1

Stereoselective reactions of alkenes

I
I2
O
Me O H Me O O

• Earlier, we saw that stereospecific reactions can produce single diastereoisomers

• If there is a pre-existing stereogenic centre reactions can be stereoselective
• In other words, the faces of the alkene are diastereotopic
• Following two examples show highly diastereoselective iodolactonisations
Me Me Me Me
I2 I2
I
OH I
O O O OH O O
O
82% de 88% de

• These cyclisations are probably under thermodynamic control

• This means the reactions are reversible and equilibrate
• Therefore the product is the most stable compound

• If the reactions are under kinetic control we have to look at other factors and need to
...look at conformation again...
Advanced organic
2

Stereoselective reactions of alkenes II

O O
Me m-CPBA Me Me
+
Me SiMe2Ph Me SiMe2Ph Me SiMe2Ph

>95% <5%

• Two diastereoisomers formed as a result of attack from the two diastereotopic faces
• Look at possible conformations...
• Arguably the lowest energy conformations have greatest separation of substituents
H H Me H H Me
Me H H H Me if no cis substituent
rotate then only small
H bond Me H
Me energy difference
lowest energy: H slightly higher energy: Me
eclipses plane of alkene eclipses plane of alkene

H Me H Me

X
H H

Me Me H Me Me
cis substituent
H Me H present then only
Me Me high energy: Me–Me ONE conformation
lowest energy: H interaction disfavours
eclipses plane of alkene conformation

• The control of conformation by the interaction of methyl group and stereocentre is

...called allylic strain or A(1,3) strain
Advanced organic
3

Stereoselective reactions of alkenes III

• Apply this knowledge to the real system...
X

O O
Me m-CPBA Me Me

Me H SiMe2Ph Me H SiMe2Ph Me H SiMe2Ph

>95% <5%

m-CPBA
m-CPBA
silyl group blocks
X

approach
Me Ph Me Ph H H H
lowest energy H H Si Me H H Si Me Me Me
conformation
Me H Me OH Si Me
Me Me Ph Me
formation of minor
m-CPBA diastereoisomer results
from m-CPBA
approaching alkene in
above conformation or
m-CPBA approaches approaching passed
from unhindered face the silyl group

Advanced organic
4

Importance of A(1,3) strain

Me Me O O
m-CPBA Me Me Me Me
+
H SiMe2Ph H SiMe2Ph H SiMe2Ph
61% 39%

• The importance of a cis-substituent is made clear by the reduced stereoselectivity

• This is explained as follows...
m-CPBA
X
Ph Me Ph Me
O
lowest energy Me H Si Me Me H Si Me Me Me
conformation H H
gives major product H OH H SiMe2Ph
Me Me 61%

Me Me m-CPBA attacks both conformations low

form least hindered energy -- so mixture of
H SiMe2Ph face products

O
Me H H Me H H O
H Me H Me Me
Me
X

Si Me Si Me H SiMe2Ph
Ph Me Ph Me 39%

m-CPBA
Advanced organic
5

Other reactions...
• Epoxidation is not the only stereoselective reaction of alkenes
• Below is an example of hydroboration, a useful reaction that you should be familiar
with...
H Me Me H Me H Me H2O2 H Me H Me
BH3 NaOH

O OBn O H2B OBn O OH OBn

74% de

Attack from the least sterically

O O demanding face of the alkene
H CH2OBn H CH2OBn as it resides in the most
H Me H Me favoured conformation.
H2B H Followed by stereospecific
Me
H2B H
Me
oxidation

preferred
approach Selectivity in addition to cis alkenes

S H L S H L
S H R 1 1
R 3R R
L H S 3
L R1
R1 R1 R1
S = smaller group favoured destabilised by repulsion between C-1 & C-3
L = larger group substituents or A(1,3) strain
Advanced organic
6

Directed epoxidation
OH OH OH
reagent
+
O O

reagent: syn t anti

m-CPBA 92 : 8
t-BuO2H, VO(acac)2 98 : 2

• A hydroxyl group can reverse normal selectivity and direct epoxidation

• Epoxidation with a peracid, such as m-CPBA, is directed by hydrogen bonding and
favours attack from the same face as hydroxyl group
• The reaction with a vanadyl reagent results in higher stereoselectivity as it bonds /
chelates to the oxygen

Ar hydrogen
bond O
t-BuO
O
O Me O V O Me V
O O O O O
O H
H Me Me
O
vanadyl acetylacetonate H
H

Advanced organic
7

Directed epoxidation in acyclic systems

Me Me O O
m-CPBA Me Me Me Me
+
Me H OH Me H OH Me H OH
95 5

hydrogen
Ar bond
Me H H
O O Me Me
O Me H OH
O H H O
H O
Me H H
Me H O O
O
Me H Me
Ar
favoured Me disfavoured
conformation conformation

• Hydroxyl group can direct epoxidation in acyclic compounds as well

• Once again, major product formed from the most stable conformation
• Thus the cis methyl group is very important
• The minor product is formed either via non-directed attack or via the less favoured
...conformation

Advanced organic
8

Directed epoxidation: effect of C-2 substituent

Me t-BuO2H Me Me
VO(acac)2 Me Me
Me +
O O
H OH OH OH
19 : 1 steric
interaction
Me t-Bu O L
H V
O H O L
favoured disfavoured
conformation as H Me H Me conformation as
only Me & H eclipse O Me Me & Me eclipse
L O
V H
O L
t-Bu H

• The presence of a substituent in the C-2 position (Me) facilitates a highly

diastereoselective reaction
• The preferred conformation minimises the interaction between the two Me (& Me)
groups
• With C-2 substituent (H) there is little energy difference between conformations
• Therefore, get low selectivity
Me
t-BuO2H H
Me Me VO(acac)2 Me Me Me Me O H
+ H too small to
O O H H differentiate
H OH OH OH
O conformations
: L
2.5 1 V
O L
t-Bu Advanced organic
9

Directed reactions
SiMe3 t-BuO2H SiMe3
VO(acac)2 TBAF Me Me
Me Me Me Me
O
O OH
H OH OH
25:1

• It is possible to form the desired allylic epoxide in a highly selective manner by

utilising a temporary blocking group
• The silyl group causes one conformation to predominate & can be removed at end
• As silyl group bigger than methyl reaction more selective
• Other diastereoselective reactions of alkenes can be controlled by a directing group
• Below is an example of cyclopropanation by the Simmons-Smith reagent

CH2I2
Zn Zn I
OH O CH2 OH
H C Zn
H2 H
C I + I O
I Zn
H
carbenoid >98% de

Advanced organic
10

Stereoselective reactions of enolates

M
O O O
R2 E R2
R2
R1 R1 R1
H H H E
H

• The stereoselectivity of reactions of enolates is dependent on:

• Presence of stereogenic centres on R , R or E (obviously!)
1 2

• Frequently on the geometry of the enolate (but not always)

C-α re face C-α si face

M M
O O
α R2 MO α R2 α H MO α H
R1 R1
H R1 H R2 R1 R2
(Z)-enolate (E)-enolate
(cis) (trans)
C-α si face C-α re face

• Use terms cis and trans with relation to O–M to avoid confusion
Advanced organic
11

Enolate formation and geometry

• Enolate normally formed by deprotonation
• This is favoured when the C–H bond is perpendicular to C=O bond as this allows σ
orbital to overlap π orbital
• σ C–H orbital ultimately becomes p orbital at C-α of the enolate p bond
enolate
C–H σ π orbital
orbital
C=O π H
orbital O R2 base O R2 + H base

R1 H R1 H

• Two possible conformations which allow this

• First is given below and results in the formation of cis enolate
• Initial conformation (Newman projection) similar to transition state
• Little steric interaction between R1 and R2

base base base H base

H
H
H R2
O O R2 O R2
R1
H
O
R2
≡ R1 H R1 H R1 H

transition (Z)-enolate
state (cis)

Advanced organic
12

Enolate formation and geometry II

base base base H base
H
H
O H H O H O H
R1
R2 H
O ≡ R1 R2 R1 R2 R1 R2
(E)-enolate
(trans)

• Second conformation that places C–H perpendicular to C=O gives trans-enolate

• Only differs by relative position of R and R2
1

• The steric interaction of R1 and R2 results in the cis-enolate normally predominating

• As results below demonstrate stereoselectivity is influenced by the size of R1

LDA Li
O Li O
THF O
+
Me –78°C Me R
R R
Me
cis trans
R = Et 30 : 70
i-Pr 60 : 40
t-Bu >98 : <2
OMe 5 : 95
NEt2 >97 : <3

Advanced organic
13

Enolate formation and geometry III

• Previous table shows that stereoselectivity of enolate formation not always obvious
• In ketones trans-enolate favoured if R is small but cis-enolate if R1 is large
1
• Can explain this with transition state (again...)
i-Pr
if R is large, this TS‡ is H OLi
destabilised by R–Me interaction O N
and cis predominates Li i-Pr
R R = small
H
R Me Me
O trans
Me LDA
R i-Pr
Me OLi
if R is small, 1,3-diaxial interaction O N
Li i-Pr Me R = large
is important as it destabilises this R
TS‡ and trans predominates H
R H cis

• With esters the R vs OMe interaction is alleviated and 1,3-diaxial interaction controls
...geometry - hence trans-enolate predominates
i-Pr
OLi
H
O N
Li i-Pr MeO predominates
Me H
O Me Me
O trans
Me LDA
MeO i-Pr
Me OLi
O N
Li i-Pr Me
Me H MeO
O H cis Advanced organic
14

Enolate formation and geometry IV

i-Pr
H OLi
O N
Li i-Pr
H Et2N
Et
N Me Me
O
Et trans
Me LDA
Et2N
i-Pr
Me OLi
O N
Li i-Pr Me predominates
H Et2N
R H cis

• Amides invariably give the cis-enolate; remember restricted rotation of C–N bond
• The previous arguments are good generalisations, many factors effect geometry
• Use of the additive HMPA (hexamethylphosphoric triamide) reduces coordination and
favours the thermodynamically more stable enolate
1. LDA OTBS
O OTBS
2. TBSCl
+
Me Me EtO
EtO EtO
Me
cis trans
THF 6 94
THF / HMPA 82 18

Advanced organic
15

Addition of an electrophile to an enolate

σ* orbital (LUMO
electrophile)
X = leaving
group X X

H H H H
R R H
H R
O R2
≡ O

H
R2 O R2

R1 H R1 R1 H

π orbital (HOMO
nucleophile)

• Finally, need to know the trajectory of approach of the enolate and electrophile
• Reaction is the overlap of the enolate HOMO and electrophile LUMO
• Therefore, new bond is formed more or less perpendicular to carbonyl group
• Above is simple SN2 with X = leaving group

Advanced organic
16

Enolate alkylation
LDA R OEt Me Me
R OEt [Li–N(i-Pr)2] Me I R OEt + R OEt
Me O Me O
Li Me O Me O
R syn : anti
R = Ph 77 : 23
R = Bu 83 : 27
R = SiMe2Ph 95 : 5

• Simple alkylation of a chiral enolate can be very diastereoselective

• As we have a cis-enolate diastereoselectivity can be explained in an analogous
(1,3)
fashion to simple alkenes via A strain
• Larger the substituent, R, greater the selectivity

alkylation on face
I opposite to R
Me
Me H Me Me
OEt Me
most stable OEt
conformation; C–H
parallel to C=C
H O
Li H
H O ≡ R OEt

R R Me O

• Note: minor diastereoisomer probably arises from electrophile passing by R group

• Therefore, size does matter...
Advanced organic
17

Enolate alkylation II
S H O LDA S H OEt S H OLi

L OEt L OLi L OEt

(E)-enolate (Z)-enolate
trans cis

≡
preferred preferred
approach approach

S H S H O
S H
OEt OLi E
L L L OEt
E H
OLi OEt

• In this example enolate geometry is not important - both are cis-alkenes

• Therefore, selectivity the same in both cases
• If we want to reverse selectivity, change the electrophile to H
• This route far less selective as H is small so less interaction with substituents
H
Me H H Me
Me Me OEt Me OEt
R OEt LDA
H O
Me
H O ≡ R OEt

Me O R Li R Me O

Advanced organic
18

Nomenclature (again!!)
M
O
R1
R
R2

• You may have noticed some annoying changes nomenclature!

• With ester enolates the E / Z nomenclature changes depending on the nature of M (if
we use the Cahn-Ingold-Prelog rules)
• As1 a result we will classify enolates as cis or trans with respect to O–M
R = cis
R2 = trans

O Y O Y

R1 R2 R1 R2
X X
syn anti

• Syn and anti in the aldol reaction refer to relative stereochemistry of enolate
...substituent X and hydroxyl group (or equivalent) Y
Advanced organic
19

The aldol reaction

M M O OH
O O O O
+
R1 R1 R3 R1 R3
R3
R2 R2 R2

Zimmerman–
Traxler

• The aldol reaction is a valuable C–C forming reaction

• In addition it can form two new stereogenic centres in a diastereoselective manner
• Most aldol reactions take place via a highly order transition state know as the
Zimmerman–Traxler transition state
• It will not come as much surprise that this is a 6-membered, chair-like transition state
• Interestingly, enolate geometry effects diastereoselectivity
only possible
enolate O
O OLi O OH
LDA H Ph
Ph
H
trans-enolate anti aldol

O
O OH
O LDA OLi
H Ph
Me Me t-Bu Ph
t-Bu t-Bu
Me
cis-enolate syn aldol Advanced organic
20

The aldol reaction II

O
O OH
OLi
H R
Me X R
X
Me
cis-enolate syn aldol
O
OLi O OH
H R
X X R
Me Me
trans-enolate anti aldol

• Generally speaking the above guideline sums up aldol chemistry!

• To understand why this happens we need ‡to examine Zimmerman-Traxler TS‡
• So need to be able to draw a chair-like TS
draw final line
tops should allparallel
be to first
draw two add axial groups so that they
level parallel lines are vertical and alternate up
& down. Each carbon should
H H be tetrahedral
HlevelH
start at one H H new line
end of 6-ring H H parallel to first
levelH
H add equatorial substituents
add equatorial substituents H H so that they are parallel to
so that they are parallel to should have 3 pairs add equatorial
two C–Csubstituents
bonds
two C–C bonds of parallel lines so that they are parallel to
bottom should be two C–C bonds
level with initial
lines Advanced organic
21

Zimmerman-Traxler transition state

1,3-diaxial
interaction
X X
cis-enolate H M cis-enolate R
M
O O
H O H O
R H
Me Me
R pseudo-equatorial R pseudo-axial
disfavoured

• We only have one choice in the aldol reaction - the orientation of the aldehyde
• Enolate substituents are fixed due to the double bond
• Aldehyde substituent is pseudo-equatorial to avoid 1,3-diaxial interactions
O
O OH
OLi X
H R
Me X R H M
X O
Me H
cis-enolate syn aldol O
R
Me
to ‘see’ relative
X X stereochemistry
H H consider S as plane
M M and see which groups
re face of enolate attacks O O are above and which
si face of aldehyde H H below
O O
R R
Me Me
Advanced organic
22

Zimmerman-Traxler transition state II

O
O OH
OLi
H R
Me X R
X
Me
cis-enolate syn aldol Me

H O
R O
M
X
Me Me H

H O H O visualising relative
stereochemistry
R O R O
M M
X X
H H
si face of enolate attacks
re face of aldehyde

• Attack via the enantiomeric transition state (re face of aldehyde) gives the
enantiomeric aldol product
• This differs only by the absolute stereochemistry - the relative stereochemistry is the
same

Advanced organic
23

Zimmerman-Traxler transition state III

O
OLi O OH
H R
X X R
Me Me
H
trans-enolate anti aldol
Me O
R O
M
X
H H H
O O visualising relative
Me Me stereochemistry
R O R O
M M
X X
H H
re face of enolate attacks
re face of aldehyde

• The opposite stereochemistry of enolate gives opposite relative stereochemistry

• Once again the enolate has no choice where the methyl group is placed

Advanced organic
24

Enolisation and the aldol reaction

• Hopefully, all the previous discussion highlights that selective enolisation is essential
for diastereoselective aldol reaction
• Each geometry of enolate gives a different relative stereochemistry
• With the lithium enolates of ketones the size of the non-enolised substituent, R, is
important

OLi
O LDA OLi
+
Me Me R
R R
Me
R = t-Bu 98% 2%
R = Et 30% 70%

• With boron enolates we can select the geometry by altering the boron reagent used

O
O OH
O Et3N H Ph
+ B
Me B O Ph Ph
Ph
Cl Me
Ph
bulky Me
substituents trans-enolate anti aldol (>90% de)
forces enolate to
adopt trans geometry Advanced organic
25

Enolisation and the aldol reaction II

O
O OH
O Et3N H Ph
+ B
Me Ph Ph
Ph B O
Me
TfO Me
Ph
cis-enolate syn aldol (96% de)

• 9-BBN (9-borabicyclononane) looks bulky

• But most of it is ‘tied-back’ behind boron thus allowing formation of the cis-enolate

Advanced organic