C5: Control in Organic Chemistry

C5: Control in Organic Chemistry 1
Part II Chemistry 2003
Control in Organic Chemistry

Lectures 7-12
Dr David Spring
drspring@ch.cam.ac.uk
Tel. 01223 336364
Lab 180
O O
O O
BrMg
Me Me
CuBr•SMe2
O O
Course Outline
1. Introduction to Stereoselectivity
2. Stereochemical Control in Four- and Five-Membered Rings
3. Stereochemical Control in Six-Membered Rings
4. Stereochemical Control with Bicyclic Compounds
5. Open Chain Stereochemical Control
Essential Reading
Clayden, Greeves, Warren, Wothers “Organic Chemistry” Oxford, 2001.

Introduction to Stereoselectivity
How are rxns controlled?
Kinetically and thermodynamically controlled rxns:
If treatment of a starting material can give more than one product then the amount of each product
is determined by its rate of formation (kinetic control). However, if the rxn is reversible then the
product distribution is determined by the relative thermodynamic stability of each product.
O
O S OH
H2SO4
80 ˚C
O O
H2SO4 S
OH
160 ˚C
∆G
O ∆G˚
O O O S OH
S H2SO4
OH
H2O H2O
The majority of this course will be concerned with kinetically controlled rxns that involve the
formation of tetrahedral (sp3) carbon atoms within a molecular framework.
What type of selectivity are we talking about?
Chemoselectivity – functional group discrimination
Regioselectivity – product structural isomer discrimination
Stereoselectivity – product stereoisomer discrimination
O O
O O
BrMg
Me Me
CuBr•SMe2
O O
Stereochemistry involves diastereomers and enantiomers. Therefore stereoselectivity encompasses

diastereoselectivity (product diastereomer discrimination) and enantioselectivity (product
enantiomer discrimination). This course will focus on diastereoselectivity. Enantioselective rxns
will be covered in detail next year. So from now on, when we talk about stereoselectivity, more
specifically we mean diastereoselectivity.
E Enantiomeric transition E Diastereomeric transition

states must be the states are not necessarily
same energy the same energy
OLi
O O BuLi
OLi BuLi OLi Ph OLi
Bu Ph
Ph H Ph H H Ph
Bu Bu Ph Me * Bu
H Me
Me
Rxn Coordinate Rxn Coordinate
As you know enantiomers are equal in energy, therefore enantiomeric transition states are also
equal in energy. So it is impossible to achieve any selectivity, we get a racemic mixture. However,
if we have a chiral centre in the substrate then we form diastereomers, then the transition state
energies need not be equal and we should observe some selectivity. This simple statement in fact
forms the basis for all diastereoselectivity (and enantioselectivity! – except that the chirality is not
in the substrate).
Selective or Specific?
If a rxn proceeds via a mechanism with a strict stereochemical requirement, then the rxn is
stereospecific. So in a stereospecific rxn, the starting material goes to only one possible product
stereoisomer, there is NO selectivity. For example, substitution by the SN2 mechanism must involve
an inversion of configuration of the carbon atom that is reacting:
Me Me
Me Si Me Me Si Me
N3-
Me O Me
O O O
O O N
S O
(±) (±) N+
Me
N-
What does the other enantiomer look like?
Me
Me Me Si Me
Me Si Me NaN3
O Me
O Me O
O N
O O
S O N+
Me N-
Stereospecific rxns are enantiospecific for chiral starting materials where a stereospecific rxn occurs
at all stereocentres. For example:
Br OH
HO- Me
Me
Me Me
95% e.e. 95% e.e.
Stereospecific rxns are also possible with achiral starting materials:

In contrast, for a stereoselective rxn, the mechanism does not prevent the formation of two (or
more) stereoisomeric products. Even if the rxn is completely selective giving only one stereoisomer,
it still NOT ‘stereospecific’. As we will only be discussing diastereoselectivity, the selectivity will
be between diastereomeric products and we shall talk about diastereomeric ratios (d.r.) and
diastereomeric excesses (d.e.). [Enantioselectivity concerns selectivity between product
enantiomers]
Two common cases of diastereoselective rxns are:
1. Rxns that involve the formation of one (or more) new stereocentres in a chiral substrate:
O NaBH4 OH OH
+
Me Me Me
Me Me Me
90% 10%
si face addition re face addition
Chiral Starting Material Diastereomeric Products
d.r. = 9:1
d.e. = 80%
2. Rxns in which two prochiral substrates react to give a product where two new stereocentres are
formed, where one new stereocentre originated from each substrate.
OH O OH O
Me Me + Me Me
Me Me
Me Me Me Me
O Li
O 44% 6%
Me
Me H + Me Me
Me
OH O OH O
Me Me Me Me
+ Me +
Me
Me Me Me Me
44% 6%
Stereoselective rxns of cyclic compounds
Revision of Conformational Analysis
DRAW IN 3-D!!
H H
H
H H
H
H
H
H
H H H
H
H
H
H H H
H H H H
H H
H H
H Ring Flip H
H H H H
H H
H H
HH
H HH H
Chair
H H
H H
H H H H H
H H
H
H H H
H
Boat Twist-Boat
Learn how to draw a cyclohexane on p. 459-460 of Clayden et al.

OH
Me Me
Me
H
OH
H
OH
H
Stereochemical Control in Four- and Five-Membered Rings
Four-membered rings
Just one sp2 centre

O OH
NaBH4
R R
More than one sp2 centres
O (i) LDA, -78 ˚C, THF O

(ii) BnBr
O O
Me Me
Me Me
(±)
d.r. >98 : 2
Five-membered rings
Just one sp2 centre

O OH OH
LiAlH4
Me Me + Me
THF
(±) 77% 23%
O OH OH
LiBH(s-Bu)3
Me Me + Me
THF
(±) 1.5% 98.5%

More than one sp2 centre
M
O O O
(R1)2CuLi R2 X R2
TBSO TBSO R1 TBSO R1
CO2H
Me
HO
OH
PGE2
O
CuI, Bu3P, THF
+ Li Me
then Ph3SnCl, HMPA
H OTBS
TBSO
O O O
I OMe
OMe
HMPA, Et3N Me
TBSO
-78 to 23 ˚C
OTBS
Suzuki, Noyori et al. J. Am. Chem. Soc. 1985, 107, 3348-3349.

Chiral Memory:
Me
Me (i) LDA O
O O O Me O
H+ Me O (ii) PrBr Me
+ Me Me Me
H O
HO O
Me Me
OH
How do we make both epoxides stereoselectively?

Me
Me
Me
O
Me
Me
Me
Me
Me
Me
Me
Me
O
Me
Stereochemical Control in Six-Membered Rings
Just one sp2 centre-addition to cyclohexanones
O Me
OH
NaBH4 MeMgBr OH
Me Me Me
Me Me Me
Me Me Me
OH O OH
LiBH(s-Bu)3 Al(Oi-Pr)3
Me Me Me
Me i-PrOH Me
Me Me Me
Me
equitorial axial
diastereomer diastereomer
H OH
Me O [H] Me Me
OH + H
Me Me Me
Me Me Me
% axial diastereomer
0 100%
10 20 30 40 50 60 70 80 90
Me
Li/NH3 (99:1)
DIBAL (72:28) Me
Me K-Selectride (3:97)
LiAlH4 (93:7) NaBH4 (79:21)
M+ H B L-Selectride (8:92)
LiAlH(Ot-Bu)3 (92:8) Me
Me
Me
More than one sp2 centre
N (i) n-PrI O
O N (ii) H+, H2O
H Me
Me Me
Me Me
Me Me Me
Me Me
MgBr
O O
Me O Me O
Me Me Me
Me
Me O CuBr•SMe2 Me O
Me Me
Me
> 80% Me
Trans-diaxial ring opening (Fürst-Plattner Rule)
Nu- OH
O
Me Me
Me Me Nu
Me Me 95%
But:
Nu- Nu
O
Me Me
Me Me OH
Me Me 95%
Br
Br2 Me
Me Me Br
Me Me 100%
Me
OMe Br
Br2
+ Me
Me
Me MeOH Br Me OMe
Me
Me Me Me
47% 53%
Me
Pasto, J. Am. Chem. Soc. 1970, 92, 7480.

Chelation can reverse the stereoselectivity.
O
O
O O H O
O Me O Me
Cl
O
O
O
O H
OH OH
Cl
O
OH OH
t-BuOOH
VO(acac)2 O
Dihydroxylation:
OH OH
OH
OH OsO4,NMO OsO4, TMEDA
OH
Acetone,H2O CH2Cl2, -78 ˚C
Me Me
Me OH Me Me
Me OH
Me Me
Me
Prévost and Woodward Methods:
O O
Ag Me Me
Me O Ag
Me O OH
OH
I2, C6H6 AcOH, I2, H2O
Me Me
Me Me OH
Me OH Me
then NaOH Me then NaOH Me
Me
Iodolactonisation in Synthesis
O O O
O O
O O O O Me
I2, H2O Me DBN Me mCPBA Me HBr
OH
Me NaHCO3 HO
I
O Br
O O O O
O O O (i) Zn OMe
Me MnO Me Me
2 R2CuLi (ii) TsOH, MeOH Me
HO O O R O R
O O
OMe (i) O3 then Me2S OMe
Me (ii) [O] Me
O O
OMe
O O
O
O
OMe MeONa Me O (i) NaOH Me O
MeOH O (ii) HCl
Me
O O
OMe
OMe O
O O H H
O
Stereochemical Control with Bicyclic Compounds
Cyclopentane Fused Bicyclic Spiro-cyclic Bridged Bicyclic
LiAlH4 H OH
O +
THF OH H
norbornane
Me Me Me
Me Me Me Me Me
Me LiAlH4 H OH
O +
THF OH H
camphor
Fused rings
cis-fused only
trans possible, but difficult
trans more stable than cis

H
O
H
R R R R=H
Et Me
Li
EtI Me
O NH3 LiO LiO
H
Me Me Me R = Me
O
H
Et Me
H (i) NaH H H
O O O H
(ii) (MeO)2C=O NaBH4
O O
O O O OH
H H H
O O
MeO MeO
H H H
mCPBA
O
H H H
Open Chain Stereochemical Control
Nucleophilic Attack on Carbonyls with α–Chiral Centres
Me O Me OH
NaBH4
Me Me
Me Me Me
Me
Me Me
Molecules with a high degree of flexibility tend to react unselectively.
But carbonyls with adjacent chiral centres show some selectivity. Why?
O LiAlH4 OH OH
+
Et Et Et
Me Me Me
anti : syn
3:1
O EtMgBr OH OH
+
H Et Et
Me Me Me
anti : syn
1:3
Well, as with the cyclic molecules we have been discussing previously, the key to understanding
this selectivity is conformation: so you still must draw in 3-D to explain things.
O O O O O O
Me Me H H Ph Ph
Ph H Me Ph H Me
H Ph Ph Me Me H
H H H H H H
The trajectory for attack on a carbonyl group was determined by two crystallographers Bürgi and
Dunitz in the 1970s: the ‘Bürgi-Dunitz angle’ of attack is about 109˚, not 90˚ as previously thought.
Nu-
109˚
O
The major product results from the most reactive conformer.
O O
Me H
Ph Ph
H Me -
-Nu H Nu
Nu- H Nu-
Not all ‘flight paths’ for the nucleophile are equally favourable.
This is called the ‘Felkin-Anh’ model and correctly predicts major products in such rxns; however
we need to be aware of two other possibilities: electronegative groups and chelating groups.
Orbital Control in the Felkin-Anh model
Consider Reetz’s synthesis of an unusual amino acid present in the anticancer compound
Dolastatin.
Li
O
Me O Me OH O Me OH O
OMe +
Et H Et OMe Et OMe
NBn2 NBn2 NBn2
anti : syn
24 : 1
92% d.e.
Me
O O
H Bn Bn Et
N N
Et Bn Bn H
H H
Me
Me
Bn Et
N
Bn H
Why is the stereocontrol so good when NBn2 and CH(Me)Et are fairly similar in size to each other?
Why does NBn2 want to be perpendicular to C=O for the model to work?
The reason is that conformations where electronegative groups are perpendicular to C=O are more
reactive to nucleophilic attack. Why?
new LUMO
O
Me
X π* of the X σ* of the X
C=O bond C-X bond
X is an electronegative group combine
but not a leaving group O O
(OR, NR2, SR, etc.)
-Nu
Energy σ*C-X
O
Orbital overlap is best
X with this conformation
π*C=O
π* + σ* New LUMO
Lower energy
More reactive
Note that the most heavily populated conformations will be those where the bulky groups are
perpendicular to the C=O bond, but the more reactive conformations will be when the most
electronegative atom is perpendicular to the C=O bond (cf. Curtin-Hammett principle).
Chelation Control
Sometimes the result depends on the reagent:
O Nu OH HO Nu
OMe OMe OMe
+
Me Me Me
(±) NaBH4 73% 27%
Me2Mg 1% 99%
When chelation is possible the direction of stereocontrol inverts and the level of stereocontrol is
higher (usually). Note this fits nicely with the ideas presented earlier in the course: stereoselectivity
is likely to be high if a cyclic transition state is involved. Chelation involves just such a transition
state, so it should be no surprise that it lets us achieve much higher levels of control than the acyclic
Felkin-Anh model does.
Transition states with different metal counterions:

With Na+ With Mg2+
Mg2+
O O
Me OMe
OMe Me
H
H- Ph Ph
H -Me
Two things are required for chelation control:
1. A heteroatom with lone pairs available for coordination to a metal ion.

2. A metal ion that favour coordination to both C=O and the heteroatom. For example:
Mg2+, Zn2+, Al3+, Ce3+ and Ti4+ are excellent

Li+ is sometimes okay
Na+ and K+ are bad
Note that the best ones are usually more highly charged ions.
Summary:
O Is there a metal ion Use chelation model:

Is there a heteroatom YES YES consider rxns on
Z at the chiral centre? capable of chelation
R Y with the heteroatom? conformation with C=O
X and heteroatom held
NO NO close together in space
Use Felkin-Anh model: Use Felkin-Anh model:

consider rxns on consider rxns on
conformations with the conformations with the
largest group most electronegative
perpendicular to C=O atom perpendicular
to C=O
Diastereoselective Rxns of Acyclic Alkenes
As we discovered before molecules with a high degree of flexibility tend to react unselectively; but
carbonyls with adjacent chiral centres show selectivity.
O O
Me mCPBA Me + Me
Me SiMe2Ph Me SiMe2Ph Me SiMe2Ph
>95%
As with rxns at C=O, conformation is the key.
The Houk Model
Calculations by Ken Houk found that low energy conformations of alkenes with allylic substituents
have one substituent eclipsing the double bond. Lets look at the alkene below. The lowest energy
conformation is the one that has the hydrogen atom (the smallest group) eclipsing the double bond.
Another low energy conformation (only 3.1 kJ mol-1 higher) has one of the methyl groups eclipsing
the double bond, so that when we start to look at rxns of this type of alkene (including trans
alkenes) we should consider both conformations.
H
E > 8 kJmol-1
H Me Me
This is NOT
a minimum!
Ψ Me Me
Me H
H H H Me
E=3.1
E=0
0
Ψ
0 60 120 180
The allylic 1,3-strain between H and a methyl group is not large so a significant proportion of the
slightly higher energy conformation is present at equilibrium. So what happens when we try to
epoxidise the alkene shown below?
Me Me O O
mCPBA Me Me Me Me
+
SiMe2Ph SiMe2Ph SiMe2Ph
61 : 39
22% d.e.
Me Me
Me Si
H H
Me major conformer:
H eclipsing C=C
Me Me
SiMe2Ph
Me H
H Me
Si
Me
Me
minor conformer:
Me eclipsing C=C
What about the conformations of cis alkenes?
Me
H H
E Me Me
Me Me Me
E = 16.8 kJmol-1 E = 14.4 kJmol-1
Ψ Me
Me
Me H
E=0
0
Ψ
0 60 120 180
So for cis alkenes only one conformer is heavily populated and this leads to the high
diastereoselectivity we observed earlier.
What if we have a directing group?
O O
Me Me mCPBA Me Me + Me Me
Me OH Me OH Me OH
(±) 95 : 5
Summary:
To explain the stereoselectivity of rxns of chiral alkenes:

• Draw the conformer with H eclipsing the double bond.
• Allow the reagent to attack the less hindered face (or syn to a coordinating group).
• Draw product in same conformation as starting material.
• Redraw the product as a ‘2-D’ structure with the longest chain in the plane of the paper.
Stereoselective enolate alkylation on carbonyls with β-chiral centres
The same model can be used to explain the diastereoselectivity of enolates with an adjacent chiral
centre.
Me Me
PhMe2Si OEt LDA PhMe2Si OEt MeI PhMe2Si OEt + PhMe2Si OEt
Me O Me O
Li Me O Me O
95 : 5
Diastereocontrol in Aldol Rxns
We have now come the second common case of a diastereoselective rxn: i.e. rxns in which two
prochiral substrates react to give a product where two new stereocentres are formed, where one new
stereocentre originated from each substrate.
So with substituted enolates we need to consider which diastereomer is the major product, and why!
O O OH O OH
Li
O LDA, THF O Me
-78 ˚C H Ph Et + Ph Et
Me Me
Ph Ph Me Me
cis-enolate syn aldol anti aldol
major minor
Note that the rxn is diastereoselective not because of attack onto one of two diastereotopic faces,
but because of the way in which two prochiral reagents, each with enantiotopic faces, come
together. Also note that aldol rxns can be under thermodynamic or kinetic control depending on the
conditions. We will consider cases under kinetic control.
With substituted enolates we have the possibility of two geometrical isomers: c i s– or

trans–enolates, and this is an important factor controlling the diastereoselectivity. A very
approximate generalisation (with many exceptions) is that:
cis–enolates give mainly syn aldol products

while
trans–enolates give mainly anti aldol products
[This is an oversimplification since enolates of some metals (Sn, Zr, Ti) give syn aldols regardless
of enolate geometry; however, you will not meet these in this course.]
How do we know this is the case?
O
Li O OH
O O H
LDA, THF
-78 ˚C
only the trans- anti aldol

enolate can form
The Zimmerman–Traxler Transition State
The reason why enolate geometry is so important is due to the aldol rxn having a cyclic transition
state. The six-membered ring transition state was proposed by Zimmerman and Traxler, hence the
name of the transition state model.
cis-enolates give syn aldol products:

Phenyl group is
pseudoaxial:
R R disfavoured
Li H Ph
O O Li Li
O O
Me H or H
R H Ph O O
Ph H
Me Phenyl group is Me
pseudoequitorial: B
A favoured
R R
H H
Li Li redraw O OH
O O syn aldol
H H R Ph
O O
Ph Ph Me
Me Me
A
trans-enolates give anti aldol products:
Phenyl group is
pseudoaxial:
R R disfavoured
Li H Ph
O O Li Li
O O
Me or Me
R H Ph O O
Me Ph H
H Phenyl group is H
pseudoequitorial: D
C favoured
R
H Li redraw O
Li O
O anti aldol
Me O R Ph
O
Ph
H
C
Stereoselective Enolization: Boron Enolates
The cyclic transition state explains how the enolate geometry controls the stereochemical outcome
of the aldol rxn (cis gives syn; trans gives anti). But what controls the geometry of the enolate? For
lithium enolates of ketones the most important factor is the size of the group that is not enolized
(the R group in diagrams above). Large groups force the enolate to adopt the cis geometry; small
groups allow the trans-enolate to form. But we cannot separate lithium enolates so really we need a
better way to make each enolate geometry.
O OLi OLi
LDA
Me Me +
R R R
Me
R = t-Bu 98% 2%
R = Et 30% 70%
The answer to our problem is boron enolates. By choosing which boron triflate we use:
B O OH
O
PhCHO Ph
Me
Me
B cis-enolate syn aldol product

OTf
> 94% d.e.
(i-Pr)2NEt
O
Me
B O OH
B
OTf O
PhCHO Ph
(i-Pr)2NEt
Me
Me
anti aldol product
trans-enolate 72% d.e.
Aldol rxns of boron enolates are frequently more diastereoselective than lithium enolates. One
reason for this is because of the relatively short B–O bond length (B–O = 1.36-1.47 Å, Li–O = 1.92-
2.00 Å) which exacerbates unfavourable 1,3-diaxial interactions in the transition state.
Evans’ oxazolidinone chiral auxiliary
An extremely important example of diastereoselectivity is the use of chiral auxiliaries. This topic
will be covered in courses next year. But you should not feel intimidated by asymmetric synthesis,
it follows all the principles we have learnt in this course: if we want to make chiral centres
selectively we need to have diastereomeric transition states (under kinetic control). One widely used
chiral auxiliary is the oxazolidinone shown below:
Li
O O O O O O
Me LDA Me BnBr Me
O N O N O N
Me Me Me
from L-Valine Me Me Me
d.r. 120:1
Note high diastereoselectivity results from:
• Exclusive formation of the cis-enolate

• Chelation results in a single rigid conformation
• π–Facial selectivity results from steric hindrance with i–propyl group
Added advantages are:
• Auxiliary is easily made from L-Valine

• Removal of the oxizolidinone is easy (compared to an amide) without racemisation
• Products are often crystalline: recrystallisation can give diastereomerically pure material
• Opposite enantiomer can be made with an auxiliary derived from norephedrine
Definitions:
Stereoisomer Compounds made up of the same atoms bonded by the same sequence of
bonds but having different three-dimensional structures (configurations) that
are not interchangeable.
Enantiomer Molecule that is non–superimposable on its mirror image.
Diastereomer Stereoisomers that are not enantiomers.
Epimer Two diastereomers that have a different configuration at only one chiral
centre.
Racemic Mixture of equal amounts of enantiomers.
Conformations Different three-dimensional arrangements in space of atoms in a molecule

that are interconvertible by free rotation about bonds.
Supervision Work:
Essential Reading:
Clayden, Greeves, Warren and Wothers “Organic Chemistry” Oxford, 2001.
Chapters 16, 18, 32, 33 and 34. READ THEM!
Additional Reading:
Carey and Sundberg “Advanced Organic Chemistry” Kluwer Academic, 2000.
March “Advanced Organic Chemistry” Wiley, 2001.
Procter “Stereoselectivity in Organic Synthesis” Oxford Primer, 1998.
Eliel, Wilen and Mander “Stereochemistry of Organic Compounds” Wiley, 1994.
1. Write brief notes, which will be valuable for your revision, and include an example on the
following keywords (how about looking them up in several books?):
a. Chemoselectivity.
b. Regioselectivity.
c. Diastereoselectivity.
d. Stereospecific reactions.
e. Thermodynamic and kinetic control.
f. Axial attack (with six membered rings).
g. Fürst-Plattner rule.
h. Felkin-Anh model.
i. Houk model.
j. Zimmerman-Traxler transition state.
2. (i) Explain the stereochemical control in the following sequence. Perhaps you would like to
represent these 2-D structural representations in 3-D.
O OH OMs
R1
R1 NaBH4 MsCl NH3 HN
R1 R1
Et3N R2
HO R2 HO R2 MsO R2
(ii) What does Ms stand for in MsCl? What is the structure? What is the mechanism of mesylation
(you should probably look it up even if you think you know)?
3. Explain how the stereo- and regiochemistry of these compounds are controlled. To do this
properly you must work out the lowest energy conformation of the starting materials or
intermediates (you might like to use molecular models) and draw it clearly in 3-D.
HO CO2Me HO O
CO2Me CO2Me
mCPBA O RNH2 ∆ N
RHN
R
Why is the epoxidation only moderately stereoselective? Why does the amine attack where it does?
4. In the previous half of this course you met the following rxn. You should now be able to explain
the diastereoselectivity.
O OH
Me Me
NaBH4
O O
5. How would you make each diol from the same alkene? Give the mechanisms of all rxns and
explain the stereochemical control.
Me Me
HO HO
Me C8H17
HO HO
H H H
Me ????
H Me
HO
H
HO
H
Start by working out the lowest energy conformation of the steroid (you might like to use molecular
models) and draw it clearly in 3-D. Then think of different ways to achieve dihydroxylation (some
methods involve more than one step). Now put them together and bear in mind stereochemical
control.
6. Consider the following sequence:
OH
O O O
AcO HO HO
(i) MsCl, Et3N (i) PhSeSePh, NaBH4
AcOH, H+ (ii) K2CO3, MeOH (ii) H2O2 Reagent?
OBn OBn OBn OBn OBn

A B C
(i) Explain the formation of the stereochemistry of A.

(ii) Reduction of PhSeSePh with NaBH4 gives the nucleophile PhSe-. Give mechanisms for
the steps involved in forming B.
(iii) Suggest a reagent to make C and explain why you think it will give the product with the
correct stereochemistry.
(iv) Explain the regioselectivity of the two epoxide opening rxns.
7. Explain the stereoselectivities of the following rxns (you will need to draw Newman projections).
O Et OH
EtMgBr
Me Me
Me Me
Cl Cl
SPh SPh
L-Selectride Ph
Ph Ph
Ph
O OH
SPh SPh
Zn(BH4)2
Ph Ph
Ph Ph
O OH
8. Explain the stereochemical outcomes of the following rxns.
OH Me CH I , Zn/Cu OH Me OH Me
22
+
Me Me Me
99 : 1
OH OH OH
CH2I2, Zn/Cu
+
Me Me Me Me Me Me
55 : 45
The rxn involved is the Simmons-Smith rxn. Draw a sensible mechanism (p.1067 of CGW&W
should help).
9. Predict the structures of the products in the following rxns, showing their stereochemistry clearly.
Explain your answer.
H
(i) LDA
O (ii) MeI O
(i) Me2CuLi
H (ii) Allyl Bromide
OH
H
mCPBA
mCPBA
H
Me
H2, Pd/C
O
H
10. Explain the formation of essentially one stereoisomer in the following rxn.
O O OH
(i) LDA
Me Me Me
Me (ii) Me
Me Me Me Me
Me
H
O
(+)-S
11. Provide the stereostructure of the major product and rationalise the stereochemical outcome of
the following rxn.
Me BF3•OEt2
Ph CH2Cl2, -78 ˚C ?
H +
OTMS d.r. 16 : 1
O
12. Account for the differences in the aldol addition products between the two substrates.
O (i) LDA O
Me O (ii) MeCHO Me O
Me 80% yield
Me
O Me d.r. 4 : 1
Me Me Me O
OH
Me
O (i) LDA
Me O Me O O
(ii) MeCHO 52% yield
Me Me d.r. 6 : 1
Me O Me O i-Pr
Me
OH
Me Me
13. Draw a rxn mechanism and explain the diastereoselectivity in the following rxn.
O HO
(i-Bu)3Al
Ph Ph
O O
Me Me
(i-Bu)3Al is a Lewis acid, but also serves as the reducing agent (with loss of isobutylene).
This is not an easy problem. Try to see what is going on first mechanistically then look at the key
steps more closely and consider stereochemical issues. The rxn was published in J. Am. Chem. Soc.
1995, 117, 6395.
14. Explain the following selectivities:
Me
Me2CuLi anti : syn
96 : 4
O O
Me Me
Me
O O
Me2CuLi anti : syn
4 : 96
Me
Me
Again this is not an easy problem. What you have to do is firstly identify the rxn we are looking at,
and don’t be confused by the way I have drawn the second product. Secondly, find out the preferred
conformation of the unsaturated ten-membered rings that minimises strain and transannular
interactions (molecular models will definitely help). Draw the conformation clearly in 3-D. Once
you have done this the explanation should follow. This work was published in Tetrahedron 1981,
37, 3981.

C5: Control in Organic Chemistry

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C5: Control in Organic Chemistry

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C5: Control in Organic Chemistry 1

Part II Chemistry 2003

Control in Organic Chemistry

2. Stereochemical Control in Four- and Five-Membered Rings

3. Stereochemical Control in Six-Membered Rings

4. Stereochemical Control with Bicyclic Compounds

5. Open Chain Stereochemical Control

Clayden, Greeves, Warren, Wothers “Organic Chemistry” Oxford, 2001.

How are rxns controlled?

Kinetically and thermodynamically controlled rxns:

What type of selectivity are we talking about?

Chemoselectivity – functional group discrimination

Regioselectivity – product structural isomer discrimination

Stereoselectivity – product stereoisomer discrimination

Stereochemistry involves diastereomers and enantiomers. Therefore stereoselectivity encompasses

E Enantiomeric transition E Diastereomeric transition

Rxn Coordinate Rxn Coordinate

What does the other enantiomer look like?

95% e.e. 95% e.e.

Stereospecific rxns are also possible with achiral starting materials:

Two common cases of diastereoselective rxns are:

si face addition re face addition

Chiral Starting Material Diastereomeric Products

Stereoselective rxns of cyclic compounds

Revision of Conformational Analysis

Learn how to draw a cyclohexane on p. 459-460 of Clayden et al.

Stereochemical Control in Four- and Five-Membered Rings

Just one sp2 centre

More than one sp2 centres

O (i) LDA, -78 ˚C, THF O

Just one sp2 centre

(±) 77% 23%

(±) 1.5% 98.5%

More than one sp2 centre

TBSO TBSO R1 TBSO R1

Suzuki, Noyori et al. J. Am. Chem. Soc. 1985, 107, 3348-3349.

How do we make both epoxides stereoselectively?

Stereochemical Control in Six-Membered Rings

Just one sp2 centre-addition to cyclohexanones

More than one sp2 centre

Trans-diaxial ring opening (Fürst-Plattner Rule)

Pasto, J. Am. Chem. Soc. 1970, 92, 7480.

Chelation can reverse the stereoselectivity.

Prévost and Woodward Methods:

Stereochemical Control with Bicyclic Compounds

Cyclopentane Fused Bicyclic Spiro-cyclic Bridged Bicyclic

trans possible, but difficult

trans more stable than cis

Open Chain Stereochemical Control

Nucleophilic Attack on Carbonyls with α–Chiral Centres

Molecules with a high degree of flexibility tend to react unselectively.

The major product results from the most reactive conformer.

Orbital Control in the Felkin-Anh model

Sometimes the result depends on the reagent:

(±) NaBH4 73% 27%

Transition states with different metal counterions:

Two things are required for chelation control:

1. A heteroatom with lone pairs available for coordination to a metal ion.

Mg2+, Zn2+, Al3+, Ce3+ and Ti4+ are excellent

O Is there a metal ion Use chelation model:

Use Felkin-Anh model: Use Felkin-Anh model:

Diastereoselective Rxns of Acyclic Alkenes

Me SiMe2Ph Me SiMe2Ph Me SiMe2Ph

As with rxns at C=O, conformation is the key.