1
Stereoselectivity 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! e.g. SN2 reactions
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 predominates.
Diastereoselective reactions - a stereogenic centre is introduced into a molecule in
such a way that diastereoisomers are produced in unequal amounts
O
HO Ph
PhMgBr
Me
Me
Me
HO Ph
Me
+
Ph H
91.5%
Ph H
Me
Me
Ph H
8.5%
• Enantioselective reactions - a reaction that produces two enantiomers of a
...product in unequal amounts
O
H
Me2Zn
(–)-DAIB (2%)
H OH
H OH
Me
Me
+
95.5% (S)
Me
4.5% (R)
91% ee
Me
NMe2
OH
Me
(–)-DAIB
123.702 Organic Chemistry
2
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
R
H Ph
25%
2%
H Ph
R = Me
R = t-Bu
R
H OH
+
Me
:
:
H Ph
75% (50% de)
98% (96% de)
R
% 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
1
O
view from
this face
H
view from
this face
Ph
Ph
2
O
anti-clockwise
Si face
H
3
123.702 Organic Chemistry
3
Felkin-Ahn model
O
H OH
EtMgBr
Ph
H
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
H
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
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
123.702 Organic Chemistry
4
Felkin-Ahn model II
• Nucleophiles attack the carbonyl group along the Bürghi-Dunitz angle of ~107°
Nu
R
R
Nu
Nu
R
C O
R
maximum overlap with π*
- nucleophile attacks at
90° to C=O
R
C O
R
repulsion from full π
orbital - nucleophile
attacks from obtuse angle
C O
compromise, nucleophile
attacks π* orbital at 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
close
to Ph
Nu
Ph
X
H Me
Me O
X
close
to Me
Ph
unhindered
approach
H H
Nu
Nu
X
close
to Ph
Nu
• Favoured approach passed smallest substituent (H) when molecule in most stable
...conformation
123.702 Organic Chemistry
5
Felkin-Ahn model IV
M O
O
L
M S
M
L
R
Nu
S R
OH
Nu OH
L
Nu
S
L
R
R
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 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 affect this...
123.702 Organic Chemistry
6
Diastereoselective addition to carbonyl group
O
Ph
HO H
RMgBr
H
Me H
R = Me
R = Et
R = Ph
Ph
O
Me(metal)
Ph
R
Me H
40% de
50% de
60% de
H
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
R
H Ph
50% de
50% de
66% de
96% de
123.702 Organic Chemistry
7
Effect of electronegative atoms
Me
OLi
O
Et
Me
OH
Me
O
O
OMe
H
Et
OMe
NBn2
Me
Et
OLi
Bn2N
NBn2
H H
>92% de
Et
HO
OMe
Bn2N
H
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
R
O
X
Nu
Z
R
X
Z = electronegative group
C=O π*
C–Z σ*
nucleophile interacts
with π* orbital
new π*+σ*
LUMO
Y
Nu
Z
R
X
C–Z σ*
C=O π*
new π*+σ*
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 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
123.702 Organic Chemistry
...overlap
8
Effect of electronegative atoms II
O
Li R3BH
Et
O
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
H
MeS
rotate to
allow
chelation
Ph H
H3B H
MeS O
MeS
Et
H Ph
OH
Et
H
H
Ph
• A good example of the previous effect is shown on the left hand-side
• 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!
123.702 Organic Chemistry
9
Chelation control
M
O
M
L
Z
L
Z
R
S
Nu OH
O
R
R
S
Z
L
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
Me
O
O
PhMgI
H
Me
O HO Ph
96% de
123.702 Organic Chemistry
10
Chelation control II
Me Ph2PO
NaBH4
MeOH, 20°C
Me Ph2PO
NaBH4, CeCl3
EtOH, –78°C
Me Ph2PO
Me
Me
H OH
Me
H OH
O
Ce
O
O Me
O
Ph P O
Ph
P
Ph
Ph
H BH3
H
Me
H3B H
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
123.702 Organic Chemistry
11
Felkin-Ahn control in total synthesis
t-Bu
t-Bu Si
O
Me
O
Me
O
H
Me
Me
t-Bu
TiCl4, DCM,
–90°C
O
+
t-Bu Si
O
Me3Si
Me
Me
Me
94%
95% d.e.
O
Me
O
OMe
Me
OH
Me
OMe
Me
HO
Cl3Ti
O Me
H
O
OH
MeO
Me
O
O
HO
H H
Me
Me
HO
SiMe3
Me
O
OMe
Me
OH
OH
Me
preswinholide
• An example of the Sakurai reaction from the synthesis of preswinholide A
• Preswinholide A is effectively the monomer of swinholide A (the dimer), a compound
displaying potent cytotoxic activity that was isolated from a Red Sea sponge
• Ian Paterson, Richard A. Ward, Julian D. Smith, John G. Cumming and Kap-Sun
Yeung, Tetrahedron, 1995, 51, 9437
123.702 Organic Chemistry
12
Chelation control in total synthesis
O
n-C4H9
H
TiCl4, –78°C,
DCM
OSiMe3
+
OMe
OBn
77%
100% de
OMe
OBn
BnO
BnO O
BnO
OH
n-C4H9
n-C4H9
Me3SiO
O
n-C4H9
TiCln
O n-C4H9
H H
OH
MeO
O
H H
H
H
MeO
• An example of the Mukaiyama aldol reaction
• Comes from the synthesis of canadensolide, a fungicidal agent
• Yung-Son Hon & Cheng-Han Hsieh, Tetrahderon, 2006, 62, 9713
O
O
H
H
n-C4H9
O
O
canadensolide
123.702 Organic Chemistry