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 SiPhMe2 Me SiPhMe2 Me SiPhMe2

X
NaN3 NaN3
Enantiospecific O O
N3
O O
OMs
O O
N3

Me Me Me
N N N

Me HO OH HO OH
OsO4
+
Me H H CH2OH O
CH2OH H CH2OH Me H
Diastereospecific syn
diastereoisomer
syn
diastereoisomer
Ms = S Me
O

racemic mixture
Advanced organic
2

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 HO Ph HO Ph
PhMgBr Me Me
Me +
Diastereoselective Me Me Me
Ph H Ph H Ph H
91.5% 8.5%

O Me2Zn H OH H OH
(–)-DAIB (2%)
H Me + Me
Enantioselective
95.5% (S) 4.5% (R)
Me Me
91% ee
NMe2
OH
Me
(–)-DAIB
Advanced organic
3

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
KOH Me Me
TsO Me Me OTs H2S HS Me Me OTs

Me S S Me Me R S Me
Me S Me
R R

• SN2 reaction occurs with complete inversion - retain stereochemical information

• Very useful if we already have incorporated stereochemistry
inversion R Me Me R no change in
O stereochemistry;
only name
Li•H2N(CH2)2NH2 + R S OH
>90%
O OMe O OMe
Me Me 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
4

Stereospecific reactions II
A number of very useful reactions of alkenes are diastereospecific
Electrophilic epoxidation
H Ph O
m-CPBA
Ar
H Ph
O Ph H Ph H Note: only
O H (E) anti controlling relative
O stereocheimstry
H H O NOT absolute
H Ph
m-CPBA stereochemistry
Ph H H H
Ph Ph Ph Ph
(Z) syn

• 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 Ph Ph
Ph
H HOO H Note: only
H H
BR2 controlling relative
BR2 BR2 OH stereocheimstry
O OH NOT absolute
syn retention of stereochemistry
addition stereochemistry
Advanced organic
5

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
Br
Me H Me Br H
Br2 Me Note: only controlling relative
Me stereocheimstry NOT
H Me H Me absolute stereochemistry
Br Br
(E) anti
Br Br
H H H Br H
Br2 Br Me
Me rotate Me
Me Me Me Me central bond
Br Me Br
(Z) syn
Iodolactonisation
• Proceeds in an analogous fashion via an iodonium species
• Geometry of alkene controls relative stereochemistry
I I I
I2
O
O
Me O H Me O H Me O
Me O H O O
(E) I anti
Me I
I2
O
O H Me O O
(Z) syn
Advanced organic
6

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
O LiAlH4 H OH H OH
H3O+ Me Me
Me +
R R R
H Ph H Ph H Ph
R = Me 25% : 75% (50% de)
R = t-Bu 2% : 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

1 1
O O O
clockwise view from view from anti-clockwise
Re face H Ph this face H this face Ph H Si face
Ph
3 2 2 3

Advanced organic
7

Felkin-Ahn model
O H OH HO H
EtMgBr Ph Ph
Ph +
H Et Et
Me H Me H Me H
25% 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)
H are eclipsed - unfavoured
Me H Me H
H

• 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 O O Me Me O O Ph

H Ph Me H Ph Me

Me H H Me Ph H H Ph H H H H
largest largest
substituent substituent
(Ph) furthest (Ph) furthest
from O & H from O & H
Advanced organic
8

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

R R R
C O C O C O
R R R

maximum overlap with π* repulsion from full π compromise, nucleophile

- nucleophile attacks at orbital - nucleophile attacks π* orbital at angle
90° to C=O attacks from obtuse angle of 107°

• 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
Bürghi-Dunitz
angle: 107°
O H Me O

close Ph close unhindered Ph close

to Ph
X H Me
X to Me approach
H H
X to Ph

Nu Nu Nu Nu

• Favoured approach passed smallest substituent (H) when molecule in most stable
...conformation Advanced organic
9

Felkin-Ahn model III

O Me O Me OH Me OH HO H
EtMgBr rotate
Ph Ph Ph Et Ph Ph
H Et
Et H
Me H Et H H H H H 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 1. So, assuming we have used the Felkin-Ahn model and
Ph Newman projections to predict the product, how do we
H Et
draw the correct ‘zig-zag’ representation?
Me H Me H

O HO H Me H 2. First, remember which parts of the molecule have not

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

O HO H Me OH
EtMgBr Ph 4. Remember, we prefer to draw the main carbon chain
Ph Et Ph in the plane of page, therefore, align Ph and Et in
H Et
Newman projection as well
Me H Me H H H

Me OH HO H
Ph 5. Me and OH on same side, therefore, as Me not
Et Ph Et effected by reaction & is ‘up,’ OH must be ‘up.’ This
leaves both H down.
H H Me H
Advanced organic
10

Felkin-Ahn model IV

O M O M OH Nu OH
L L Nu L L
R R
M S S R S R M S
Nu
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 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...

Advanced organic
11

Diastereoselective addition to carbonyl group

O HO H O HO H
RMgBr Ph Me(metal)
Ph Ph Ph
H R H Me
Me H Me H Me H Me H
R = Me 40% de Me(metal) = MeMgI
R = Et 50% de 33% de
R = Ph 60% de Me(metal) = MeTi(OPh)3 86% de

• 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 H OH
LiAlH4
Me Me
R R
H Ph H Ph
R = Me 50% de
R = Et 50% de
R = i-Pr 66% de
R = t-Bu 96% de

Advanced organic
12

Effect of electronegative atoms

OLi
Me O Me Me
Me OH O
OMe O Et HO Et
Et H Et OMe OLi
Bn2N Bn2N
NBn2 NBn2
OMe H CO2Me
>92% de H H H

• 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 O new π*+σ*
O C–Z σ*
Y C=O π* Y LUMO
Y
Nu Nu Nu
R Z Z Z C=O π*
R R
X new π*+σ*
X C–Z σ* X LUMO
Z = electro- nucleophile interacts new low energy orbital formed from C=O & C-Z anti-
negative group with π* orbital bonding orbitals favours nucleophilic attack at carbonyl

• 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
• 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
13

Effect of electronegative atoms II

O HO H O H OH
Et Li R3BH Et Et Zn BH4 Et
Ph Ph Ph Ph
SMe SMe SMe Cram-chelation SMe
control
Felkin-Ahn
attack Zn
rotate to MeS O
O Et HO Et O Et allow MeS OH
chelation
MeS MeS H MeS Et H Et

H BR3 H3B H H Ph Ph
Ph H Ph H Ph H H

• 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 O Nu OH
L M Z L
R R R
Z S S L Z S
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 H
PhMgI
Me Me
O O HO Ph
O
96% de

Advanced organic
15

Chelation control II
Me Ph2PO NaBH4 Me Ph2PO NaBH4, CeCl3 Me Ph2PO
MeOH, 20°C EtOH, –78°C
Me Me Me
H OH O H OH

Ce
O Me O
O
P Ph P O
Ph Ph
Ph H BH3 Me
H
Me H3B H H
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