This document discusses stereospecific and stereoselective organic reactions. It defines different types of stereospecific reactions, such as enantiospecific and diastereospecific reactions. It also defines stereoselective reactions. The document then discusses the Felkin-Ahn model for predicting the stereoselectivity of nucleophilic additions to carbonyl groups with adjacent stereocenters. It explains how the model uses Newman projections and predicts attack based on sterics. Finally, it discusses factors that can influence stereoselectivity such as the size of substituents and nucleophiles, and the use of electronegative atoms or metal chelation to further control stereoselectivity.

1. Advanced organic
O
Me SiPhMe2
N3
Me
O O
Me SiPhMe2
N3
Me
O
N N N
O
Me SiPhMe2
OMs
Me
O
NaN3
O
Me SiPhMe2
N3
Me
O
NaN3
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
1
Ms = S
O
O
Me
Enantiospecific
Diastereospecific
Me
CH2OH
OsO4
HO
H
Me H
CH2OH
HO
Me
H CH2OH
H
OH OH
+
syn
diastereoisomer
syn
diastereoisomer
racemic mixture
X

2. Advanced organic
Me
H OH
Me
H OH
95.5% (S) 4.5% (R)
+
Me
Me
H
Ph
HO Ph
Me
Me
H
Ph
HO Ph
91.5% 8.5%
+
Me
Me
O
H
Ph
PhMgBr
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
2
Diastereoselective
Enantioselective
H
O Me2Zn
(–)-DAIB (2%)
Me
OH
NMe2
Me
Me
(–)-DAIB
91% ee

3. Advanced organic
Me
O
O
OMe
Me Me
Li•H2N(CH2)2NH2
O OMe
Me Me
Me
OH
R
R
S
R
+
>90%
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
3
Enantiospecific reactions
Me Me
TsO OTs
KOH
H2S
Me Me
HS OTs
S
Me Me
Me Me
S S R S
R R
Me
Me
Me
Me
• SN2 reaction occurs with complete inversion - retain stereochemical information
• Very useful if we already have incorporated stereochemistry
• 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)
no change in
stereochemistry;
only name
inversion

4. Advanced organic
Ph
H
BR2
O OH
Ph
H
OH
HOO
retention of
stereochemistry
Ph
H
BR2
syn
addition
Ph
H
BR2
Ph
H
Ph
H
O
m-CPBA
syn
Ph
H
H
Ph
O
m-CPBA
anti
Ph
H
H
Ph
(Z)
Ph
Ph
H
H
(E)
Ph H
Ph
H
O
O
O
H
Ar
Stereospecific reactions II
• 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
4
A number of very useful reactions of alkenes are diastereospecific
Electrophilic epoxidation
Note: only
controlling relative
stereocheimstry
NOT absolute
stereochemistry
Note: only
controlling relative
stereocheimstry
NOT absolute
stereochemistry

5. Advanced organic
I
Me O O
syn
O
O
H
Me
I2
(Z)
I
Me O O
H
I
Me O O
anti
I
Me
Me
Br
Br
syn
rotate
central bond
Br2
H
Me Me
H
Br
Br
Me
Br
Me
Br
H
Me Me
H
(Z)
Me
Me
Br
Br
anti
Br2
Me
H Me
H
Br
Br
Me
H Me
H
(E)
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
5
Iodolactonisation
• Proceeds in an analogous fashion via an iodonium species
• Geometry of alkene controls relative stereochemistry
Note: only controlling relative
stereocheimstry NOT
absolute stereochemistry
O
O
H
Me
I2
(E)
O
O
H
Me
I

6. Advanced organic
view from
this face H
Ph
O
2 3
1
anti-clockwise
Si face
H Ph
O
2
3
1
H Ph
O
2
3
1
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
6
Me
R
O
H Ph
LiAlH4
H3O+
Me
R
H Ph
H OH
Me
R
H Ph
H OH
+
R = Me
R = t-Bu
75% (50% de)
98% (96% de)
25%
2%
:
:
O
Ph
H
view from
this face
clockwise
Re face
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
% de = diastereisomeric excess = [major] – [minor]
[major] + [minor]
= %major – %minor

7. Advanced organic
Ph
Me
H H
O
Ph
Me
H H
O
Ph
H
Me
H
O
Ph
H
Me
H
O
Ph
H
O
Me H
Ph
H
O
Me H
Ph
H
Me
H
O
two substituents (C=O & Ph)
are eclipsed - unfavoured
Felkin-Ahn model
• 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
7
Ph
H
O
Me H
EtMgBr Ph
Et
Me H
Ph
Et
Me H
H OH HO H
25% 75% (50% de)
+
• Rotate around central bond so that substituents are staggered
• Two favoured as largest substituent (Ph) furthest from O & H
• Continue to rotate around central bond and find 6 possible conformations
Me
Ph
H
H
O
Me
H
Ph H
O
H
Me
Ph
H
O
H
Ph
Me H
O
largest
substituent
(Ph) furthest
from O & H
largest
substituent
(Ph) furthest
from O & H

8. Advanced organic
C O
R
R
C O
R
R
Nu
C O
R
R
C O
R
R
Nu
Felkin-Ahn model II
• As a result of the Bürghi-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
8
• Nucleophiles attack the carbonyl group along the Bürghi-Dunitz angle of ~107°
maximum overlap with π*
- nucleophile attacks at
90° to C=O
C O
R
R
Nu
C O
R
R
repulsion from full π
orbital - nucleophile
attacks from obtuse angle
compromise, nucleophile
attacks π* orbital at angle
of 107°
Ph
H
Me
H
O
Ph
Me
H H
O
Nu Nu
Nu Nu
Bürghi-Dunitz
angle: 107°
Ph
H
Me
H
O
Ph
Me
H H
O
Nu Nu
Nu Nu
close
to Ph
close
to Ph
close
to Me
unhindered
approach
X X X
• Favoured approach passed smallest substituent (H) when molecule in most stable
...conformation

9. Advanced organic
Ph
Me
H
OH
Et
H
Ph
Me
H
OH
Et
H
Ph
Et
Me H
HO H
Ph
Et
Me H
HO H
Ph
Et
Me H
HO H
Ph
Et
Me H
HO H
Ph
Me
H H
O
Ph
H
O
Me H
EtMgBr
Felkin-Ahn model III
• Apply the Felkin-Ahn model to our example
• Most problems seem to occur when swapping between different representations...
9
Ph
Et
Me H
HO H
Ph
H
O
Me H
EtMgBr 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
Et
Me H
HO H
Ph
H
O
Me H
EtMgBr
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
Ph
Me
H
H
HO
Et
Ph
Et
Me H
HO H
Ph
H
O
Me H
EtMgBr 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
Ph
Me
H
OH
Et
H
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.
Et
Ph
Me
H
OH
Et H
Ph
Me
H
OH
Et
H
rotate

10. Advanced organic
Felkin-Ahn model IV
• 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 Bürghi-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...
10
L
R
O
M S
L
M
S R
O
Nu
L
M
S
OH
Nu
R
L
R
M S
Nu OH
L = large group, M = medium group, S = small group

11. Advanced organic
Diastereoselective addition to carbonyl group
• 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
11
Ph
R
Me H
HO H
Ph
H
O
Me H
RMgBr
R = Me
R = Et
R = Ph
40% de
50% de
60% de
Ph
Me
Me H
HO H
Ph
H
O
Me H
Me(metal)
Me(metal) = MeMgI
Me(metal) = MeTi(OPh)3
33% de
86% de
Me
R
O
H Ph
Me
R
H Ph
H OH
R = Me
R = Et
R = i-Pr
R = t-Bu
50% de
50% de
66% de
96% de
LiAlH4

12. Advanced organic
Effect of electronegative atoms
• 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
12
Me
Et
NBn2
O
H
OLi
OMe
Me
Et
NBn2
OH
OMe
O
>92% de
Bn2N
H
H
O
Me
Et
OLi
OMe
Bn2N
H
HO
H
Me
Et
CO2Me
• Overlap results in a new, lower energy orbital, more susceptible to nucleophilic attack
• Thus if electronegative group perpendicular, C=O is more reactive
Z
Y
X
O
R
Nu
Z = electro-
negative group
• When an electronegative group is perpendicular to the C=O it is possible to get an
...overlap of the π* orbital and the σ* orbital
Z
Y
X
O
R
Nu
C=O π*
C–Z σ*
nucleophile interacts
with π* orbital
C=O π*
C–Z σ*
new π*+σ*
LUMO
Z
Y
X
O
R
Nu
new π*+σ*
LUMO
new low energy orbital formed from C=O & C-Z anti-
bonding orbitals favours nucleophilic attack at carbonyl

13. Advanced organic
Et
MeS
H Ph
O
Zn
rotate to
allow
chelation
MeS
Et
H
Ph
O
Ph
Et
O
SMe
Zn
Ph
Et
SMe
H OH
BH4
Ph
Et
O
SMe
Li R3BH
Ph
Et
SMe
HO H
Effect of electronegative atoms II
• A good example of this effect is shown
• But as always, chemistry not that simple...
13
MeS
Et
H
Ph
O
H BR3
MeS
Et
H
HO
H
Ph
Felkin-Ahn
attack
Cram-chelation
control
Et
MeS
H
OH
H
Ph
H
H3B
• 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!

14. Advanced organic
Chelation control
• Chelation controlled additions are easy to predict
• Normally do not need to draw Newman projection (yippee!)
• Simple example shown below
14
L
R
Nu OH
Z S
M
R
O
Z
M
S L
L
R
O
Z S
Z = heteroatom capable of coordination; M = metal
capable of coordinating to more than one heteroatom
Nu
Nucleophile attacks
from least hindered face
O
H
O
Me
PhMgI
O
H
Me
HO Ph
96% de

15. Advanced organic
Me
Me
Ph2PO
H OH
NaBH4, CeCl3
EtOH, –78°C
Me
O
Me
Ph2PO
Me
Me
Ph2PO
H OH
NaBH4
MeOH, 20°C
Chelation control II
• Example shows normal Felkin-Ahn selectivity gives one diastereoisomer
• Electronegative and bulky phosphorus group in perpendicular position
15
• Chelation control gives opposite diastereoisomer
• Chelation can occur through 6-membered ring
• Lower temperature typical of activated, chelated carbonyl
P
Me
H
O
Me
O
Ph
Ph
H BH3
Me
P
H
O
H
H3B
Me
O
Ph
Ph
Ce