1

Stereospecificity in organic synthesis

Stereospecific reactions - a reaction where the mechanism means the

stereochemistry of the starting material determines the stereochemistry of the

product; there is no choice. Occasionally, the term may be used with chiral reagents
or catalysts if the configuration of the product depends uniquely on the
configuration of the catalyst or reagent.
If the reaction starts with a chiral material the reaction will be enantiospecific
If the reaction forms only one diastereoisomer (control of relative stereochemistry
not absolute stereochemistry) it is diastereospecific
A typical example is substitution by a SN2 reaction
The reaction must proceed with inversion
Me

Enantiospecific

SiPhMe2
N3

Me

SiPhMe2

NaN3
O

Me
NaN3

OMs

Me

SiPhMe2

Me

N3

O
Me

N N N
Me

Diastereospecific

OsO4
CH2OH

HO
Me

OH

H
H
CH2OH
syn
diastereoisomer

HO
+

OH

H
Me

CH2OH
H
syn
diastereoisomer

O
Ms =

S Me
O

racemic mixture

Advanced organic

Stereoselectivity in organic synthesis

Stereoselective reactions - a reaction where one stereoisomer of a product is

formed preferentially over another. The mechanism does not prevent the formation
of two or more stereoisomers but one does predominate.
If a stereogenic centre is introduced into a molecule in such a way that
diastereoisomers are produced in unequal amounts the reaction is
diastereoselective
If a chemical reaction produces the two enantiomers of a chiral product in unequal
amounts it is as an enantioselective reaction
O

Diastereoselective

HO Ph
PhMgBr

Me

Me

Me

Ph H
91.5%

Ph H

Enantioselective

Me

HO Ph

Me2Zn
()-DAIB (2%)

Me

Me

Ph H
8.5%

H OH

H OH

Me

95.5% (S)
Me

Me

Me
4.5% (R)

91% ee
NMe2
OH

Me

()-DAIB

Advanced organic

Stereospecific reactions
Initially, we will look at the general principles of stereo-specific and -selective
reactions
This is intended to familiarize the terminology we have just covered and to instill a
number of the basic principles we will be utilising in the rest of the course
In future lectures we will look at asymmetric synthesis or various strategies for
enantioselective synthesis

Enantiospecific reactions
TsO Me
Me S

Me OTs

KOH
H2S

S Me

HS Me

Me

Me OTs

Me R

S Me

Me

Me

Me

SN2 reaction occurs with complete inversion - retain stereochemical information

Very useful if we already have incorporated stereochemistry
R Me

inversion

no change in
stereochemistry;
only name

Me R

O
LiH2N(CH2)2NH2

R
O
Me

OMe
Me

>90%

S OH
O
OMe
Me

Me

Epoxides are excellent candidates for enantiospecific reactions

Highlights area of potential confusion: (R,S) nomenclature is independent of the

...chemical process occurring (stereochemistry at Me (R) inverted yet still (R)

Advanced organic

Stereospecific reactions II
A number of very useful reactions of alkenes are diastereospecific
Electrophilic epoxidation
H

Ph

Ar
O
O

H
Ph

Ph

m-CPBA
H
Ph

H
(E)

H
H
Ph
H

Ph

H
anti

Ph

m-CPBA
H
Ph

Ph

Note: only
controlling relative
stereocheimstry
NOT absolute
stereochemistry

H
Ph

syn

(Z)

Epoxidation with peracids occurs via a concerted process

Results in conservation of alkene geometry

Hydroboration
Again occurs via a concerted reaction (bonds made & broken at same time)
Observe syn addition of hydrogen and boron
Further stereospecific transformations possible
Ph

H
BR2

Ph

Ph
H
BR2

syn
addition

HOO

Ph
H

BR2
O OH
retention of
stereochemistry

OH

Note: only
controlling relative
stereocheimstry
NOT absolute
stereochemistry

Advanced organic

Stereospecific reactions III

Bromination
Bromination of alkenes proceeds with the anti addition of Br2 across the double bond
This is the result of the formation of a bromonium cation followed by SN2 attack
The geometry of the starting material controls the stereochemistry of the product
Me

Br2

Me

Me

Me
H

Br

(E)

Br
anti

Me

Br

Br
Br

Br

(Z)

Me

Note: only controlling relative

stereocheimstry NOT
absolute stereochemistry

Me

H Br H

Br2

Me

Br

Me Br H

Me

Me

Me
Me
Me rotate
central bond
Br
syn

Iodolactonisation
Proceeds in an analogous fashion via an iodonium species
Geometry of alkene controls relative stereochemistry
O
Me

Me

(E)

Me

I2

O
O
(Z)

I2

Me

I
O

H
I

Me

O
anti

I
Me

O
syn

Advanced organic

Stereoselective reactions

Nucleophilic addition to C=O

Reaction of a nucleophile with a chiral substrate gives two possible diastereoisomers
Reaction is stereoselective if one diastereoisomer predominates
LiAlH4
H3O+

O
Me

H OH
Me

H Ph
25%
2%

H Ph
R = Me
R = t-Bu

H OH
+

Me

:
:

H Ph
75% (50% de)
98% (96% de)

% de = diastereisomeric excess = [major] [minor] = %major %minor

[major] + [minor]

Prochiral Nomenclature
Trigonal carbons that are not stereogenic centres but can be made into them are prochiral
Each face can be assigned a label based on the CIP rules

If the molecule is chiral (as above) the faces are said to be diastereotopic
If the molecule is achiral (as below) the faces are enantiotopic
O

clockwise
Re face H
3

1
Ph
2

view from
this face

view from
this face
Ph

Ph
2

anti-clockwise
Si face
H
3

Advanced organic

Felkin-Ahn model
O

H OH
EtMgBr

Ph

Ph

Et

HO H
+

Me H
25%

Me H

Ph

Et

Me H
75% (50% de)

The diastereoselectivity can be explained and predicted via the Felkin-Ahn model
It is all to do with the conformation of the molecule...
Easiest to understand if we look at the Newman projection of the starting material
Ph
O

O
Ph

two substituents (C=O & Ph)

are eclipsed - unfavoured

Me H

Me

Rotate around central bond so that substituents are staggered

Continue to rotate around central bond and find 6 possible conformations
Two favoured as largest substituent (Ph) furthest from O & H
Ph O

O H
H

Me H

H O

Ph

O Me
Me

H Me

largest
substituent
(Ph) furthest
from O & H

Ph H

Me O

O Ph
Ph

H
H Ph

H H

largest
substituent
(Ph) furthest
from O & H

Me
H H

Advanced organic

Felkin-Ahn model II
Nucleophiles attack the carbonyl group along the Brghi-Dunitz angle of ~107
Nu

R
R

Nu

Nu
R

C O

maximum overlap with *

- nucleophile attacks at
90 to C=O

C O

repulsion from full

orbital - nucleophile
attacks from obtuse angle

C O

compromise, nucleophile
attacks * orbital at angle
of 107

As a result of the Brghi-Dunitz (107) angle there are four possible trajectories for

the nucleophile to approach the most stable conformations

Three are disfavoured due to steric hindrance of Ph or Me
Therefore, only one diastereoisomer is favoured
Brghi-Dunitz
angle: 107
O H
close
to Ph
Nu

Ph

H Me

Me O

close
to Me

Ph

unhindered
approach
H H

Nu

Nu

close
to Ph
Nu

Favoured approach passed smallest substituent (H) when molecule in most stable
...conformation

Advanced organic

Felkin-Ahn model III

Me O

Me OH

EtMgBr

Ph

Ph

Me H

Et
H

H H

Et

rotate
Ph
H

Me

OH

HO H
Ph

Et
H

Ph

Et

Me H

Apply the Felkin-Ahn model to our example

Most problems seem to occur when swapping between different representations...
O

HO H
EtMgBr

Ph

Ph

HO H
EtMgBr
H

Ph

Et

Me

HO H
EtMgBr
H

Ph
Me H

Me H
Me

Et

Me

OH

Et
H

OH

Ph

4. Remember, we prefer to draw the main carbon chain

in the plane of page, therefore, align Ph and Et in
Newman projection as well

H
HO H

Ph

Et
H

Et

Ph

2. First, remember which parts of the molecule have not

been effected by the reaction and draw them
3. As the original stereogenic centre has not changed,
we will compare the relative orientation of the
substituents on the new centre to these

HO

Me H

Me H

Ph

Et

Me H

Me H

Ph

1. So, assuming we have used the Felkin-Ahn model and

Newman projections to predict the product, how do we
draw the correct zig-zag representation?

Ph
Me H

Et

5. Me and OH on same side, therefore, as Me not

effected by reaction & is up, OH must be up. This
leaves both H down.

Advanced organic

10

Felkin-Ahn model IV
M O

O
L
M S

M
L

R
Nu

S R

OH

Nu OH
L

Nu
S

M S

L = large group, M = medium group, S = small group

To explain or predict the stereoselectivity of nuclophilic addition to a carbonyl group

with an adjacent stereogenic centre, use the Felkin-Ahn model

Draw Newman projection with the largest substituent (L) perpendicular to the C=O
Nucleophile (Nu) will attack along the Brghi-Dunitz trajectory passed the least
sterically demanding (smallest, S) substituent
Draw the Newman projection of the product
Redraw the molecule in the normal representation

Whilst the Felkin-Ahn model predicts the orientation of attack, it does not give any
information about the degree of selectivity
Many factors can effect this...

Advanced organic

11

Diastereoselective addition to carbonyl group

O
Ph

HO H
RMgBr
H

Me H
R = Me
R = Et
R = Ph

Ph

O
Me(metal)

Ph

Me H
40% de
50% de
60% de

HO H
Ph

Me

Me H
Me(metal) = MeMgI
33% de
Me(metal) = MeTi(OPh)3 86% de

Me H

The size of the nucleophile greatly effects the diastereoselectivity of addition

Larger nucleophiles generally give rise to greater diastereoselectivities
Choice of metal effects the selectivity as well, although this may just be a steric effect
The size of substituents on the substrate will also effect the diastereoselectivity
Again, larger groups result in greater selectivity
Should be noted that larger substituents normally result in a slower rate of reaction
O
Me
H Ph
R = Me
R = Et
R = i-Pr
R = t-Bu

LiAlH4
R

H OH
Me

H Ph
50% de
50% de
66% de
96% de

Advanced organic

12

Effect of electronegative atoms

Me

OLi

Et

Me

OH

Me
O

OMe

Et

OMe

NBn2

Me
Et
OLi

Bn2N

NBn2

H H

>92% de

Et

HO

OMe

Bn2N
H

CO2Me

It is hard to justify the excellent selectivity observed above using simple sterics
The Bn2N group must be perpendicular to C=O but a second factor must explain why

the selectivity is so high (& the reaction much faster than previous examples)
There is an electronic effect
O
Nu

O
Y

Y
Z

Nu
Z

R
X

Z = electronegative group

C=O *

CZ *

nucleophile interacts
with * orbital

new *+*
LUMO
Y

Nu
Z

R
X

CZ *
C=O *
new *+*
LUMO

new low energy orbital formed from C=O & C-Z antibonding orbitals favours nucleophilic attack at carbonyl

When an electronegative group is perpendicular to the C=O it is possible to get an

of the * orbital and the * orbital

Overlap results in a new, lower energy orbital, more susceptible to nucleophilic attack
Thus if electronegative group perpendicular, C=O is more reactive
Advanced organic
...overlap

13

Effect of electronegative atoms II

O
Li R3BH

Et

HO H
Ph

Et

Ph
SMe

SMe

H OH
Zn BH4

Et

H BR3

H
Ph

O Et

Et

MeS
Ph H

Ph
SMe

Zn
HO

MeS

Cram-chelation
control

SMe

Felkin-Ahn
attack
O Et

Et

Ph

MeS

rotate to
allow
chelation

Ph H

H3B H

MeS O

MeS
Et

H Ph

OH
Et

H
H

Ph

A good example of this effect is shown

But as always, chemistry not that simple...

If heteroatom (Z) is capable of coordination and...

...a metal capable of chelating 2 heteroatoms is present we observe chelation control

Metal chelates carbonyl and heteroatom together
This fixes conformation
Such reactions invariably occur with greater selectivity
Reactions are considerably faster
The chelating metal acts as a Lewis acid and activates the carbonyl group to attack
As shown, chelation can reverse selectivity!
Advanced organic

14

Chelation control
M

O
M

L
Z

R
S

Nu OH

Nu
Nucleophile attacks
from least hindered face
Z = heteroatom capable of coordination; M = metal
capable of coordinating to more than one heteroatom

Chelation controlled additions are easy to predict

Normally do not need to draw Newman projection (yippee!)
Simple example shown below

H
Me
O

PhMgI

H
Me
O HO Ph
96% de

Advanced organic

15

Chelation control II
Me Ph2PO

NaBH4
MeOH, 20C

Me Ph2PO

NaBH4, CeCl3
EtOH, 78C

Me Ph2PO

Me

Me
H OH

Me
H OH

Ce
O

O Me

Ph P O
Ph

Ph
Ph

H BH3
H
Me

H3B H

Me
Me

Example shows normal Felkin-Ahn selectivity gives one diastereoisomer

Electronegative and bulky phosphorus group in perpendicular position
Chelation control gives opposite diastereoisomer
Chelation can occur through 6-membered ring
Lower temperature typical of activated, chelated carbonyl

Advanced organic