R2 R2 Boat H O M HO R3 H H R1 O R3 O M

82

Disfavored Chair

Boat: R1-R2 1,3-interaction is gone

Summary of Aldol Transition State Analysis: 1. Enolate geometry (E- or Z-) is an important stereochemical aspect. Z-Enolates usually give a higher degree of stereoselection than E-enolates. 2. Li+, Mg 2+, Al3+= enolates give comparable levels of diastereoselection for kinetic aldol reactions. 3. Steric influences of enolate substituents (R1 & R2) play a dominent role in kinetic diastereoselection.
O- M+ Path A R2 H Path B O H R2 Path A R1 R2 R1 R2 O HO R3 R1

O- M+ R1

HO R3

When R1 is the dominent steric influence, then path A proceeds. If R2 is the dominent steric influence then path B proceeds. 4. The Zimmerman-Traxler like transition state model can involve either a chair or boat geometry. Noyori "Open" Transition State for non-Chelation Control Aldols Absence of a binding counterion. Typical counter ions: R4N+, K+/18-C-6, Cp2Zr2+ - Non-chelation aldol reactions proceed via an "open" transition state to give syn aldols regardless of enolate geometry. Z- Enolates:
R1 H H O R1 H R3 O ODisfavored R2 H H H R R2 3 O H R2 O OFavored R2 R3 R3 H O H R2 H O Favored R1 OH R3 R1 R2 R3 R2 R1 OR1 R3 OH R1 R2 O HO R3

Syn Aldol
O HO

R1

O-

Disfavored

Anti Aldol

C-C BOND FORMATION E- Enolate:
-

83

O H

R1 favored R2 H

O H

R1 R3 H R2 H

O

R1 O H R1 R3 R2 R2 HO

R3 O
-

R3

O

O favored
-

Syn Aldol

O H

R1 disfavored R2

-

O

O

R1 H

R1 O R3 R1 R3 R2 R2 HO

H O

R3

H H R3 R2 O H O disfavored

Anti Aldol

NMR Stereochemical Assignment. Coupling constants (J) are a weighted average of various conformations.
O R1 R2 HA 60 ° HA H O O HB R2 R1 R3 R1 O H O HB 60 ° HA R3 R2 R1 HB R3 O HA OH R2 H O HB R3

Syn Aldol JAB = 2 - 6 Hz

non H-bonded H

O R1

OH B R3

Anti Aldol JAB = 1 - 10 Hz
60 ° 60 ° HB O R2

R2 HA HA H O O R3 R2 R1 HB R1 O H O R3 HA HB HA OH R2 R1 R3

non H-bonded

Boron Enolates:

Comprehensive Organic Synthesis 1991, 2, 239. Organic Reactions 1995, 46, 1; Organic Reactions 1997, 51, 1. OPPI 1994, 26, 3. - Alkali & alkaline earth metal enolates tend to be aggregates- complicates stereoselection models. - Boron enolates are monomeric and homogeneous - B-O and B-C bonds are shorter and stronger than the corresponding Li-O abd Li-C bonds (more covalent character)- therefore tighter more organized transition state. Generation of Boron Enolates:
O R2B-X iPrEtN OBR2 X= OTf, I R= Bu, 9-BBN

C-C BOND FORMATION
R3N: R1 H _ + BL2OTf O R2 R1 Z-enolate OBL2 R2

84

H

R3N: R1 R2
O

H

_ + BL2OTf O H R1

OBEt2

R2 E-enolate
OBR2 R

R 3B

OSiMe3

R2B-X

OBR2 + Me3 Si-X

O R N2

R' 3B R

OBR'2 R' Hooz Reaction

Diastereoselective Aldol Condensation with Boron Enolates
O Ph Ph pure Z-enolate OBEt2 O RCHO Ph OBEt2 R

100% Syn Aldol

OBEt2 R1 R2

O R3CHO R1 R2 O R3CHO R1

OH R3 generally > 95 : 5 syn : anti

Z-enolate OBEt2 R1 R2 E-enolate

OH R3 R2 generally ~ 75 : 25 anti : syn

Asymmetric Aldol Condansations with Chiral AuxilariesD.A. Evans et al. Topics in Stereochemistry, 1982, 13 , 1-115. - Li+ enolates give poor selectivity (1:1) - Boron and tin enolates give much improved selectivity
Bu O Me N O O B Bu2BOTf, EtNiPr2 , -78° O - O + N O RCHO R Me Bu OH O N O O

> 99:1 erythro
O Me N O Ph O 1) Bu2BOTf, EtNiPr2 , -78° 2) RCHO R Me OH O X

C-C BOND FORMATION
L O B _ L O
+

85

H R O

L O
+

L B _ O N O O R

L O B _

L O
+

O N O

N

RCHO

H R

L O
+

L B _ O N O O R

L O B _

L O
+

N O O

preferred conformation
R2 O L B L O O N H O O H R3 L B L O N O O Disfavored O O N R2 R2 H R3

R3

Favored O O N R2

O

OH R3

O

OH R3

Oppolzer Sultam
O N S O2 1) LDA 2) Bu3SnCl R3 Sn O S O N R2 S O2 L 2B N O R2 R3CHO N S O2 R2 O OH R3

O R2

R3CHO N S O2

O

OH R3 R2

C-C BOND FORMATION Chiral Boron
O StBu when large, higher E-enolate selectivity iPrEt2N, PhCHO,-78°C BOTf Ph OH O StBu + Ph OH O StBu

86

1 : 33 (> 99 % ee)

Ph O R SPh ArO2SN B Br

Ph NSO2Ar Ph R > 95 : 5 (> 95 % ee) OH O SPh + Ph R OH O SPh

iPrEt2N, PhCHO,-78°C

• In general, syn aldol products are achievable with high selectivity, anti aldols are more difficult Mukaiyama-Aldol- Silyl Enol Ethers as an enolate precursors. Lewis acid promoted condensation of silyl ketene acetals (ester enolate equiv.) with aldehydes: proceeds via "open" transition state to give anti aldols starting from either E- or Z- enolates.
OSiMe3 OEt RCHO, TiCl4, CH2Cl2, -78°C R OH CO2Et CH3 R= iPr (anti : syn) = 100 : 0 C6H11 94 : 6 Ph 75 : 25 RCHO, TiCl4, CH2Cl2, -78°C R OEt OH CO2Et CH3 R= iPr (anti : syn) = 52 : 48 C6H11 63 : 37 Ph 67 : 33 + R OH CO2Et CH3 + R OH CO2Et CH3

OSiMe3

Asymmetric Mukiayama Aldol:
Ph H 3C O OSiMe3 NMe2 RCHO, TiCl4, CH2Cl2, -78°C OH R O Rc (90-94% de) syn : anti = 85 : 15 selectivity insenstivie to enolate geometry + R OH O Rc

C-C BOND FORMATION
Ph N SO Ph 2 O OSitBuMe2 iPrCHO, TiCl4, CH2Cl2, -78°C Rc CH3 O HO 96 % de anti : syn = 93 : 7

87

O OSitBuMe2 SO2N(C6H11)2

RCHO, TiCl4, CH2Cl2, -78°C

O Rc

HO + Syn product CH3

E-Enolate R= Ph % de= 90 nPr 85 iPr 85 Z-Enolate R= iPr % de= 87

anti : syn = 91 : 19 94 : 6 98 : 2 anti : syn = 97 : 7

Mukaiyama-Johnson Aldol- Lewis acid promoted condensation of silyl enol ethers with acetals:
OSiMe3 O TiCl4 or SnCl4 R RCHO or RCH(OR')2 CH2Cl2, -78°C
O O O TiCl4, CHCl2, -78 °C HO O O

OH Mukaiyama-Johnson Aldol via Ti or Sn enolate

O O

O

OTMS

+
Cl4Ti O+ O Cl4Ti O

O OSiMe3

OTMS Ph

TiCl4, (CH3)2C(OEt)2 (78 %) Ph

O

OEt

Fluoride promoted alkylation of silyl enol ethers
OSiMe3 nBu4NF, THF, MeI O

Acc. Chem. Res. 1985, 18, 181

C-C BOND FORMATION Meyer's Oxazolines:
O N (ipc)2BOtf iPrEt2N, Et2O N (ipc)2B Ester equiv. O 1) RCHO 2) 3N H2SO4 3) CH2N2 (~ 30%) H 3C R OH CO2Me + R OH H 3C CO2Me

88

R= nPr %ee (anti) = 77 anti : syn = 91 : 9 C6H11 84 95 : 5 tBu 79 94 : 6

Anti-Aldols by Indirect Methods:
SePh O PhSe C6H11 OTBS chiral auxillary 1) TBS-Cl 2) DiBAl-H 3) TsCl 4) Ba(CN)BH3 1) (C5H7)2BOTf R3N 2) RCHO HO syn aldol CH3 R OTBS
CO2Me N 2) RCHO N CH3 MOMO O MeO N O MeO O 1) LDA, THF, -78 °C 2) RCOCl MOMO N CH3 OMOM Zn(BH4)2 O O CH3 MOMO N CH3 OMOM KBEt3H, Et2O, -78 °C N CH3 OMOM O HO CH3 syn : anti 97 : 3 O O 1) LDA, THF, -78 °C O R

OTBS R O C6H11

1) HF 2) [O] R 3) NaIO4 4) CH2N2 HO CO2Me R HO

CO2Me

O3 R

CH3 CHO OTBS

Anti Aldol Product

1) HIO6 2) CH2N2

OH MeO2C CH3 Anti Aldol HO CH3 syn : anti 1 : 99 R

Syn Aldols by Indirect Methods:
O O N O 1) LDA, THF, -78 °C O 2) RCOCl O N CH3 O O Zn(BH4)2 R O N CH3 O O OH R syn : anti = 100 : 1

C-C BOND FORMATION Aldol Strategy to Erythromycin:
O
10 11 12 15 14 13 O 1 3 9 8

89

4
7 6 5 4

3

2

1 CO2H Erythromycin seco acid

OH

OH OH

OH

OH

O

OH

OH

O

2

[O] syn aldol 3

[O]

Erythromycin aglycone CHO OH syn aldol 4

CO2H O syn aldol OH OH 1

CHO

+
CHO O syn aldol OH

CHO

+
CO2H

2

CHO O
1 HO2C OH 3 OH 5 O 9 OH 11 OH 13

+

CHO

O O N

O

LDA, CH3CH 2COCl O 83%, (96:4)

O

O N 1

O

TiCl4, iPr 2EtN, CH2Cl2 O CHO

O N

O

O

OH 5

1) Zn(BH3)2 2) (H3C)2C(OMe)2 CSA (100%)

Ph Ph

90% (> 99:1)

Ph

O O N

O

O 3

O 5

1) 9-BBN, THF 2) Swern oxid. 73% (85:15) O

O N

O

O

O CHO

Ph

Ph 1) Na BH(OAc)3 2) TBS-OTf, 2,6-lutidine 3) AlMe3, (MeO)MeNH•HCl MeO 72% (>99:1)

O O N

O

O

Sn(OTf)2, Et3N, CH2Cl2 O CH3CH 2CHO 84% (> 96:4)

O

O N 9

O 11

OH 13

O N CH3

OH

OTBS

Ph O EtMgBr 86% 8 11 13 OH OTBS

Ph 1) PMBC(NH)CCl3 TfOH 2) (PhMe2Si)2NLi, TMS-Cl 48 %

PMBO TMSO

OTBS

C-C BOND FORMATION
H3C H Sn H O L O L X O X CH3 CH3
anti-syn

90

X O O OH R L L L O Ti O O H

H CH3
Disfavored

H CH3 CH3 O X

X O

H

H L CH3 Sn H O O L
Disfavored

O

OH R

H3C H

X H

H CH3 CH3 O Ti L L
J. Am. Chem. Soc. 1990,112, 866

CH3 CH3
anti-syn

O

H3C CH3

H

O L

H3C CH3

O O N

O

O 3

O 5 CHO 7

PMBO TMSO

OTBS 13

BF3•OEt2, CH 2Cl2, -78 °C O 83% (95:5)

O N

O

O 3

O 5

OH 7

PMBO O 9 11

OTBS 13

+
8

11

Ph O 1) Zn(BH3)2 2) DDQ 95% Ph p-MeOC 6H4 O O N O O O O O O N O O O

p-MeOC 6H4 OH O O OTBS

Ph 1) NaH, CS2, MeI 2) nBu3SnH, AIBN 70%

p-MeOC 6H4 OTBS 1) LiOOH 2) TBAF HO 63% 13 O O O O O OH Cl3C6H2COCl iPr2EtN, DMAP (86%

Ph

p-MeOC 6H4 O
10 11 12 13 9 8 7

O
9

1) Pd(OH)2, iPrOH 2) PCC 3) 1M HCl, THF
6

11

OH
5 13

O
5 4 3 2

58 % O

O
1 3

OH OH

O
1

O O

O

Michael Addition - 1,4-addition of an enolate to an α,β-unsaturated carbonyl to give 1,5-dicarbonyl compounds
O M Ph
+

O R Ph

O

O

R

Organometallic Reagents Grignard reagents:
O R-Br Mg(0) THF OH R-MgBr R

O OH R-MgBr THF R + R O often a mixture of 1,2- and 1,4-addition

C-C BOND FORMATION
O OH R-MgBr THF, CeCl3
O R-MgBr

91

R
O

1,2-addition

CuI,THF, -78C R

1,4-addition

Organolithium reagents - usually gives 1,2-addition products - alkyllithium are prepared from lithium metal and the corresponding alkyl halide vinyl or aryl- lithium are prepared by metal-halogen exchange from the corresponding vinyl or aryl- haidide or trialkyl tin with n-butyl, sec-butyl or tbutyllithium.
R-Br X X= Br, I, Bu3Sn nBu-Li Et2 O Li(0) R-Li Li Et2 O

Organocuprates Reviews: Synthesis 1972, 63; Tetrahedron 1984, 40 , 641; Organic Reactions 1972, 19 , 1. - selective 1,4-addition to α,β-unsaturated carbonyls
2 R-Li
O R2CuLi R

CuI, THF
O

R2CuLi

- curprate "wastes" one R group- use non transferable ligand
MeO Cu

_

MeO Cu R

R-Li

Li+

non-transferable ligand
Other non transferable ligands _ _ + Bu3P Cu R Li Me2S Cu R Li+ 2S Cu R CN 2Li
+

_ NC Cu R Li

_
+

F3B Cu R

Li+

Mixed Higher Order Cuprate B. Lipshutz Tetrahedron 1984, 40 , 5005 Synthesis 1987, 325.

Addition to Acetals
O R H3C O R (n-C6H13)2CuLi BF3•OEt 2

Tetrahedron Asymmtetry 1990, 1, 477.
n-C6 H13 O CH3 OH 1) PCC 2 NaOEt n-C6 H13 CH3 TL 1984, 25, 3087

OH Chiral axulliary is destroyed 99 % ee LA O H R Nu O

R H

O O CH3

LA CH3 Nu: R H O O

C-C BOND FORMATION
TMS O O 1) TiCl4 2) [O] 3) TsOH JACS 1984, 106, 7588 OH

92

98 % ee

Stereoselective Addition to Aldehydes - Aldehydes are "prochiral", thus addition of an organometallic reagent to an aldehydes may be stereoselective. - Cram's Rule JACS 1952, 74 , 2748; JACS 1959, 84 , 5828. empirical rule
O R
1

*

M S

1) "R2 - " 2) "H + "

-

OH R1 R
2

M S L

L

O M L R1 S M

OH S R
2

R2

-

R

1

L

- Felkin-Ahn TL 1968, 2199; Nouv. J. Chim. 1977, 1 , 61. based on ab initio calculations of preferred geometry of aldehyde which considers the trajectory of the in coming nucleophile (Dunitz-Burgi trajectory).
O M L R
1

vs. R2
-

S

O L

R2

-

S

M

R

1

better

- Chelation Control Model- "Anti-Cram" selectivity - When L is a group capable of chelating a counterion such as alkoxide groups +
M O OR' R1
*

worse

OH

R

2

R

1

S M

M S

OR' "Anti-Cram" Selectivity

M+ O OR' HO OR' R2 R1 S

R2
M R
1

-

S

M

Umpolung - reversal of polarity Aldrichimica Acta 1981, 14, 73; ACIIE 1979, 18, 239. i.e: acyl anion equivalents are carbonyl nucleophiles (carbonyls are usually electophillic)
O R usually R O +

Benzoin Condensation
KCN PhCHO Ph OH CN

Comprehensive Organic Synthesis 1991, 1, 541.
OH Ph - CN Cyanohydrin anion PhCHO HO Ph CN OPh -O Ph CN OH Ph Ph O OH

Ph Benzoin

C-C BOND FORMATION 93 Thiamin pyrophosphate- natures acyl anion equivalent for trans ketolization reactions
NH2 H NH2

+
N H 3C N N S OPO3PO3 H 3C N N

_ +
N S OPO3PO3

H 3C

H 3C

Thiamin pyrophosphate
CHO H H H H 2C OH OH OH OPO3 H 2C OH O CHO H 2C OH O HO H OH OH OH OPO3

+

thiamin-PP

H H H 2C

OH OH OPO3

H H 2C

OH OPO3

+

H H

D-ribose-5-P (C5 aldose)

D-ribulose-5-P (C5 ketose)

glyceraldehyde-3-P (C3 aldose)

H H 2C

sedohepulose-7-P (C7 ketose)

Trimethylsilycyanohydrins
O R H

TMS-CN

TMSO R

CN H

LDA, THF

TMSO R

CN

_

acyl anion equivalent
O

NC OMs NaHMDS, THF, -60°C CN O OEE O (72%) O O O O OEE CSA, tBuOH

Tetrahedron Lett. 1997, 38, 7471

Dithianes
B:, THF S R S H S R S R'-I S R S R' R R' Hg(II)
O

Aldehyde Hydrazones
H N N R H tBu

B:
N tBu O E R E

E+
R

N

H

Heteroatom Stabilized Anions Sulfones
Ph R O S O

(Dithiane anion is an example)
_
O Ph R O S O R' R' R' R' Ph R O S O R OH

LDA, THF

Al(Hg)

R' R'

OH

Sulfoxides
O

_
Ph R S O

R' R' R'

OH

LDA, THF

Ph R S O

R'

Raney Ni
Ph S O

R' R' R

OH

R

C-C BOND FORMATION Epoxide Opening Asymmetric Synthesis 1984, 5, 216.
Nu: R O Acid (SN1-like) Condition R O+ Nu H Nu
OH OH BnO OH Me2CuLi AlMe3 6:1 1:5 OH OH + BnO OH TL 1983, 24, 1377

94

Basic (SN2) Condition R

Nu

Steric Approach Control
HO

R

OH

Nu: attachs site that best stabilizes a carbocation

O BnO

O

Me3Al

JACS 1981, 103, 7520

S O _

S

OH S S

JOC 1974, 3645

O S Ph S _

+
(69 %) 1) TBS-Cl 2) MeI, CaCO 3, H+ Ph O OH Ph

S

S

OH

Tetrahedron Lett. 1992, 33, 931

Cyclic Sulfites and Sulfates (epoxide equivalents)
O OH R1 OH
O S O R1 O R2 Nu:

Synthesis 1992, 1035.
O S O R2 RuCl3, NaIO4 O R1 O R2 O

R2

SOCl2, Et3N

S O R1 sulfite
O S O R1 O
-

sulfate
H2O

H R2 Nu

HO R1

H R2 Nu

H2O O S O R1 O R2 O Nu: O O S O R1 OH R2 Nu Nu: Nu2 H R1 H R Nu1 2

C-C BOND FORMATION
O SO2 R1 O R2 CO2Me CO2Me NaH R1 R2 MeO2C CO2Me

95

O SO2 CO2Me O

1) (CH3)2CuLi 2) TBS-Cl
OBn

OTBS CO2Me CH3
MeO

1) H2, Rh 2) HF

O O carpenter Bee pheromone

OMe NCH3

O SO2

OMe H3C

H N ∆

OMe OMe

OBn OMe 1) Ac2O 2) HCl

O MeO OBn meso MeO BnO OAc

OH MeO HO NCH3 OBn OMe OBn OBn MeO BnO OMe NCH3

Irreversible Payne Rearrangement
O OH O O SO2 OTBS O Bu 4NF OH O OH

Payne Rearrangement of 2,3-epoxyalcohols Sigmatropic Rearrangements Nomenclature:
σ bond that breaks
1 1 2 3 2 1
R H

Aldrichimica Acta 1983, 16, 60

Asymmetric Synthesis 1984, 3, 503.
∆ 1 1 2 3 4 5 ∆
R

2 3 R

2 3 R

3 R

3

R

σ bond that forms

[3,3]-rearrangement

2 1
H

4 5

[1,5]-Hydogen migration σ bond that forms

σ bond that breaks

1

1

3,3-sigmatropic Rearrangements Cope Rearrangemets- requires high temperatures
R

Organic Reaction 1975, 22, 1

R

C-C BOND FORMATION Chair transition state:
CH3 H 3C H H 220 °C H 3C E CH3 Z

96

E,Z (99.7 %)

E,E (0.3 %)

Z,Z (0 %)

H H 3C H 3C H HH

CH3

CH3

H 3C H 3C E

E

CH3 Z

H 3C

Z

E,Z (0 %)

E,E (90 %)

Z,Z (10 %)

"Chirality Transfer"
Ph R CH3 Ph CH3 H E S CH3 (87 %) Diastereomers Ph Ph H 3C R E H 3C Z CH3 R (13 %) H

Ph

R CH3 Z Ph

E CH3

CH3 R H

Diastereomers Ph Ph H 3C R Z H 3C Z H S CH3

- anion accelerated (oxy-) Cope- proceeds under much milder conditions (lower temperature) JACS 1980, 102 , 774; Tetrahedron 1978, 34, 1877; Organic Reactions 1993, 43, 93; Comprehensive Organic Synthesis 1991, 5, 795. Tetrahedron 1997, 53, 13971.

C-C BOND FORMATION
OH OMe O

97

KH, DME, 110°C

OMe

OH

KH OO

Ring expansion to medium sized rings
OH KH, ∆ O 9-membered ring

Claisen Rearrangements - allyl vinyl ether to an γ,δ-unsaturated carbonyl Chem. Rev. 1988, 88, 1081.; Organic Reactions 1944, 2, 1.; Comprehnsive Organic Synthesis 1991, 5, 827.

O O

OH O

O CHO

220 °C
O H O

Hg(OAc)2
O H O

JACS 1979, 101 , 1330
O H O

Chair Transition State for Claisen
R H E-olefin O R X X X=H X= OEt, NMe2, etc R O X R H O O 1,3-diaxial interaction X R X Z-olefin E/Z = 90 : 10 E/Z = > 99 : 1 O

new stereogenic centers R old stereogenic center H O O X R X

C-C BOND FORMATION 98 - Chorismate Mutase catalyzed Claisen Rearrangement- 105 rate enhancement over non-enzymatic reaction
CO2H Chorismate mutase O OH Chorismate CO2H OH Prephenate HO2C O CO2H J. Knowles JACS 1987, 109, 5008, 5013

- Claisen rearrangement usually proceed by a chair-like T.S.
H HO2C O H CO2H Chair T.S HO2C O H H

OH H H O CO2H CO2H Boat T.S

OH

Opposite stereochemistry
CO2H O CO2H

H H

OH

OH
OH + OH

OH

J. Org. Chem. 1976, 41, 3497, 3512 J. Org. Chem. 1978, 43, 3435

O +

O

O R H O R H

s CH3 O R H

O R H s CH3

CH3

O H

CH3 CH3 O H CH3

OH

CH3

OH

CH3 OH CH3 OH

CH3 CO2R

Tocopherol 94 - 99 % ee

hydrophobically accelerated Claisen - JOC 1989, 54, 5849

C-C BOND FORMATION Johnson ortho-ester Claisen:
EtO OEt OH H3C-C(OEt)3 H+ O ∆ - EtOH O OEt [3.3] O OEt

99

Ireland ester-enolate Claisen.
O O

Aldrichimica Acta 1993, 26, 17.
OTMS LDA, THF TMS-Cl O [3.3] O OH

O O Me OBn LDA, THF TMS-Cl Me Me Me CO2H OBn JOC 1983, 48, 5221

Eschenmoser
R OH EtO BF3 R NMe2 OEt O NMe2 R ∆ O NMe2

"Chirality Transfer"
R N O Ph Ph R= Et, Bn, iPr, tBu N O Ph (86 - 96 % de) R N O R aldehyde oxidation state

[2,3]-Sigmatropic Rearrangement
H Z :X Y R R H

Comprehensive Organic Synthesis 1991, 6, 873.
H R R1 X Y: R1 :X Y H X Y: R X Y: R H E :X Y

R

-Wittig Rearrangement
O

Organic Reactions 1995, 46, 105
_ base HO

Synthesis 1991, 594.

O

SnR3

BuLi

_ O

C-C BOND FORMATION
TBDPSO H MeO O OH MeO O O SnMe3 TBDPSO H MeO O (58%)
CH3 Ph _

100

KH, 18-C-6, Me3SnCH2I

TBDPSO nBuLi H

TBDPSO H MeO O O Li

J. Am. Chem. Soc. 1997, 119, 10935

TBDPSO

+
MeO OH O (42%)

H

H3C H

H3C Ph

CH3 OH (87 %)

O

CH3 H O _ CH3 Ph H3C Ph

CH3 (13 %) OH

Sulfoxide Rearrangement
R S O
-

R

S O

(MeO) 3P HO O

O CO2Et (MeO) 3P

CO2Et

Ph

S

O-

HO

Ene Reaction Comprehensive Organic Synthesis 1991, 5, 1; Angew. Chem. Int. Ed. Engl. 1984, 23, 876; ; Chem. Rev. 1992, 28, 1021.
H H

- Ene reaction with aldehydes is catalyzed by Lewis Acids (Et2AlCl)
R H O H O H R

OH CHO Et2AlCl CH2Cl2 -78°C JOC 1992, 57, 2766

Ph O

O O H SnCl4 O Ph O

O OH 99.8 % de

Ph O SnCl4

OH + syn isomer

H3C

(94 : 6)

C-C BOND FORMATION
O TiCl2 O O + H CO2Me O PhS R + H CO2Me PhS R anti (99 % ee) OH + CO2Me (9 : 1) syn (90 % ee) PhS R CO2Me OH CO2Me OH (97% ee) Tetrahedron Lett. 1997, 38, 6513

101

- Metallo-ene Reaction

Angew. Chem. Int. Ed. Engl. 1989, 28, 38
CH3 C6H13 C6H13 ClMg C6H13 H 3C H2O H 3C H 3C (> 1%) C6H13 H2O H 3C CH3 C6H13 (10 %)

CH3

Cl

MgCl ClMg

intramolecular

BrMg + MgBr + (11 : 1)

BrMg

1)

Li Cl

1) Mg(0), Et2 ) 2) 60 °C MgCl

CH3 MgCl

CHO 2) SOCl2

O

CH3 OH SOCl2

CH3

Cl

1) Mg(0), Et2 ) 2) 60 °C

CH3 MgCl O2 H 1) PCC 2) MeLi 3) O3 H3C

CH3

MgCl

H

OH

CH3 CHO H O

4) KOH 5) H2 6) Ph3 P=CH2

H Capnellene

C-C BOND FORMATION Synthesis of Phyllanthocin
O O Ph N CH3 O (Me3Si)2 NLi Br Ph CH3 O

102

A. B. Smith et al. J. Am. Chem. Soc. 1987, 109, 1269.
O N O 1) LAH 2) BnBr

BnO 1) O3 2) H2, Lindlar's BnO CHO BnO BnO H O H CH3 OH CHO OMEM 1) MEM-Cl 2) O3 MeAlCl

BnO

O

O

O BnO 1) ZnCl2 2) H O MEMO O
+

O O BnO O

1) 2)

O (CH3 )2S(O)CH 2-

-

O

H3O +

3) Swern

O O BnO O

O

1) LDA, TMSCl 2) BnMe3 NF, MeI BnO O

O O

CH O 3

1) DBU 2) H2, Pd/C 3) RuO4

O O HO2C O

O CH3 MeO2C O

O O O O CH3 Ph Phyllanthocin

C=C BOND FORMATION C=C Bond Formation 1. 2. 3. 4. 5. 6. 7. 8. 9. 10 11. C&S Chapt. 2 # 5,6,8,9,12

103

Aldol Condensation Wittig Reaction (Smith, Ch. 8.8.A) Peterson Olefination Julia-Lythgoe Olefination Carbonyl Coupling Reactions (McMurry Reaction) (Smith Ch. 13.7.F) Tebbe Reagent Shapiro and Related Reaction β−Elimination and Dehydration From Diols and Epoxides From Acetylenes From Other Alkenes-Transition Metal Catalyzed Cross-Coupling and Olefin Metathesis

Aldol Condensation -Aldol condensation initially give β-hydroxy ketones which under certain conditions readily eliminated to give α,β-unsaturated carbonyls.
OMe LDA, THF, -78°C O O OMe OR O O CHO OMe OR O O OMe Tetrahedron 1984, 40, 4741

-78C → RT

Robinson Annulation : Sequential Michael addition/aldol condensation between a ketone enolate and an alkyl vinyl ketone (i.e. MVK) to give a cyclohex-2-en-1one JOC 1984, 49 , 3685 Synthesis 1976, 777.
O O O

O

L-proline

O Weiland-Mischeler Ketone (chiral starting material)

Mannich Reaction - α,β-unsaturated carbonyls (α-methylene carbonyls)
O H2C=O, Me2NH•HCl H 2C N + Me Me O Cl-

Mannich Reaction

C=C BOND FORMATION Wittig Reaction review: Chem. Rev. 1989, 89, 863. mechanism and stereochemistry: Topic in Stereochemistry 1994, 21, 1 - reaction of phosphonium ylide with aldehydes, ketones and lactols to give olefins
R X Ph3P R X O R1 R2 + Ph3P O R R R1 2
-

104

+ PPh3

strong base

_ R ylide

+ PPh3

R

PPh3

phosphorane - Ph3P=O R R1

Ph3P O R R R1 2

R2

betaine

oxaphosphetane

- Olefin Geometry
O L Ph3P L S O L Ph3P S L S E- Olefin S Z- olefin

- With "non-stabilized" ylides the Wittig Reaction gives predominantly Z-olefins. Seebach et al JACS
-

O S L

O O L S S L + PPh3 S L PPh3 + L S S L

+ PPh3

O L Ph3P L S S L L

O PPh3 - Ph3P=O S S S L S L

Z-olefins

- "Stabilized ylides" give predominantly E-olefins
O + Ph3P _ CO2Me L S L S CO2Me

C=C BOND FORMATION

105

- Betaine formation is reversible and the reaction becomes under thermodynamic control to give the most stable product. - There is NO evidence for a betaine intermediate. - Vedejs Model:
R O Ph Ph P H Ph H R

Cis

Pukered (cis) oxaphosphetane (kinetically favored)

H Ph Ph P Ph

R R H O

Trans

Planar (trans) oxaphosphetane (thermodynamically favored)

Phosphonate Modification (Horner-Wadsworth-Emmons)
R R X Arbazov Reaction (EtO)3P P(OEt)2 O R

_ P(OEt)2 O

- R is usually restricted to EWG such as CO2H, CO2Me, CN, SO2Ph etc. and the olefin geometry is usually E. - Still Modification TL 1983, 24, 4405.
(CF3CH2O)2P O CO2Me

- CF3CH2O- groups make the betaine less stable, giving more Z-olefin.
O Me3Si CHO (CF3CH2O)2P
+

CO2Me Me3Si CO2Me Z:E = 25:1

(Me3Si)2N K , THF, 18-C-6

JACS 1988, 110, 2248

Peterson Olefination

review: Synthesis 1984, 384
O LDA, THF Me3Si CO2Me R1

Organic Reactions 1990, 38 1.
-

O R2

Me3Si

CO2Me

R2

R1 Me3Si MeO2C H

_

Silicon can stabilize an α- negative charge O R1 Me3Si MeO2C H R2 - Me3Si-O R1 R2 CO2Me

usually a mixture of E and Z olefins

C=C BOND FORMATION Julia-Lythgoe Olefination
SO2Ph LDA, THF, -78°C R
TBSO CHO

106

TL 1973, 4833 Tetrahedron 1987, 43, 1027
OH PhO2S 1) MsCl, Et N OTBS 2) Na(Hg),3MeOH OTBS mixture of olefins R
Tetrahedron Lett. 1993, 34, 7479

TL 1991, 32, 495

R

O H O OBz O 1) tBuLi, THF, HMPA, -78°C 2) Na(Hg) NaHPO4 THF, MeOH, -40°C OSitBuPh2 HO O O OBz OSitBuPh2 O O O HO O

+
PhO2S HO

O OH

O OH

O OH Milbemycin α1

OR O O SO2Ph OTBDPS

SmI2, HMPA/THF R= H, Ac

O O

OTBDPS 75 % yield E:Z = 3 : 1

Synlett 1994, 859

Ramberg-Backlund Rearrangement
Br OSiPh2tBu OSiPh2tBu Br Cl O S O OR OR MeLi, THF O S O thiiarane dioxide OR OR - SO2 OR OR JACS 1992, 114, 7360 1) Na2S•Al2O3 2) mCPBA O S O OSiPh2tBu OSiPh2tBu SOCl2

Carbonyl Coupling Reactions (McMurry Reaction) Reviews: Chem. Rev. 1989, 89, 1513. - reductive coupling of carbonyls with low valent transition metals, Ti(0) or Ti(II), to give olefins
O "low-valent Ti" R1 R2 R1 R2 R1 R2 + R1 R2 R2 R1 usually a mixture of E and Z olefins

excellent method for the preparation of strained (highly substituted) olefins - Intramolecular coupling gives cyclic olefins

C=C BOND FORMATION

107

CHO "low-valent Ti" JACS 1984, 106, 723

CHO

OMe

OMe TiCl4, Zn, pyridine OMe (86 %) OH OH OMe Tetrahedron Lett. 1993, 34, 7005

OHC O

Tebbe Reagent Cp2Ti(CH2)ClAlMe2 - methylenation of ketones and lactones. The later gives cyclic enol ethers.
O O H2 C Ti AlMe2 Cp Cl Cp O 200 °C O

- Cp2TiMe2 will also do the methylenation chemistry JACS 1990, 112, 6393. Shapiro and Related Reactions Organic Reactions 1990, 39, 1 : 1976, 23, 405 - Reaction of a tosylhydrazone with a strong base to give an olefin.
NNHTs Et Me 2 eq. nBuLi THF Me Et _ Me N _ N Ts N N Et _ - N2 Et _ E+ E Et

Me

Me

Bamford-Stevens Reaction- initial conversion of a tosylhydrazone to a diazo intermediate
H R1 R2 R3 NNHTs base R1 R2 N N _ H R3 Ts R1 R2 +N _ N H R3

a: aprotic- decomposition of the diazo intermediate under aprotic conditions gives and olefin through a carbene intermediate.
H R1 R2 +N _ N R3 - N2 H R1 R2 R3 •• R2 R1 R3

b. protic- decomposition of the diazo intermediate under protic conditions an olefin through a carbonium ion intermediate.
H R1 R2 +N _ N R3 H+ R1 R2 + N N H R3 H - N2 H R1 R2 R3 + H -H
+

Carbene

R1 R2 R3

C=C BOND FORMATION

108

β- Eliminations Anti Eliminations - elimination of HX from vicinal saturated carbon centers to give a olefin, usually base promoted. - base promoted E2- type elimination proceeds through an anti-periplanar transition state.
B: R1 R3 X R4 H R2 R1 R3 R2 R4

- typical bases: NaOMe, tBuOK, DBU, DBN, DABCO, etc.
N N N N N DBN DBU DABCO N

- X: -Br, -I, -Cl, -OR, epoxides
O R O B: R O OH

R "unactivated"

O

R'

N AlEt2 - or TMS-OTf, DBU

R R'

OH

BCSJ 1979, 52, 1705 JACS 1979, 101, 2738

Syn Elimination - often an intramolecular process
H R1 R2 R3 R1 X R4 R3 R4 R2 X= O Se Ph O S Ph

Cope Elimination- elimination of R2NOH from an amine oxide
OLI + Me2N=CH2 I THF, -78°C O NMe2 mCPBA THF O ON Me2 O - Me2NOH

O 1) Me2CuLi + 2) Me2N=CH2 CF3CO2-

O

NMe2

JACS 1977, 99 , 944 Tetrahedron 1977, 35 , 613

C=C BOND FORMATION Selenoxide Elimination
O N SePh R R' OH Bu3P: O - or NO2 SeCN R R' SeAr O mCPBA H Se SeAr R R' - ArSeOH R R' JACS 1979, 101, 3704

109

Organic Reactions 1993, 44, 1.

H 3C H3CHN O

O H 3C N N

O Ph

PhSeO2H, PhH, 60 °C (82%)

H 3C H3CHN O

O H 3C N N

O Ph

JOC 1995, 60, 7224 JCS P1 1985, 1865

Dehydration of Alcohols - alcohols can be dehydrated with protic acid to give olefins via an E 1 mechanism. - other reactions dehydrate alcohols under milder conditions by first converting them into a better leaving group, i.e. POCl3/ pyridine, P2O5 Martin sulfurane; Ph2S[OCPh(CF3)2]2 JACS, 1972, 94, 4997 dehydration occurs under very mild, neutral conditions, usually gives the most stable olefin
OH

MSDA, CH2Cl2 JACS 1989, 111 , 278 H

BzO H

BzO

Burgess Reagent (inner salt) JOC, 1973, 38, 26 occurs vis a syn elimination
_ + MeO2CNSO2NEt3
H R1 R2 R3 R4 OH _ + MeO2CNSO2NEt3 PhH, reflux MeO2C - N SO2 H O R2 R4 R3

R1 R2

R4 R3

R1

Olefins from Vicinal Diols Corey-Winter Reaction
OH R' R OH

JACS 1963, 85, 2677; TL 1982, 1979; TL 1978, 737
S Im2C=S O R O R' R3P: R R'

C=C BOND FORMATION

110

- vic-diols can be converted to olefins with K2WCl6 JCSCC 1972, 370; JACS 1972, 94, 6538 - This reaction worked best with more highly substituted diols and give predominantly syn elimination. - Low valent titanium; McMurry carbonyl coupling is believed to go through the vic-diol. vic-diols are smoothly converted to the corresponding olefins under these conditions. JOC 1976, 41 , 896 Olefins from Epoxides
O R1 H H R2 + PPh2Me H Ph2P R1 HO H R2 MeI R1 HO H R2 H PPh2 H PPh2Me +

HO R2 R1 H

-Ph2MeP=O

R1 H

R2 H

"inversion " of R groups

O R1 H H R2

NC-Se R1

-

NCSe O H R2
-

Se H NCO R2 R1 R1 H H R2 "retention" of R groups H H

H SeCN R1 H R1 Se R2 H

O R2 H

NCO H R1 H Se

R2
-

From Acetylenes - Hydrogenation with Lindlar's catalyst gives cis-olefins
R R' Co2(CO)8 R R' Co2(CO)6 Bu3SnH H2, Rh R R'

Tetrahedron Lett. 1998, 39, 2609
H R SnBu3 R'

From Other Olefins Sigmatropic Rearrangements - transposition of double bonds Birch Reduction Tetrahedron 1989, 45, 1579
OMe OMe H3O+ O

C=C BOND FORMATION

111

Olefin Isomerization- a variety of transition metal (RhCl3•H2O) catalyst will isomerize doubles bonds to more thermodynamically favorable configurations (i.e. more substituted, trans, conjugated)
RhCl3•3H2O EtOH OH
Cl Ti Cl

JOC 1987, 52 , 2875 OH

+

JACS 1992 114 , 2276

up to 80% ee

Olefin Inversion Tetrahedron 1980, 557 - Conversion of cis to trans olefins - Conversion of trans to cis- olefins
R R' hν, PhSSPh R R'
OH CO2Me C5H11 OH OH I2, CH2Cl2 HO C5H11 OH JACS, 1984, 107, xxxx

OH CO2Me

Transition Metal Catralyzed Cross-Coupling Reactions Coupling of Vinyl Phosphonates and Triflates to Organometallic Reagents - vinyl phosphates review: Synthesis 1992, 333.
O R2CuLi R
O (EtO)2PCl O OP(OEt)2 O R2CuLi R O

OP(OEt)2 Li, NH3, tBuOH R

- preparation of enol triflates
O

Synthesis 1997, 735
OTf kinetic product

LDA, THF, -78°C Tf2NPh

O

Tf2O, CH2Cl2

OTf thermodynamic product

tBu

N

tBu

C=C BOND FORMATION - reaction with cuprates.
OTf

112

Acc. Chem. Res. 1988, 25, 47
Ph Ph2 CuLi tBu TL 1980, 21 , 4313

tBu

- palladium (0) catlyzed cross-coupling of vinyl or aryl halides or triflates with organostannanes (Stille Reaction) Angew. Chem. Int. Ed. Engl. 1986, 25, 508.; Organic Reactions 1997, 50, 1-652
O O O SnMe3 1)LDA, Tf2NPh 2) Pd(PPh3)4 O O JOC 1986, 51 , 3405

OH I Bu Sn 3 O HO TBSO HO (-)-Macrolactin A TBSO I O

OTBS

Bu3Sn I O OH OH

J. Am. Chem. Soc. 1998, 120, 3935

Bu3Sn

BOMe TESO CHO 1)
2

1) O3, Me 2S 2) allyl bromide, Zn 3) Dess-Martin Periodinane (70%)

TBSO

OH

1) HF, MeCN 2) Me4NBH(OAc)3 3) TBSCl, imidazole (76%)

MgBr 2) TESOTf, 2,6-lutidine (52%) TESO TESO O3, NaBH4 (77%) OPiv OH TESO

OTES

a) nBu3SnH, (Ph3P)2PdCl2 OH b) I2 (83% 1) Dess-Martin Periodinane 2) Ph3P+CH2I, INaHMDS 3) DIBAL (50%) I

TESO

OTES OH

I OPiv OH TBSO TBSO

Bu3Sn PdCl2(MeCN)2

TBSO TBSO

TESO CHO

Bu3SnCHBr2, CrCl2 (42%)

TESO SnBu3

I CO2H PdCl2(MeCN)2 (65%) I TESO

Bu3SnH, AIBN (38%) Bu3Sn

TESO

CO2H

CO2H

C=C BOND FORMATION
I TESO OH Bu3Sn CO2H TESO Bu3Sn

113

+

Ph3P, DEAD (50%)

TESO TESO OH

I O O

1) Pd2(dba)3 iPr2NEt 2) TBAF (35%) HO HO

O

O

TESO TESO

(-)-Macrolactin A

palladium (0) catalyzed carbonylations- coupling of a vinyl triflate with a organostanane to give α,b-unsaturated ketones.
O OTf Me3SnPh Pd(0), CO tBu Ph JACS 1994, 106 , 7500

But

Nickel (II) Catalyzed Cross-Coupling with Grignard Reagents (Kumada Reaction): Pure Appl. Chem. 1980, 52, 669 Bull Chem. Soc. Jpn. 1976, 49, 1958
X R-MgBr (dppp)NiCl2 R R= alkyl, vinyl or aryl

Aryl or vinyl halide or triflate

Br

AcO

OMe

Br

HO Ni

1)
N H OAc

Ni Br

OMe Tetrahedron Lett. 1998, 39, 2537, 2947, OH

(2 equiv), 65 °C 2) LiAlH4 , Et2 O (72%)
N H

(±)-Neocarazostatin B

Olefin Metathesis
R1

Tetrahedron 1998, 54, 4413, Acc. Chem. Res. 1995, 25, 446.
+
olefin metathesis R2 catalyst R1 R2

catalyst (CH 2)n (CH 2)n catalyst (CH 2)n (CH 2)n

Ring-Opening Metathesis Polymerization (ROMP)
n

Ring-Closing Metathesis (RCM)

C=C BOND FORMATION Metathesis Catalysts:
iPr H3C F3C F3C F3C F3C N O Mo O CH3 Ph iPr (C6H11)3P Cl Ru Cl (C6H11)3P Ph Ph (C6H11)3P Cl Ru Cl (C6H11)3P

114

Ph

Schrock' s Catalyst

Grubbs' Catalyst

Mechanism:
R1 R1 [M] R1 R2 R2

+

R2 [M] R1 [M]

+

[M]

C≡C BOND FORMATION C≡C Bond Formation 1. 2. 3. 4. 5. 6. From other acetylenes From carbonyls From olefins From Strained Rings Eschenmosher Fragmentation Allenes

115

From Other Acetylenes - The proton of terminal acetylenes is acidic (pKa= 25), thus they can be deprotonated to give acetylide anions which can undergo substitution reactions with alkyl halides, carbonyls, epoxides, etc. to give other acetylenes.
R R1-X R H R _ M+ O Et2AlCl R OH R1

O R2 R3 OH R R R2 3

- Since the acetylenic proton is acidic, it often needs to be protected as a trialkylsilyl derivative. It is conveniently deprotected with fluoride ion.
R H B:, R3SiCl FR SiR3 R H

Acetylide anions and organoboranes
R1 _ Li+ R3B _ R1 BR3 Li+ I2 R1 R JOC 1974, 39 , 731 JACS, 1973, 95 , 3080

Palladium Coupling Reactions:
O O O Cl iPr3Si SnBu3 Cl O JACS 1990, 112, 1607 iPr3Si SiiPr3

(Ph3P)4Pd

C≡C BOND FORMATION
OTBS OTBS CO2Me OTBS Br C5H11 OTBS Pd(Ph3P)4, CuI iPr2NH, PhH OTBS CO2Me

116

TBSO

C5H11

JACS 1985, 107, 7515

OH HO CO2H OH

Copper Coupling- 1,3-diynes
R1

+

R2

Cu(OAc)2

R1

R1

Adv. Org. Chem. 1963,4 , 63

Nicholas Reaction - acetylenes as their Co2(CO)8 complex can stabilize an α-positive charge, which can subsequently be trapped with nucleophiles.
OR4 R1 R3 Nu: R2 (CO)6Co2 R1 Nu R3
CO2Me

Co2(CO)8

(CO)6Co2 R1

OR4 R3 R2

(CO)6Co2 R1

+ R R3 2

oxidative decomplexation R2

Nu R1 R2 R3

N

Tf2O, CH2Cl2, MeNO2, -10°C O tBu N tBu (OC)6Co2

N

CO2Me I2 O

N

CO2Me JCSCC 1991, 544

TBSO HO Co2(CO)6

Co2(CO)6-acetylene deocomplexation: JOC 1997, 62, 9380 From Aldehydes and Ketones
R'-X RCHO P3P, CBr4 R Br Br 2 eq. nBuLi R _ Li+ ClCO2Et H2O R H R R'

R

CO2Et

C≡C BOND FORMATION
Br2C OHC OHC OSitBuPh2 OSitBuPh2 CBr4, Ph3P Br2C a) nBuLi, THF, -78°C b) ClCO2Me MeO2C MeO2C

117

OSitBuPh2 OSitBuPh2

OSitBuPh2 OSitBuPh2 JACS 1992, 114 , 7360

- by conversion of ketones to gem-dihalides followed by elimination
O R R' PCl5 Cl R Cl R' tBuOK - HCl R Cl R' tBuOK - HCl

R

R'

- by conversion of ketones to enol phosphates followed by elimination
O R R' R LDA, (EtO)2P(O)Cl O P(O)(OEt)2 LiNH , NH 2 3 R' R R' JOC 1987, 52 , 4885

- Insertion reaction of a vinyl carbene (terminal acetylenes)
N2 O R R' N2CHP(O)(OMe)2 tBuOK R C R' -N2 + C

••
R R' R'

JOC 1982, 47 , 1837

R

O Me3Si _ N2 Synlett 1994, 107

THF, -78°C → RT

Via Elimination Reactions of Vinyl Halides - Treatment of vinyl halides with strong base gives acetylenes.
X R H X= Cl, Br, I, OTf, O3SR, OP(O)R2 R' Base - HX Base= LDA; tBuOK; NaNH2, DBU R R'

- Addition of Grignard reagents to 1,1-difluoroethylene yields an acetylide anion which can be subsequently trapped with electrophiles.
R-MgX H2C=CF2 R _ E+ R E TL 1982, 23 , 4325 JOC 1976, 41 , 1487

Strained Rings Topics in Current Chemistry 1983, 109, 189. - Cyclopropenones and cyclobutendiones can be photolyzed or thermolyzed (FVP) to give acetylenes.
O O hν (209 nm) 8 °K C C O Benzyne - CO O - CO JACS 1973, 95 , 6134

O

C≡C BOND FORMATION
1) 370 °C 2) 12°K - CO

118

O

ACIEE 1988,27 , 398 JACS 1991, 113 , 6943

R1 R2 FVP (retro- D-A) +

R1

R2

CL 1982, 1241

Eschenmoser Fragmentation
Ph N N R R' R O R'

O

Ph

Base -orheat

R O R' HCA 1972, 55 , 1276

O

O tBuOOH, triton B, C6H6 O

HN NH2 iPr iPr O iPr AcOH, CH2Cl2 JOC 1992, 57, 7052

Allenes Tetrahedron 1984, 40, 2805 - from dihalocyclopropanes
R R' Br Br R R' _ Br R H R R' H

••

R'

- From SN2' Reactions
Nu: R R' R R' X Nu H

- from sigmatropic rearrangements from propargyl sulfoxides and phosphine oxides.
Ph OH R R' R R' Ph2PCl, Et3N :P O Ph O Ph2P R R' H TL 1990, 31 , 2907 JACS 1990, 112 , 7825

FUNCTIONAL GROUP INTERCONVERSIONS Functional Group Interconversions C&S Chapter 3 #1; 2; 4a,b, e; 5a, b, d; 6a,b,c,d; 8 1 2 3 4 5 6 7 sulfonates halides nitriles azides amines esters and lactones amides and lactams

119

Sulfonate Esters - reaction of an alcohols (1° or 2°) with a sulfonyl chloride
R OH R'SO2Cl O R O S O sulfonate ester R' CF3 CH3 triflate tosylate R'= CH3 mesylate

- sulfonate esters are very good leaving groups. competing side reaction

Elimination is often a

Halides - halides are good leaving groups with the order of reactivity in SN2 reactions being I>Br>Cl. Halides are less reactive than sulfonate esters, however elimination as a competing side reaction is also reduced. - sulfonate esters can be converted to halides with the sodium halide in acetone at reflux. Chlorides are also converted to either bromides or iodides in the same fashion (Finkelstein Reaction).
O R O S O
NaI, acetone reflux

R'

X-

R X

X= Cl, Br, I

R Cl

R

I

- conversion of hydroxyl groups to halides:
R OH

Organic Reactions 1983, 29, 1
R X

- R-OH to R-Cl - SOCl2 - Ph3P, CCl4 - Ph3P, Cl2 - Ph3P, Cl3CCOCCl3

FUNCTIONAL GROUP INTERCONVERSIONS

120

- R-OH to R-Br - PBr3, pyridine - Ph3P, CBr4 - Ph3P, Br2 - R-OH to R-I - Ph3P, DEAD, MeI Nitriles - displacement of halides or sulfonates with cyanide anion
R X KCN, 18-C-6 DMSO R C N

- dehydration of amides
O R NH2 R C N

-

POCl3, pyridine TsCl, pyridine P2O5 SOCl2

- Reaction of esters and lactones with dimethylaluminium amide TL 1979, 4907
Me Me2AlNH2 O O Ar H 3C NC Ar OH JOC 1987, 52, 1309

- Dehydration of oximes
R CHO H2NOH•HCl R N OH P2O5 H R C N

- Oxidation of hydrazones
O O N NMe2 (97%) C N Tetrahedron Lett. 1998, 39, 2009

- Reduced to aldehydes with DIBAL. DIBAL

RC≡N

RCHO

FUNCTIONAL GROUP INTERCONVERSIONS Azides - displacement of halides and sulfonates with azide anion
O O SO2N(C6H11)2 O O SO2N(C6H11)2 NH2 HO NH2 LDA, THF NBS O SO2N(C6H11)2 Br O NaN3 O SO2N(C6H11)2 N3 O TL 1986, 27, 831 O

121

- activation of the alcohol
R OH + + N Me TsO Ph3P, NaN3 EtO2C

F

+ N Me

R N3 OR

+ N Me O

+ PPh3 N N _ CO2Et

R OH

+

EtO2C N N CO2Et DEAD + R O PPh3

activated alcohol R-OH R N3 + Ph3P=O
N3 SN2 + DBU-H
+

JOC 1993, 58, 5886
HO (PhO)2P(O)-N3 O DBU, PhCH3 (99.6 % ee) Ar O O P(OPh)2 + N3
-

(91 %)

O (97.5 % ee)

- Photolyzed to aldehydes Amines - Gabriel Synthesis
O N - K+ O R X O N R O H2NNH2 R NH2

- reduction of nitro groups R NO2 H2, Pd/C Al(Hg), H2O NaBH4 LiAlH 4 Zn, Sn or Fe and HCl H2NNH2 sodium dithionite

R NH2

FUNCTIONAL GROUP INTERCONVERSIONS - reduction of nitriles R C N H2, PtO 2/C B2H6 NaBH4 LiAlH 4 AlH3 Li, NH3 - reduction of azides R N3 H2, Pd/C B2H6 NaBH4 LiAlH 4 Zn, HCl (RO)3P Ph3P thiols
OH NH2 R' R R'

122

R CH2 NH2

R NH2

- reduction of oximes (from aldehydes and ketones)
N R

H2, Pd/C Raney nickel NaBH4, TiCl4 LiAlH 4 Na(Hg), AcOH - reduction of amides
O R N R'' R' R N R'' R'

H2, Pd/C B2H6 NaBH4, TiCl4 LiBH4 LiAlH 4 AlH3 - Curtius rearrangement
O NaN3 R Cl R O
•• •• N N N +

∆ - N2 R NH2 R

O
•• N

••

••

nitrene

R N O isocyanate

H2O

FUNCTIONAL GROUP INTERCONVERSIONS - reductive aminations of aldehydes and ketones - Borsch Reaction - Eschweiler-Clark Reaction - alkylation of sulfonamides
Tf N N HN HN Tf Tf Br Br Tf K2CO3, DMF 110°C Tf N N N N Tf Na, NH3 Tf NH HN NH HN cyclam

123

TL 1992, 33 , 5505

Tf

- transaminiation
O PhCH2NH2 H+ N Ph tBuOK N Ph H3O + NH2

Can. J. Chem. 1970, 48, 570

Esters and Lactones - Reaction of alcohols with "activated acids" - Baeyer-Villigar Reaction Organic Reactions 1993, 43, 251 - Pd(0) catalyzed carboylation of enol triflates
OTf CO, DMF Pd(0), ROH CO2R TL 1985, 26 , 1109

- Arndt-Eistert Reaction
O R Cl CH2 N2 Et2 O R

Angew. Chem. Int. Ed. Engl. 1975, 15, 32.
O R diazo ketone C O H ketene N2 hν ROH R O

•• CH
O

Wolff Rearrangement

R'OH

R

OR'

O R CO2Me

TsN3, Et3N R

O N2

- Diazoalkanes: carbene precursors
R-CHO 1) NH2NH2 2) Pb(OAc)4, DMF R3N
H 2N R N R

R-N2
TsN3 R

JOC 1995, 60, 4725
N2 R

- Halo Lactonizations
CO2H

review: Tetrahedron 1990, 46 , 3321
+ I2-KI H2O, NaHCO3 O H O O I I O

FUNCTIONAL GROUP INTERCONVERSIONS
Pd(OAc)2 (5 mol %) CO2H DMSO, air (86%) O O

124

JOC 1993, 58, 5298

- Selenolactonization
PhSe O OH PhSeCl, CH2Cl2 O O H 2O 2 O O JACS 1985, 107 , 1148

- Mitsunobu Reaction

Synthesis 1981 , 1; Organic Reactions, 1991, 42, 335 Mechanism: JACS 1988, 110 , 6487
O DEAD, Ph3P R''CO2H R O R' R'' Inversion of alcohol stereochemistry

OH R R'

Amides and Lactams - reaction of an "activated acid" with amines - Beckman Rearrangement Organic Reactions 1988, 35, 1
O R R' R
O R R'

N

OH R'

PCl5 R
O R NR'

O NR'

- Schmidt rearrangement
HN3 H+

- others
O OTf CO, DMF Pd(0), R2NH NR2 TL 1985, 26 , 1109

O O PhCH2NH2 AlMe3 OTHP

OH O N H OTHP Ph TL 1977, 4171

-Weinreb amide Tetrahedron Lett. 1981, 22, 3815
DIBAL O R OR' H3CNH(OCH3) •HCl AlMe3 R O N OCH3 O R1-M R R1 R CH3 O H

THREE-MEMBERED RING FORMATION 3 Membered Rings 1. epoxides a. peracids, hydroperoxides and dioxiranes b. transition metal catalyzed epoxidations c. halohydrins d. Darzen's condensation e. sulfur ylides cyclopropanes a. Simmons-Smith reactions b. diazo compounds c. sulfur ylides d. S N2 displacements aziridines a. nitrenes b. SN2 displacements

125

2.

3.

Epoxides - peracid, hydroperoxide and dioxirane oxidation of alkenes - transition metal catalyzed epoxidation of alkenes - Sharpless epoxidation - Metal oxo reagents (Jacobsen's reagent) - from halohydrins
NBS, H2O Br base OH bromohydrin O

- Darzen's Condensation
O B: BrCH2CO2Et _ BrCHCO2Et R R' R R' Br OCO2Et O R R' CO2Et

- sulfur ylides Chem. Rev. 1997,97, 2421.
O Me S + CH2Me Corey O + Me2SCH2Ph S CH2NMe2 Johnson sulfoximine Trost + _ SPh2

THREE-MEMBERED RING FORMATION

126

- dimethylsulfoxonium methylide and dimethylsulfonium methylide (Corey's reagent) review: Tetrahedron 1987, 43 , 2609.
O R R' O DMSO, NaH
-

O R'

SMe2

O R R'

R

- cyclopropyldiphenylsulfonium ylide (Trost's reagent) ACR 1974, 7, 85.
O R R'
_

SPh2

+

O
-

O R'

SPh2

O R R'

BF3 R

R'

R

- sulfoximine ylides (Johnson's reagent)
O R R' O Ph S CH2NMe2 O R R'

ACR 1973, 6 , 341

Cyclopropanes - Simmons-Smith Reaction
ZnCu + CH2I2

Org. Reactions 1973, 20, 1.
ICH2ZnI

- polar groups (-OH, -NR2- CO2R) can direct the cyclopropanation
OH ZnCu, CH2I2 OH JACS 1979, 101 , 2139

- sulfur ylides
O O Me2S CH2O Tetrahedron 1987, 43 , 2609

Ph O

Ph

O _ Ph S NMe2

Ph O

Ph

ACR 1973, 6 , 341

THREE-MEMBERED RING FORMATION

127

- diazo alkanes and diazo carbonyls Synthesis 1972, 351; 1985, 569 - cyclopropanation with diazoalkanes; olefin requires at least on electron withdrawing group.
CO2Me MeO2C (MeO)2HC CH2N2 MeO2C (MeO)2HC N N CO2Me hν MeO2C (MeO)2HC CO2Me JACS 1975, 97 , 6075

- diazoketones; photochemical or metal catalyzed decomposition of diazoketones to carbenes followed by cyclopropanation of olefins. Org. Rxns. 1979, 26, 361; Tetrahedron 1981, 37, 2407
N2 CuSO4 , ∆ JACS 1970, 92 , 3429 JACS 1969, 91 , 4318 O

O

O Ph N2 O O O

Rh2(OAc)2 Ph Ph Ph

O O O O 91 % yield 89 % de JACS 1993, 115, 9468

Asymmetric cyclopropanation: Doyle, Chem Rev. 1998, 98, 911 Aldrichimica Acta 1997, 30, 107
O CO2Et TsN3 , Et3N N2 C5H11 O O CO2Et
- SPh

O CO2Et

C5H11 JACS 1977, 99, 1940 C5H11 SPh

CO2Et

C5H11

- SN2 Reactions
O O Br CO2Et O DBU O CO2Et O O JACS 1978, 99 , 1940

- Electrophillic Cyclopropanes review: ACR 1979, 12 , 66 in many ways, cyclopropanes react silmilarly to double bonds - homo-1,4-addition
CO2R Nu: CO2R Nu CO2R CO2R ACR 1979,12 , 66

THREE-MEMBERED RING FORMATION Nu:= malonate anion, amines, thiolate anion, enamines, cuprates (usually requires double activation of cyclopropane)
H MeO2C O Me2CuLi MeO2C O TL 1976, 3875 Me

128

- hydrogenation
CO2Me CH2I2, Zn-Cu H O H2, PtO2, AcOH H CO2Me TL 1982, 23 , 1871 CO2Me ArCO3H, Na2HPO4 H O CO2Me

H

- hydrolysis
OH CH2I2, Zn-Cu OH H , MeOH
+

OH JACS 1967 89 , 2507

OMe

MeO

O

Aziridines
R2 R1 R3 Cu(acac)2 PhN=ITs R2 R1 Ts N R3 J. Org. Chem. .1991, 56, 6744

FOUR-MEMBERED RING FORMATION 4 Membered Rings 1. 2. cyclobutanes & cyclobutenes oxatanes

129

Cyclobutanes - [2+2] cycloadditions - photochemical cycloadditions (2πs +2πs) Acc. Chem. Res. 1968, 1, 50; Synthesis 1970, 287; Acc. Chem. Res. 1971, 4, 41; Organic Photochemistry 1981, 5, 123; Angew. Chem. Int. Ed. Engl. 1982, 21, 820; Acc. Chem. Res. 1982, 15, 135; Organic Photochemistry 1989, 10, 1 Organic Reactions 1993, 44, 297 - for synthetic purposes, cyclic α,β-unsaturated carbonyl are the most useful.
E
1

E*

intersystem crossing

3

E*
* O

- symmetry requirements
2πs + 2πs
HOMO LUMO O hν ~ 340 nm

- enones with olefins
O + CH2 CH2 (90%)
O hν + O + H Caryophellene O H E.J. Corey JACS 1963, 85 , 362

O hν +

O

O +

O JCSCC 1966, 423 O

Hot Ground State?
O hν O

Base

O H2C=CH2 2πs + 2πa thermal cyclization

H isomerization H cis ring-fusion

CH3 N H O

H2C=CH2 hν, CH2Cl2 CH3 Ph O CH3 H

CH3 N CH3 O JACS 1986, 108 , 306 CH3 grandisol

HO

FOUR-MEMBERED RING FORMATION
O O H + hν H 2:1 H

130

O

H JACS 1984 106 , 4038

- enones with acetylenes
O O hν O O O JACS 1982 104, 5070

- DeMayo Reaction
O O hν, pyrex O O H O O pTSA, MeOH reflux H O CO2Me JACS 1986, 108 , 6425

O O O

R

hν O

O

R R H 70-80 % de
O hν O H H

O

MeO2C
O O H 3C O CH3 H O O CH3 H H TL 1993, 34, 1425 O H 3C H H

O
favored O

H

H

O O H 3C O CH3

controls conformation O O CH3 controls addition

H 3C

disfavored O H 3C

- Photochemistry of Ketones (Norrish Type I and II reactions)
H O hν 254, 307 nm Norrish II cleavage HO Yang reaction OH • • OH + O• • H Norrish I cleavage O • •

FOUR-MEMBERED RING FORMATION - filtering photchemical reaction to prevent Norrish reactions quartz 180 nm Vycor 200 nm Pyrex 280 nm Uranium glass 320 nm - Yang Reaction
MOMO O hν (254 nm) C6H6 SEMO CH3 SEMO CH3 OH JACS 1987, 109 , 3017 MOMO

131

- thermal cycloadditons (2πa + 2πs) - symmetry requirements
2πa + 2πs O HOMO

LUMO

- ketenes
O O O Cl H O Cl Cl O R N2 hν R O H Zn O Et3N O ∆ H O H

- thermal cyclization of ketene with olefins Tetrahedron 1986, 42, 2587; 1981, 37, 2949; Organic Reactions 1994, 45, 159.
LUMO of ketene 2πa py O HOMO of olefin 2πs

pz

FOUR-MEMBERED RING FORMATION
O Ph O CH3 CH3 Cl CCl3 Cl O Zn-Cu, Et2O Ph CH3 CH3 CH2N2 Cl O Cl Cl R*O Ar

132

O

CH3

JACS 1987, 109 , 4753

H 3C N+ H 3C OMe

1) 2) H2O

O H 3C H 3C N+

H JACS 1982, 104, 2920 H

OMe

-reaction of ketene with enamines
H NR2 H O O NR2

O R' NR2

O R'

- reaction of ketene with imines to give β-lactams (Staudinger Reaction)
R H N O H NR O

O O N Ph O R + N H Bn

CH2Cl2 -78°C → 0°C

O N Ph

O H

R O N

O N Ph O

O R NBn

H

Bn

(90-96 % de)

- reaction of difluorodihaloethylene with olefins Organic Reactions 1962, 12, 1
F2C=CX2 R F X= F, Cl R F X X

- reaction of difluorodihaloethylene with acetylenes- biradical mechanism
F2C=CX2 R X= F, Cl F R F X X R hydrolysis O O

FOUR-MEMBERED RING FORMATION - SN2 Reaction
O KH, DMSO O JACS 1980, 102 , 1404

133

OTs
CN OR HO OR OH

O

_

CN

JACS 1974, 96, 5268, 5272

Grandisol

- acyloin reaction
CO2Me (CH2)n CO2Me

Organic Reactions 1976, 23, 259
Na, TMS-Cl (CH2)n OTMS OTMS F(CH2)n OH O

R R

CO2Me CO2Me

R R

O

OH

- benzocyclobutanes

ACIEE 1984, 23, 539; Synthesis 1978, 793
O O O O O

benzocyclobutane

o-quinodimethane

O

- cyclotrimerization of 1,5-diyenes with an acetylenes
SiMe3 SiMe3 Me3Si Me3Si

CpCo(CO)2

- sulfur ylides
+

O R R'

_

SPh2

O O R R' BF3 R' R

Oxatanes Organic Photochemistry 1981, 5, 1 - [2+2] cycloaddition (Paterno-Buchi Reaction)
O R
O R R'

hν R'

O R R'

hν (254 nm)

O R R'

FOUR-MEMBERED RING FORMATION

134

O

O O

hν Me2C CMe2 O

O O

TL 1975 1001

- SN2 reaction
OH SiMe3 Br OH CO2Me HO C5H11 OTBS
OH Br CO2Me HO O C5H11 OH (MeO)3P, DEAD Br O O C5H11 OH CO2Me JACS 1984, 107 , 6372

NBS

O SiMe3

JCSCC 1979, 421

Tf2O, CH2Cl2

O C5H11 OH

CO2Me

TL 1980,21 , 445

- sulfur ylides
O O H2C S Me _ NTs O
-

O NTs S CH3

O

JACS 1979, 101 , 6135

β-Lactones
R2 R1 H O LDA, THF SPh R3
OH N H CO2H

OR4 R3

O O SPh

O JOC 1991, 56 , 1176 R3 R4 R1

O R4

R2 R1

R2

O BnO

DEAD, Ph3P BnO

O N H

O O

R2CuLi

R BnO O

CO2H NH

JACS 1987, 109 , 4649

O OBn O + H SiMe3 H

1) MgBr2•OEt2 2) KF, H2O, CH3CN

OBn

O

O 96 % de

TL 1995, 36, 4159

BALDWIN'S RULES FOR RING CLOSURE Baldwin's Rules (Suggestions) for Ring Closure JOC 1977, 42 , 3846 JCSCC 1976, 734, 736, 738

135

Approach Vector Analysis - for an SN2 displacement at a tetrahedral center, the approach vector of the entering nucleophile is 180° from the departing leaving group
Nu: L Nu L Nu :L

- for the addition of a nucleophile to an Sp2 center, the nucleophile approaches perpendicular to the π-system.
Nu Nu

Nomenclature 1. indicate ring size being formed 3 membered ring = 3 4 membered ring = 4 etc. 2. indicate geometry of electrophilic atom if Y= Sp3 center; then Tet (tetrahedral) if Y= Sp2 center; then Trig (trigonal) if Y= Sp center; then Dig (digonal)
Z Y

X:

3. indicate where displaced electrons end up - if the displaced electron pair ends up out side the ring being formed; then Exo - if the displaced electron pair ends up within the ring being formed; then Endo
Z Y Z

Y

X: Exo

X: Endo

BALDWIN'S RULES FOR RING CLOSURE 136 4. Ring forming reaction is designated as Favored or Disfavored disfavored does not imply the reaction can't or won't occur- it only means the reaction is more difficult than favored reactions. Rules (Suggestions) for Ring Closure - All Exo-Tet reactions are favored

X:

Y

Z

X: Y

Z

X:

Y Z 5-

X: Y Z 6-

X: Y Z 7-

3-

4-

- - - - - - - - - - - - - - - - - - - - - - - - --Favored- - - - - - - - - - - - - - - - - - - - - - - - -

- 5-Endo-Tet and 6-Endo-Tet are disfavored
Z X: 5Y X: 6Z Y

- - - - -Disfavored- - - - -

- All Exo-Trig reactions are favored

X:

Y

Z

X: Y

Z

X:

Y Z 5-

X: Y Z 6-

X: Y Z 7-

3-

4-

- - - - - - - - - - - - - - - - - - - - - - - - --Favored- - - - - - - - - - - - - - - - - - - - - - - - -

- 3-Endo-Trig, 4-Endo-Trig and 5-Endo-Trig are disfavored; 6-Endo-Trig, 7Endo-Trig, etc. are favored
Z X: 5Z X: Y X: Y Z

Z X: 3Y 4-

Z X: Y

Y

- - - - - - - - - - - - -Disfavored- - - - - - - - - - - -

76- - - - - -Favored- - - - - -

BALDWIN'S RULES FOR RING CLOSURE 137 - 3-Exo-Dig and 4-Exo-Dig are disfavored; 5-Exo-Dig, 6-Exo-Dig, 7-Exo-Dig, etc. are favored

X:

Y Z 3-

X:

Y Z 4-

X:

Y Z 5-

X: Y Z 6-

X: Y Z 7-

- - - - - -Disfavored- - - - - -

- - - - - - - - - - - - -Favored- - - - - - - - - - - -

- All Endo-Dig are favored
Z Z X: 3Y X: 4Z Y X: 5Y X: 6Z Y X: Y 7Z

- - - - - - - - - - - - - - - - - - - - - - - - - - --Favored- - - - - - - - - - - - - - - - - - - - - - - - - - - - -

EXCEPTION: There are many !!!

(see March p 212-214)

FIVE-MEMBERED RING FORMATION 5 Membered Rings
HO CO2H O CO2H

138

HO

OH PGF2α Me H

HO

OH PGE2

Me Me Me Me Me Isocumene

Me Me Hirsutene Modhephane

1. 2. 3. 4.

5. 6. 7. 8. 9.

Intramolecular SN2 Reactions Intramolecular Aldol Condensation and Michael Addition Intramolecular Wittig Olefination Ring Expansion and Contraction Reactions a. 3 → 5 b. 4 → 5 c. 6 → 5 1,3-Dipolar additions Nazarov Cyclization Arene-Olefin Photocyclization Radical Cyclizations Others Synthesis 1973, 397; ACIEE 1982, 21 , 480;

Intramolecular SN2 Reaction
O

5-exo-tet: favored
LDA O JCSCC 1973, 233

Br

O CO2Me

O CO2Me

O

Br
CN

CN O

OH JACS 1974, 96 , 5268

FIVE-MEMBERED RING FORMATION
O O RO2C CO2R
O NaH, DMSO

139

Cl JACS 1979, 101 , 5081 CO2R

Cl
O

RO2C

JCSCC 1979, 817

TsO

Intramolecular Aldol Condensation 5-exo-trig: favored intramolecular aldol condensation of 1,4-diketones
O R O R' R'
O CH3 O CH3 CH3

O R

O CH3 TL 1982, 29, 2237

Br

Br

O O CO2Me

NaOMe, MeOH O CO2Me

JACS 1980, 102 , 4262

O NaOH O O

O O JOC 1983, 48 , 1217

Intramolecular Michael Addition 5-exo-tet: favored Organic Reactions 1995, 47, 315-552
O O MeO2C O O JACS 1979, 101 , 7107

Intramolecular Wittig Olefination
O O 2) Collins C5H11 OTHP O base C5H11 OTHP

FIVE-MEMBERED RING FORMATION Tetrahedron 1980, 36, 1717
O O O P(OMe)2

140

1) (MeO) 2P(O)CH2 -

THPO

THPO

C5H11 OTHP CO2H JOC 1981, 46 , 1954

THPO

HO

C5H11 OH

Ring Expansion Reactions - 3 → 5: Vinyl Cyclopropane Rearrangement
O _ SPh2 O

Organic Reactions 1985, 33, 247.
OTMS

O O

H

O O TMSO

H

O O

H

JACS 1979, 101 , 1328 O O H

- 4 → 5: Reaction of cyclobutanones with Diazomethane
Cl Me O O Me Cl Cl Cl Cl Me CH2N2 O Me TL 1980, 21 , 3059 CH2N2 Me Cl O Me

Cl Cl

O CH3 CH2N2 Cl

O Cl CH3 O Ph CH3 JACS 1987,109 , 4752

O Ph

CH3

FIVE-MEMBERED RING FORMATION Ring Contraction Reactions - 6 → 5: Favorskii Reaction
O Cl _ O

141

Organic Reactions 1960, 11 , 261
_

OH

-

O OH CO2H

1,3-Dipolar Addition to Olefins 1,3-Dipolar Cycloaddition Chemistry , vol 1 & 2 (A. Padwa ed.) (Wiley, NY 1984); ACIEE 1977, 16 , 10. Chem Rev. 1998, 98, 863.
+ _ b c a 1,3-Dipole (4π) LUMO

4πs + 2πs

Alkene (2π) HOMO

- trimethylenemethane (TMM)
high temperature

ACIEE 1986, 25 , 1. Synlett 1992, 107.
• • TMM

CO2Me ∆, MeCN N N -N2

MeO2C •

MeO2C H • •

CO2Me CH3

H JACS 1981, 103 , 2744

note: TMM usually reacts poorly w/ electron defficient olefins
_ Pd(0) Me3Si OAc + PdLn

O O Me3Si Pd(0), 80°C OAc

H

O O TL 1986, 27 , 4137

MeO2C

CO2Me

Ni(COD)2, 35 °C CO2Me CO2Me

ACIEE 1985, 24 , 316 TL 1983, 24 , 5847

- α,α'-dihaloketones
O O Fe(CO)9 + Br Br Ar OFeLn Ar ACR 1979, 12 , 61

- nitrones

FIVE-MEMBERED RING FORMATION ACR 1979, 12 , 396; Organic Reactions, 1988, 36 , 1
OR1
+N

142

O R2 R1 N R2 R3

R3 Nitrone

O
-

JACS 1964, 86 , 3756 N

O

N

Me O MeNHOH, EtONa H

N

O Me

1) MeI 2) H2, Pd/C

Me2N

OH Me JOC 1984, 49 , 5021

H

H

H

H

MeO2C

NH

Bn N O-

MeO2C

NH

Bn N O JACS 1983, 104 , 6460

S

C 4H 9

S C 4H 9

- nitrile oxides
O O N ArNCO
+ O N

N O

H2

O

OH JACS 1992, 104 , 4023 CO2Et

CO2Et
O N O O Bu 2BOTf, iPr 2EtN, CH2 Cl2, -78°C O Ph OTHP NaOCl, H2 O, CH2 Cl2 N OH OTHP 1) TBS-Cl, DMF, imidazole 2) nBuLi, THF Bu3Sn (80%) O O TBSO O OH (88%) H (99%)

CO2Et

CO2Et
1) DHP, PPTS CH2 Cl2, ↑↓ 2) LAH (60%) Ph + _ N O OTHP

OH

O N

O O

OTHP

1) Swern 2) NH2OH•HCl AcONa, MeOH OH (89%)

CH3

OTHP H2, Raney Ni, H2 O, MeOH, B(OMe)3 (88%) O OH O Cassiol TL 1996, 37, 9292

THPO

N O 1) PPTS, EtOH, ↑↓ 2) (CH3 )2C(OMe)2 , PPTS 3) Swern (48%) O TBSO O O

HF•pyridine, CH3 CN, pyridine (73%) O HO

OH OH

FIVE-MEMBERED RING FORMATION
OTBS OTBS LAH OTBS TL 1993, 34, 3017

143

N + O _

O N

OH

NH2

Arene -Olefin Photocyclization Organic Photochemistry 1989, 10 , 357 - the photochemistry of benzene is dominated by the singlet state
1 hν *

*

*

OAc OAc

*
O Me2CuLi Me O JACS 1982, 104 , 5805 JCSCC, 1986 247

* *
hν + +

1) FVP 2) H2, Pd/C

isocume

* *
Tetrahedron 1981,37 , 4445

hν OMe

*
OMe

*
JACS 1981, 103 , 688 OMe cedrane

AcO

AcO

*

*

HO H+

H TL 1982, 23 , 3983 TL 1983, 24 , 5325

FIVE-MEMBERED RING FORMATION Intramolecular Photochemical [2+2] "Rule of Five"
O hν O O hν O O O JOC 1975, 40 , 2702 JOC 1979, 44 , 1380 O

144

O

Nazarov Cyclization review: Synthesis 1983, 429 - cyclization of allyl vinyl or divinyl ketones
O H3PO4/HCO2H

Organic Reaction 1994, 45, 1
O

O H3PO4/HCO2H

O

- 1,4-hydroxy-acetylenes
H2SO4, MeOH OH H OH O H OH JOC 1989, 54 , 3449

HO

- Silicon-Directed Nazarov
O FeCl3 SiMe3 Me Me O Tetreahedron 1986, 42 , 2821

- Tin -directed Nazarov

TL 1986, 27 , 5947

Radical Cyclization B. Giese Radicals in Organic Synthesis: Formation of Carbon-Carbon Bonds (Pergamon Press; NY) 1986; Bull. Soc. Chim. Fr. 1990, 127 , 675; Tetrahedron 1981, 37 , 3073; Tetrahedron 1987, 43, 3541; Advances in Free Radical Chemistry 1990, 1, 121. Organic Reactions 1996, 48, 301-856. Radical Addition to multiple bonds: 1. Free radical addition is a two stage process involving an addition step followed by an atom transfer step. 2. In general, the preferred regioselectivity of the addition is in a manor to give the most stable radical (thermodynamic control)

FIVE-MEMBERED RING FORMATION Advantages of free radical reactions: 1. non-polar, little or no solvent effect 2. highly reactive- good for hindered or strained sysntems 3. insensitive to acidic protons in the substrates (i.e. hydroxyl groups do not necessarily need to be protected Mechanism of radical chain reactions 1. initiation 2. propagation 3. termination (bad) Formation of carbon centered radicals: tin hydride reduction of alkyl, vinyl and aryl halides, alcohol derivatives: xanthates, thionocarbonate, thiocarbonylimidazolides organosselenium & boron compounds carboxylic acid derivatives (Barton esters) reduction of organomercurials thermolysis of organolead compounds thermolysis or photolysis of azoalkanes. Radical Ring Closure For irreversible ring closure reaction, the kinetic product will predominate. Both the 5-exo-trig and 6-endo trip are favored reactions, with the 6 exo-trig mode producing the most stable radical. However, the 5-exo-trig is about 50 time faster
• k1,5 • k1,6 •

145

kinetically favored

thermodynamically favored

• •

+
100 : 0 • •

3-exo-trig vs 4-endo-trig 4-exo-trig vs 5-endo-trig 5-exo-trig vs 6-endo-trig

+
• 100 : 0

+
98:2 •

+
85:15 • • •

6-exo-trig vs 7-endo-trig 7-exo-trig vs 8-endo-trig

+
100 : 0

FIVE-MEMBERED RING FORMATION
• and • radicals open up fast and are not synthetically useful; often used as probes for radical reaction

146

Effects of substituent on the regiochemistry of the 5-hexenyl radical cyclization
• • •

+
48:1 • •

+
>200:1 •

+
2:3 •

+
< 1:100

Stereochemistry of 5-hexenyl radical cyclization 1-, or 3-substitued 5-hexenyl radicals give cis disubstituted cyclopentanes 2-, or 4-substituted 5-hexenyl radicals give trans disubstitued cyclopentanes
2 Br R Bu3SnH • H R H R + 65 : 35 prefered transition state R • 3 Br H H H 4 Br R R 1 Br • H Bu3SnH R R + 83 : 17 R R R + 75 : 25 R R

R • H R

+ 73 : 27 R

FIVE-MEMBERED RING FORMATION
Br nBuSnH, AIBN OH CN JACS 1983, 105 , 3720

147

OH

CN

Bu3SnH, AIBN CO2Me Br

JACS 1990, 112, 5601 CO2Me

Br Si O H Si O H

OH H2O2

Bu3SnH

OH

THPO

THPO

THPO

multiple cyclizations: D. Curran Advances in Free Radical Chemistry 1990, 1, 121.
O 1) NaBH4, CeCl3 2) Ac2O, Et3N OTBS OAc 1) LDA, THF 2) TBSCl O 70 °C O OTBS PhSe PhSeCl, CH2Cl2 O O THPO CO2H 1) PPTS, EtOH 2) LAH 3) (CF3SO2)2O pyridine 4) Bu4NI, PhH H2O2 O O THPO CuSMe2 Li+

I I

1) Me3Si Li (1.0 equiv) 2) CsF

I

Bu3SnH, AIBN PhH, reflux

Me H JACS 1985, 107 , 1148 H H (±)-hirsutene

O O

CH3MgBr, CuBr•SMe2

HO

O

1) I2 2) DBU

O O O O MgBr

CuBr•SMe2, THF O O HO O 1) LAH 2) CH3SO2Cl 3) NaI Li 4) 5) CrO3, H2SO4, H2O Bu3SnH, AIBN PhH, reflux CO2Me 1) CH3MgBr (excess) 2) Me3SiBr H H • H 3C (±)-capnellene Tetrahedron Lett. 1985, 41, 3943

Br

H

FIVE-MEMBERED RING FORMATION
O O nBuSnH, AIBN Me O O JACS 1986, 108, 1106 Me Br Me Me

148

CHO O

OH H O SmI2, THF H

O O

JACS 1988, 110 , 5064

radical trapping
OEt I O nBuSnH, AIBN RO O OEt tBuNC O JACS 1986, 108 , 6384 RO CN OEt

RO

can also be trapped with acrylate esters or acrylonitrile.
OEt I O nBuSnH, AIBN O OEt Me3Si O C5H11 O SiMe3 • RO OEt Pd(OAc)2, CH3 CN O 1) (S)-BINAL-H 2) HCl, H2O, THF C5H11 RO O HO CHO RO RO O 1) Wittig 2) deprotect C5H11 RO OH HO (+)-PGF2α HO CO2H C5H11 OEt 140° Brook rearrangement C5H11 RO OTMS O OEt

Paulson-Khand Reaction
R R' Co2(CO)6

Tetrahedron 1985, 41 , 5855; Organic Reactions 1991, 40 , 1.
O R'' R R'' R + R' R'' O Organometallics 1982, 1 , 1560

R'

O Co2(CO)8, NMO O O O O JOC 1992, 57 , 5277

FIVE-MEMBERED RING FORMATION
EtO2C CO2Et Ph Cp2TiCl2, EtMgBr, CO O CO2Et Ph CO2Et JOC 1992, 57 , 5803

149

Ring-Closing Metathesis

Tetrahedron 1998, 54, 4413, Acc. Chem. Res. 1995, 25, 446.
OH O N O O P(C6H11)3 Ph Cl Ru Cl P(C6H11)3 (97%) Ph

O N

O O

Bu2BOTf, CH2Cl 2, -78°C CHO (82 %)

Ph OH O N O O (78%) Ph LiBH4, THF, MeOH OH

J. Org. Chem. 1996, 61, 4192 OH

Diazoketones

Tetrahedron 1981, 37 , 2407; Organic Reactions 1979, 26 , 361
O R1 R2 N2 BF3 R1 TL 1975, 4225 R2 O

FVP of Acetylenic Ketones
O R1 R2 H R3 FVP R1 R2 H •• O R3 R1 R2 O R3 TL 1986, 27 , 19

6-MEMBERED RING FORMATION Six Membered Rings 1. 2. 3. 4. 5. Diels-Alder Reaction o-Quinodimethanes Intramolecular ene reaction Cation olefin cyclizations Robinson annulation

150

Diels-Alder Reaction ACIEE 1984, 23 , 876; ACIEE 1977, 16 , 10; Organic Reactions 1984, 32 , 1 W. Carruthers Cycloadditions Reactions in Organic Synthesis (Pergamon Press, Oxford) 1990 - reaction of a 1,3-diene with an olefin to give a cyclohexene. - thermal symmetry allowed pericyclic reaction - diene must reaction is an s-cis conformation - highly stereocontrolled process- geometry of starting material is preserved in the product - possible control of 4 contiguous stereocenters in one step
B A A B X Y Y B A B A B X Y Y X A Y X X Y B A

+
X

+

- Alder Endo Rule: In order to maximize secondary orbital interactions, the endo TS is favored in the D-A rxn. Tetrahedron 1983, 39, 2095
X X Y Y B A A B A X Y Y X B A

B

O O O O endo O O H H O O O major exo H H O O minor

O

Orientation Rules
X X X Y

+

Y

+
Y minor

major

6-MEMBERED RING FORMATION
X Y X Y major minor X Y

151

+

+

- when both the diene and dienophile are "unactivated" the D-A rxn is sluggish - D-A rxns with electron rich dienes and electron defficient dienophiles work the best. Some electron deficient dienophiles are quinones, maleic ahydride, nitroalkenes, α,βunsaturated ketones, esters and nitriles. - D-A rxns with electron deficient dienes and electron rich dienophiles also work well. These are refered to as reverse demand D-A rxns. - D-A rxns are sensitive to steric effects of the dienephiles, particularly at the 1- and 2postions. Steric bulk at the 1-position may prevent approach of the dienophile while steric bulk at the 2-position may prevent the diene from adopting the s-cis conformation. - The D-A rxn is promoted by Lewis acids (TiCl4, BF3 AlCl3, AlEt2Cl, SnCl4,...) - The D-A rxn is promoted by high pressure (1 kbar ~ 14200 psi) Synthesis 1985, 1.
O OMe Me O O + 5 Kbar O OMe Me JACS 1986, 108 , 3040

NHBOC + OMe H O 20 kbars, 50°C Eu(fod)3

H O OMe

NHBOC +

H O OMe

NHBOC Synthesis 1986, 928

- The D-A rxn is usually insenstive to solvent effects, except for water. ACR 1991, 24 , 159
O isooctane + krel=1 O endo H2O krel= 700 4:1 20 : 1 + H exo O

JACS 1980, 102 , 7816 TL 1983, 24 , 1901 TL 1984 , 25 , 1239

CO2- Na+ CHO H2O OHC

CO2H H + OHC (70%)

CO2H H

JOC 1984, 49 , 5257 JOC 1985, 50 , 1309 Tetrahedron 1986, 42 , 2847

(15%)

6-MEMBERED RING FORMATION

152

- The mechanism of the D-A rxn is believed to be a one-step, concerted, non-synchronous process. - concerted- bond making and bond breaking processes take place in a single kinetic step (no dip in the transition state) - synchronous- bond making and bond breaking take place at the same time and to the same extent.
+ M.J.S. Dewar JACS 1984, 104 , 203, 209.

- study of secondary D-isotope effects have indicated a highly symmetrical T.S.
D H H D k1 + H D D D D k2 + D D D D H JACS 1972, 94 , 1168 D D

Diels Alder Reactions:
O PhH, reflux O H MeO2C CHO

O O HO2C MeO

H

CO2H

MeO2C OMe

OAc

N

N H H

Tetrahedron 1958, 2 , 1

MeO2C reserpine OMe

O2CAr

CHO

H H O trans BnO2CHN O

H H H

CH3

trans

+
NHCO2Bn

CHO NHCO2Bn

BnO2CHN

JACS 1978, 100 , 5179 N H pumiliotoxin C

6-MEMBERED RING FORMATION
MeO O R O CO2Me OMe

153

+

MeO2C PhS SPh MeO O O O

O R

MeO2C

O R O MeO2C SPh

PhS

OMe

JACS 1986, 108 , 5908

Compactin

OMe R

OMe R Me3Si-O O R ACR 1981, 14 , 400

+
Me3SiO Danishefsky's Diene

OMe MeO2C CO2Me O

O H

OH H O O

+
Me3SiO O H

Vernolepin

Hetero Diels-Alder Reactions - Heterodienophiles
OMe CO2Bn PhH, reflux O CO2Bn CO2Et JACS 1982, 102 , 1428

+
Me3SiO EtO2C

N

N

O Me3SiO CO2Me PhH, 5°C TsN CO2Me HO HO N H OH

+
Ts

TL 1987, 28 , 813

N

CH(OMe)2 O + N CO2Bn

CH(OMe)2 O N CH3 CO2Bn AcO AcO

OAc OH NAc CH3 TL 1985 27 , 4727

CH3

6-MEMBERED RING FORMATION

154

Me Me + Me Me O S NTs Me Me

Me S O Me Me Me NHTs Me TL 1983, 24 , 987

NTs Me

S Ph S O S Ph Ph H Ph

S

Tetrahedron, 1983, 39 , 1487

O OMe Me3SiO

1) MgBr2 2) H3O+ OBn O OBn
OMe HF, Pyridine Ar Me Me Me O O Me Me Ar JACS 1985, 107 , 6647

+

H

O

JACS 1985, 107 , 1256

OMe

O

OMe Ar Me Yb(fod)3 Me Me3SiO O

+
Me3SiO

H

O M O C3F7 3 M(fod)3 O

C3F7 O M 3 M(hfc)3

- Heterodienes
H MeO2C OAc O O O MeO2C AcO H O O H O ACIEE 1983, 22 , 887 AcO H

+

+
H endo: exo 1:2 MeO2C

Me PhS

O

+

OEt

EtO

O

Me

HO

O

Me OH ACR 1986, 19 , 250

OAc

endo:exo 10 : 1

SPh OAc OH

6-MEMBERED RING FORMATION

155

OR' N O N OR' O

+

RO RO

O

RO RO

O

O N N

OR'

RO RO

O

OMe NHAc

JACS 1987, 109 , 285

OR

OR

CO2R'

OR

H ∆ N AcO O N O N O JOC 1985, 50 , 2719

Intramolecular Diels-Alder Reactions - Type I IDA rxns

(IDA)

Fused bicyclc

Bridged Bicyclic

- Generally, for E-dienes, the fused product is observed unless the connecting chain is very long. For Z-dienes, either the fused or bicyclic products are possible. - Type II IDA rxns: gives bridgehead olefin

395°C O

JACS 1982, 104 , 5708, 5715
O

O
O O 185°C EtO2C EtO2C O O

JACS 1987, 109 , 447 EtO2C
AcO NHBz O O OH ACIEE 1983, 24 , 419 H OH BzO AcO Taxol O

CO2Et

155°C

Ph OH

O

O

O

6-MEMBERED RING FORMATION

156

- IDA reactions to give fused 6•5 (hydroindene) and 6•6 (hydronaphthalene) ring systems are usually favorable reactions.
R' R (CH2)n n= 1 or 2 R (CH2)n R'

- Intramolecular D-A rxns that give medium sized rings (7,8,9, 10) are much less favorable. - Intramolecular D-A rxn which form large rings are often favorable reactions with the diene and olefin portions act as if they were seperate molecules
H H O H O O O O endo O O O + H O O exo H O O + H O O O O JACS 1980, 102 , 1390

6.2 : 6.8 : 1 (77% combined yield)

- Preference for endo or exo transition state depends on the substituition of the diene, dieneophile and connecting chain. - For intramolecular D-A rxns, geometric constraints can now reverse the normal regiochemistry of the addition as compared to the intermolecular rxn.
+ CO2R' R CO2R' R CO2R'

CO2R'

- for intramolecular D-A reactions, we will use endo and exo to described the disposition of the connecting chain
R R' R R' H (CH2)n R' R (CH2)n (CH2)n endo R R' R R' H (CH2)n (CH2)n exo H H

6-MEMBERED RING FORMATION

157

- Lewis acids can greatly effect the endo/exo ratio of IDA reactions especially when the olefin portion is E. The effects for Z-olefins is much more subtle
MeO2C MeO2C H + H (75% combined yield) (72% combined yield) MeO2C H JACS 1982, 104 , 2269

H 150°C (RO)2AlCl2, rt 75 : 25 100 : 0

CO2Me

MeO2C

H +

MeO2C

H

H 180°C EtAlCl2, rt 75 : 25 63 : 37

H (74% combined yield) (60% combined yield)

- the effect of substituents on the connectinng chain can influence the stereochemical course of the IDA reaction
HN O HN O MeO2C EtAlCl2 rt H MeO2C H JOC 1981, 46 , 1509

R O R O H H R R

Intramolecular Diels-Alder Reactions:
CO2Me MeO2C 130°C TBSO TBSO H JOC 1981, 46 , 1506

H

O O 150°C

O O TL 1973, 4477

6-MEMBERED RING FORMATION
OTBS H H O CF3CO2H H H OTBS JACS 1981, 103 , 4948

158

OTBS

TBSO CO2Me EtAlCl2

H

CO2Me JOC 1982, 47 , 180

H

Asymmetric Diels-Alder Reactions - Chiral Auxillaries Chem. Rev. 1992, 92 , 953; Tetrahedron 1987, 43 , 1969
OAc O M O H OAc OAc >98% d.e. + BF3•OEt2, -40°C H OAc O OH HO HO OH (-)- Shikimic Acid CO2H JOC 1983, 48, 1137 JOC 1983, 43, 4441 ACIEE 1985, 24, 1

O O O O +

TiCl4, 0°C O R* O (97:3)

TL 1984, 25 , 2191

O O

X
CO2R* O O CO2R*

∆ = 4.5 %ee TiCl4= 78% ee iBu2AlCl= 90% ee

O Ph O

O Ph + O

O OR* Ph 18 : 82 w/ BF3•OEt2 92 : 8 + O

O Ph OR* JOC 1989, 54 , 2209

d.e > 95%

O Ar O + OTMS Et2AlCl CH2Cl2, -80°C
Ph H O Me OTMS PhCHO Eu(hfc)3 O O

O R* O O
Ph O OR* + Me 8 : 92 O OR* Me JACS 1986, 108, 7060

Chem Lett. 1989, 2149 up to 70% d.e.

6-MEMBERED RING FORMATION
CH3 N + S O R SnCl4, -78C R* O O N O S R 97% d.e. PhMgBr R* O N H O S Ph R O R* O

159

O Ph O

O OH N

R JCSCC , 1985 , 1449 TL 1986, 27 , 1853

O O H H
O SO2 N EtAlCl2, -78°C Oppolzer Auxillary
O

O

(iPrO)2TiCl2, CH2Cl2, 0°C
O X

H CO2R*

Tetrahedron 1987, 43 , 1969

endo/exo= 86:4 98% de

TL 1989, 30 , 6963

O Evan's auxillaries R N Me

O O R Ph N

O O

+ O N O Me2AlCl O CO2R* endo (major) endo CO2R* CO2R*

+ CO2R* exo endo/exo endo A/ endoB k(rel) 1 equiv Me2AlCl 20:1 4:1 1 exo

2 equiv. Me2AlCl 60:1 20:1 100

_ O N O Me2AlCl O N O Me2ClAl + O O Me2AlCl

_ Me2AlCl2 + Al O O N O H O N Al O O

6-MEMBERED RING FORMATION

160

O R Ph N

O O EtAlCl2, -100°C

O R* OH JACS 1984, 106, 4261 JACS 1988, 110 , 1238

(R)-(+)-α-terpineol

O O Ph N

O R* Me2AlCl

O R* H +

O H TL 1984 , 25 , 4071 JACS 1988, 110 , 1238

Me H O O N Ph Me2AlCl 95 : 5 15 : 85 H

O

- Chiral Dienes
O OMe O O π-stacking arrangement Ph O O approach of dienophile OMe Ph O CHO OHC Ph OMe BF3•OEt2, -20°C BF3•OEt2, -78°C 4:1 94:6

O OMe O O Ph +

OH O

MeO H

O O H O OH

O only product

H

- Chiral Catalysts Chem. Rev. 1992, 92 , 1007; Synthesis 1991, 1; OPPI 1994, 26, 129158
OH CHO + EtAlCl2, -78°C
OtBu Me + TMSO Me PhCHO O Me Ph Eu(hfc)3, -10°C O TL 1983, 24 , 3451

CHO

JCSCC 1979, 437

72% (ee)

6-MEMBERED RING FORMATION
Ph Ph Ph O O N O O + Me O OH OH Ph Ph (iPrO)2TiCl2 O
O Ph Ph O N O O Ph O Me O OH OH Ph Ph (iPrO)2TiCl2 O O (30 mol % catalyst)
Ph O OH OH + OH O OAc Ph BH3, -78°C OH O OAc O JACS 1986, 108 , 3510 (98%)

161

O

N O

CL 1986, 1967

O N

O H O O H

70% yield 95% ee

Ts N Et B Br CHO + -78°C Br O O N H CHO JACS 1992, 114 , 8290

(> 99% ee)

H N O Br CHO + O N B Bu Ts Br CH2Cl2, -78 °C, 16 hrs Br Br (81%, 99% ee) O H O B O N Ts approach of diene Br CHO H N

OC O Br
H N OTBS CHO + H 3C H O O O N B H Ts CHO OTBS

HO CO2H Gibberellic Acid

OH

1) NaBH4 2) DDQ 3) F
-

O JACS 1994, 116, 3611

4) HCl O

O O

CH2Cl2, PhCH3 -78 °C, 42 hrs

HO Cassiol

OH OH

(83%, 97% ee) O

6-MEMBERED RING FORMATION

162

Ketene Equivalents in the D-A reaction - ketenes undergo thermal [2+2] cycloaddition with dienes to give vinyl cyclobutanones. - 2-chloroacrylonitrile as a ketene equiv. for D-A rxns.
AcO + Cl CN AcO Cl CN KOH, tBuOH 70 °C HO O Nature (London) 1994, 367, 630 ACIEE 1995, 34, 2079

ortho-Quinodimathanes

Synthesis 1978, 793; Tetrahedron 1987, 43 , 2873
R R R R

benzocyclobutane

o-quinodimethane
O LiNH2, NH3, THF I

O

1)

OTMS MgBr

Me3Si

SiMe3

CuI, TMS-Cl

CpCo(CO)2

O 170 °C Me3Si Me3Si H Me3Si O 1) CF3CO2H, CCl4, -30°C 2) Pb(O2CCF3)4 H HO Estrone H H Me3Si H

O H H Me3Si H

O

Me3Si

ACIEE 1984, 23 , 539 JACS 1977, 99 , 5483 JACS 1979, 101 , 215 JACS 1980, 102 , 241

O O HN HN 155 °C H
Me N 155 °C O O Me N ACIEE 1971, 11 , 1031

JACS 1971, 93 , 3836

O

O

Me O N 155 °C N OMe N O N

Me ACIEE 1971, 11 , 1031

Me O N 180 °C

O

OMe Me

N ACIEE 1971, 11 , 1031 NH

N

6-MEMBERED RING FORMATION Photoenolization
R O H R R hν

163

Tetrahedron 1976, 22, 405
R • R O• H CO2Me R O O O R CO2Me O CO2Me R O R R -H2O OH MeO2C CO2Me R OH CO2Me

R

OH O

Intramolecular Ene Reactions

ACIEE 1984, 23 , 876, Synthesis 1991, 1
H SnCl4 CHO H OH JOC 1985, 50, 4144

Me2AlCl BnO H CHO OBn OH

JACS 1991, 113 , 2071

Binaphthol CHO Me2Zn OH 90% ee)

Tetrahedron Lett. 1985, 26, 5535

Polyene Cyclization
+ +

Terpene Biosynthesis terpenes sesquiterpenes diterpenes steroids

C 10 C 15 C 20 C 30

geraniol farnesol geranylgeraniol squalene

- isoprene- basic building block
OPP isopentyl-PP isoprene unit

OPP OPP OPP

geraniol-PP (C10)

Farnesyl-PP (C15)

geranylgeraniol-PP (C20)

squalene (C30)

6-MEMBERED RING FORMATION

164

O Camphor α-Cedrane HO2C Abietic Acid

Biosynthesis of camphor:

+ OPP O +

Biosynthesis of cedrane:
OPP

H +

+

H + +

Stork-Eschenmoser Hypothesis- Olefin Geometry is preserved in the cyclization reaction, i.e. trans olefin leads to a trans fused ring jucntion A. Eschenmoser HCA 1955, 38, 1890; G. Stork JACS 1955, 77, 5068
Me R H H H Me Me + Me Me Me R H Me Me

Biosynthesis of Abietic acid:
OPP + H H H + H H H H H HO2C H
+

OPP

OPP

H

+

H

6-MEMBERED RING FORMATION -Steroid Biosynthesis:
H squalene epoxidase squalene cyclase + H+ H H

165

squalene

H +O H + H H H squalene oxide H HO H HO H

H Protosterol

H H

H HO H HO H Lanosterol HO

H

H

Cholesterol

- Polyene cyclization in synthesis ACR 1968, 1, 1; Bioorg. Chem. 1976, 5, 51; Asymmetric Synthesis 1984, 3, 341-409; ACIEE 1976, 15, 9
SnCl4 CH3NO2, 0°C (8%) H O HO H δ- Amyrin E.E. van Tamelen JACS 1972, 94 , 8229

H

OH CHO SnCl4 PhH, rt (38%) MeO MeO H JACS 1974, 96 , 3333

SnCl4 pentane (27%) O O HO
CO2Me OPO(OEt)2

H H O H H

W.S. Johnson JACS 1974, 96, 3979

1) Hg(O2CCF3)2 2) NaCl ClHg H

CO2Me O JACS 1980, 102 , 7612

6-MEMBERED RING FORMATION Robinson Annulation Synthesis 1976, 777; Tetrahedron 1976, 32, 3.
O

166

O

acid or base (thermodynamic conditions)

O

- unfavorable equillibium for the Michael addition under kinetic conditions
O

-

O

base (kinetic conditions)

-O

O

- stabilizing the resulting enolate of the Michael Addition product can shift the equilibrium as in the case of the vinyl silane shown below
O Me3Si
-

Me3Si
-

O base (kinetic conditions)

O

O

O

OR

OR a) MeLi b) Me3Si O O c) MeONa O O O O H

OR JACS 1974, 96 , 6181

O

Me3SiO

H

- Methyl Vinyl Ketone equivalents
I + Me3Si mCPBA
-

O

O Me3Si O

H+

Me3Si

O

Aldol O O O

JACS 1974, 96 , 3862

I + O O
-

O

O

O

O

O

6-MEMBERED RING FORMATION Intramolecular Aldol Condensation of 1,5-Diketones 6-exo-trig; favored process
O R' base - H2O R O O R' R

167

- DeMayo reaction to 1,5-diketones
O O O hν O H 3C O O O O DIBAL-H H

Intramolecular Alkylations (SN2 reaction) Radical Cyclizations Acyloin Reaction Birch Reduction Organic Reactions 1992, 42, 1. (Carey & Sundberg, Chapter 11)

Aromatic Substitution

Intramolecular Wittig Reaction Sigmatropic Rearrangements

7-MEMBERED RING FORMATION Medium Sized Rings 7-Membered Rings

168

[4+2] cycloadditions - [4+2] cycloadditions between dienes and allylcations leads to cycloheptadienes review: ACIEE 1984, 23 , 1; ACIEE 1973, 12 , 819
+
+ +

+

I

CF3CO2Ag -78°C Me

ACIEE 1973, 12, 819 ACIEE 1984, 23, 1

ZnCl2, -30°C + + F3CCO2 SiMe3 SiMe3 H H

ACIEE 1982, 21, 442

O OTMS + ZnCl2 Br

O JACS 1982, 104 , 1330

OMe O O O

O O O O O

O

+
+

O

O mCPBA O

O

JACS 1979, 101, 226

HO

- Noyori [4+2] cycloaddition of α,α'-dibromoketones and dienes review: ACR 1979, 12 , 61
O R Br Br R Fe2(CO)9 -orZn-Cu OM R + R O R R ACR 1979, 61 Organic Reactions 1983, 29, 163

7-MEMBERED RING FORMATION

169

O Br Br Br Br Fe2(CO)9 O Br

O Br O Zn

O O

CO2Me O Br Br Br Br 1) Fe2(CO)9 2) Zn N MeO2C N JACS 1978, 100 , 1786 Tetrahedron 1985, 41, 5879 O

OMe O O O

O O O O O

O

+
+

O

O mCPBA O

O JACS 1979, 101, 226 HO

O Me Br Br Me 1)

O O

1) H2, Pd/C 2) CF3CO3H O

O O

OH O JACS 1972, 94, 3940 JOC 1976, 41, 2075 H CO2H

Fe2(CO)9

H O

O

O

1) CF3CO3H 2) LDA, MeI OBn

O O Me OBn O

Me

Me

Me OH JCSCC 1985, 55

O O

OH

OH

OBn

- [4+2] cycloaddition between pentadienyl cations and olefins
+

+

+

O HO ∆
-

OH O +

O O Tetrahedron 1966, 22, 2387 JOC 1987, 52, 759

O

O

7-MEMBERED RING FORMATION
O SnCl4 OMe JACS 1977, 99, 8073 JACS 1979, 101, 6767 JACS 1981, 103, 2718

170

MeO OMe OMe

O

O

Seven-Membered Rings from Funnctionalization of Tropone Organic Reactions 1997, 49, 331-425
O Cl R O OO R JOC 1988, 53, 4596 JACS 1987, 109, 3147

- [6+4] cycloadditions of tropones with dienes
[6+4] O 150°C (88%) O JACS 1986, 108, 4655 JOC 1986, 51, 2400

O

HO HO HO Ingenol

OH

- [4+2] cycloaddition between tropone and olefins
O [4+2] 150°C (81%) O

Radical Ring Expansion Reactions - one carbon ring expansions
O CO2Me (CH2)n n = 1,2,3 NaH, CH2Br2 (CH2)n O CO2Me (CH2)n (CH2)n • CO2Me nBu3SnH O Br CO2Me nBu3SnH, AIBN O • CO2Me (CH2)n O JACS 1987,109, 3493 JACS 1987,109 , 6548 (CH2)n CO2Me

•O

7-MEMBERED RING FORMATION

171

O CH3 Bu3SnLi BrCH2SePh

O SePh SnBu3 O •O + SnBu3

O •

SnBu3 Tetrahedron 1989, 45, 909 Tetrahedron 1991, 47, 6795

Bu3Sn•

- more than one carbon expansion
O R X (CH2)n SnBu3 X= I, SePh n= 1,2 O (CH2)n R Tetrahedron 1989, 45, 909 Tetrahedron 1991, 47, 6795

Br + O O

Br

Bu3SnH, AIBN, C6H6, reflux O

JOC 1992, 57, 7163

Eight-Membered Rings [4+4] Cycloaddition of Dienes
MeO2C MeO2C

review:Tetrahedron 1992, 48 , 5757.
Ni(COD)2, Ph3P 60°C

MeO2C MeO2C

JACS 1986, 108 , 4678

O O Ni(COD)2, Ph3P 60°C O

O O

O

H H O Asteriscanolide

JACS 1988, 110 , 5904

Carbonyl Coupling Reactions - Acyloin Reaction
CO2Me Na O OH JACS 1971, 93 , 1673

CO2Me

- McMurry Reaction
R O O R CO2Et Ti (0)

7-MEMBERED RING FORMATION

172

CHO OHC TiCl3, Zn-Cu H H JACS 1986, 108 , 3513

Aldol-like Condensations
O O OTMS TiCl4 O OH JCSCC 1983, 703

O

SiMe3 R (CH2)n O O n= 1,2
Me3Si Cl SnCl4 OTs O tBuPh2SiO OEt tBuPh2SiO O Me3Si Cl OTs

SiMe3 Lewis Acid OMe (CH2)n O R JACS 1986, 108 , 3516

Cl

O Laurenyne JACS 1988, 110 , 2248

TiCl4 O SiMe3

JOC 1988, 53 , 50 O

Pinocol Rearrangement
Me3SiO O SnCl4 OMe OMe Me3SiO + OMe H OMe JACS 1989, 111 , 1514

Tiffeneu-Demyanov Ring Expansion - one carbon ring expansion for virtually any size ring
O 1) Me3SiCN 2) LAH HO NH2 HONO N2 O H O JOC 1980, 45 , 185

- also see Beckman and Schmidt rearrangements as a one atom ring expansion for the conversion of cyclic ketones to lactams.

7-MEMBERED RING FORMATION DeMayo Reaction
O O + OAc AcO O JCSCC 1984, 1695 O O O O hν O O O

173

O

O hν, pyrex O

O

O O

pTSA, MeOH reflux

H O H

CO2Me JACS 1986, 108 , 6425

Ring Expansion/Contraction via Sigmatropic Rearrangements - Cope Rearrangement

O SMe 55°C

O

TL 1991, 32 , 6969 O

O O O

- Anion Accelerated Cope
KH, 18-C-6 115°C O JACS 1989, 111, 8284 O OCOCH2OH Pleuromutilin

OH

- Claisen Rearrangement
O O O Tebbe reagent O 185°C H TL 1990, 31 , 6799

7-MEMBERED RING FORMATION - Ester Enolate Claisen- 4 carbon ring contractions
O O 1) LDA, TBS-Cl 2) 110°C CO2H JACS 1982, 104 , 4030 Tetrahedron 1986, 42 , 2831

174

MOMO H O O 1) LDA, TBS-Cl 2) 110°C

MOMO JOC 1988, 53 , 4141 H CO2TBS

H