1
Stereoselective reactions of alkenes
O
Me
O
I
I2
H
O
Me
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
I2
Me
I
OH
O
O
82% de
O
Me
I2
O
OH
I
O
88% de
O
• 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
Me
Me
m-CPBA
Me
SiMe2Ph
O
Me
Me
+
Me
SiMe2Ph
SiMe2Ph
<5%
>95%
• 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
Me
Me
H
H
H
H Me
H
rotate
Me
bond
lowest energy: H
eclipses plane of alkene
H Me
H
Me
Me
Me
H
H
H
Me
H
Me
lowest energy: H
eclipses plane of alkene
H Me
Me
H
slightly higher energy: Me
eclipses plane of alkene
X
H Me
H
Me
if no cis substituent
then only small
energy difference
Me
H
high energy: Me–Me
interaction disfavours
conformation
cis substituent
present then only
ONE 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
Me
m-CPBA
Me H SiMe2Ph
O
O
Me
Me
Me H SiMe2Ph
>95%
Me H SiMe2Ph
<5%
m-CPBA
lowest energy
conformation
m-CPBA
X
silyl group blocks
approach
Me Ph
H Si Me
H
Me
H
Me Ph
H Si Me
H
Me
Me
m-CPBA
m-CPBA approaches
from unhindered face
OH
Me
H H
H
Me
Me
Si Me
Ph Me
formation of minor
diastereoisomer results
from m-CPBA
approaching alkene in
above conformation or
approaching passed
the silyl group
Advanced organic
4
Importance of A(1,3) strain
Me
Me
m-CPBA
H SiMe2Ph
Me
O
Me
+
Me
O
Me
H SiMe2Ph
H SiMe2Ph
61%
39%
• The importance of a cis-substituent is made clear by the reduced stereoselectivity
• This is explained as follows...
X
m-CPBA
lowest energy
conformation
gives major product
Me
H
Ph Me
H Si Me
H
Me
H
Ph Me
H Si Me
Me
H SiMe2Ph
m-CPBA attacks
form least hindered
face
Me
H
H H
Me
X
Si Me
Ph Me
m-CPBA
O
OH
Me
Me
Me
Me
H SiMe2Ph
61%
Me
both conformations low
energy -- so mixture of
products
O
Me
H
H H
Me
Me
Si Me
Ph Me
O
Me
H SiMe2Ph
39%
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
BH3
O
O
H
Me
Me
H2B H
preferred
approach
S H
L
H
S
R
R1
L
R
favoured
O
OBn
CH2OBn
Me
H
H2B H
OH
74% de
OBn
Attack from the least sterically
demanding face of the alkene
as it resides in the most
favoured conformation.
Followed by stereospecific
oxidation
Selectivity in addition to cis alkenes
S
1
L
R1
S = smaller group
L = larger group
H2B
O
H
CH2OBn
H
Me
O
OBn
H Me H Me
H2O2
NaOH
H
L
1
H
3R
R1
S
3
R
R1
destabilised by repulsion between C-1 & C-3
substituents or A(1,3) strain
Advanced organic
6
Directed epoxidation
OH
OH
OH
reagent
+
O
syn
92
98
reagent:
m-CPBA
t-BuO2H, VO(acac)2
O
t
:
:
anti
8
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
hydrogen
bond
Ar
Me
O
O
H
O
O
H
O
Me
O V O
O
O
Me
t-BuO
O
O
V
O
Me
vanadyl acetylacetonate
H
H
Advanced organic
7
Directed epoxidation in acyclic systems
Me
Me
m-CPBA
Me
Me H OH
O
Me
favoured
conformation
O
H O
Me
O
Me H OH
5
H H
Me
H OH
H
Me
Me
H
O
Me
H
Me
Me
Me
Me
H
+
Me
Me H OH
95
O
H
Me
hydrogen
bond
Ar
O
O
O
H
O
O
Ar
disfavoured
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
Me
Me
t-BuO2H
VO(acac)2
Me
Me
O
H OH
O
OH
19
:
t-Bu
Me
H
favoured
conformation as
only Me & H eclipse
Me
O
t-Bu
O
H
H
V
OH
1
V
O
O
Me
+
O
H
L
steric
interaction
L
L
disfavoured
conformation as
Me & Me eclipse
Me
Me
O
H
L
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
Me
Me
H OH
t-BuO2H
VO(acac)2
Me
Me
O
2.5
Me
+
OH
:
Me
O
OH
H
O
H
H
O
1
V
t-Bu
H
O
L
L
H too small to
differentiate
conformations
Advanced organic
9
Directed reactions
SiMe3
Me
Me
SiMe3
t-BuO2H
VO(acac)2
Me
Me
O
H OH
Me
TBAF
Me
O
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
I
H2
C
OH
Zn
I +
carbenoid
O
Zn
CH2
I
I
H C
H
OH
Zn
O
H
>98% de
Advanced organic
10
Stereoselective reactions of enolates
O
O
R2
R1
M
R2
R1
H H
O
E
R1
R2
H E
H
is dependent on:
• The stereoselectivity of reactions of enolates
1
2
• Presence of stereogenic centres on R , R or E (obviously!)
• Frequently on the geometry of the enolate (but not always)
C-α re face
O
R1
C-α si face
M
α R2
H
(Z)-enolate
(cis)
MO
R1
α
O
R2
H
C-α si face
R1
M
MO
α H
R2
(E)-enolate
(trans)
R1
α
H
R2
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
π orbital
C–H σ
orbital
C=O π
orbital
H
O
R2
R1
H
base
O
R2
R1
H
+
H
base
• 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
O
R2
≡
H
base
H
H
R1
H
base
O
R1
H R2
H
R2
O
R1
H
transition
state
R2
O
R1
H
(Z)-enolate
(cis)
Advanced organic
12
Enolate formation and geometry II
base
base
R2
O
H
H
base
H
H
R1
base
O
≡
R1
H H
O
R2
H
R1
O
R2
R1
H
R2
(E)-enolate
(trans)
perpendicular to C=O gives trans-enolate
• Second conformation that places C–H
1
of R and R2
• Only differs by relative position
• 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
O
R
Me
LDA
THF
–78°C
O
Me
R
R = Et
i-Pr
t-Bu
OMe
NEt2
O
Li
cis
30
60
>98
5
>97
+
:
:
:
:
:
Li
R
Me
trans
70
40
<2
95
<3
Advanced organic
13
Enolate formation and geometry III
of enolate formation not always obvious
• Previous table shows that stereoselectivity
1
• In ketones trans-enolate favoured if R is small but cis-enolate if R1 is large
• Can explain this with transition state (again...)
i-Pr
TS‡ is
if R is large, this
destabilised by R–Me interaction
and cis predominates
O
R
N
Li
i-Pr
R
R = small
R
H
O
Me
OLi
H
Me
trans
Me
LDA
i-Pr
O
if R is small, 1,3-diaxial interaction
is important as it destabilises this
TS‡ and trans predominates
Me
Li
N
OLi
i-Pr
H
R
Me
R
R = large
cis
H
• With esters the R vs OMe interaction is alleviated and 1,3-diaxial interaction controls
...geometry - hence trans-enolate predominates
i-Pr
O
Me
O
MeO
Me
H
N
Li
OLi
i-Pr
H
predominates
MeO
O Me
trans
LDA
Me
i-Pr
O
Me
Me
Li
N
H
O
H
OLi
i-Pr
Me
MeO
cis
Advanced organic
14
Enolate formation and geometry IV
i-Pr
O
Et
O
Me
Et2N
LDA
H
OLi
N
Li
i-Pr
Et2N
H
N Me
Et
Me
trans
i-Pr
O
Me
Li
N
OLi
i-Pr
H
R
Me
Et2N
H
predominates
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
2. TBSCl
O
EtO
Me
Me
EtO
THF
THF / HMPA
OTBS
OTBS
+
EtO
Me
cis
6
82
trans
94
18
Advanced organic
15
Addition of an electrophile to an enolate
σ* orbital (LUMO
electrophile)
X = leaving
group
X
H
X
H
R
R2
O
R1
H
H
≡
O
R1
H
R
H
H
R2
H
R
R2
O
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
R
OEt
Me
LDA
[Li–N(i-Pr)2]
R
OEt
Me
O
O
Me
Me
I
Me
R
Li
OEt + R
Me
R
R = Ph
R = Bu
R = SiMe2Ph
OEt
Me
O
:
:
:
:
syn
77
83
95
O
anti
23
27
5
• Simple alkylation of a chiral enolate can be very diastereoselective
can be explained in an analogous
• As we have a cis-enolate diastereoselectivity
(1,3)
•
fashion to simple alkenes via A
strain
Larger the substituent, R, greater the selectivity
alkylation on face
opposite to R
I
Me
most stable
conformation; C–H
parallel to C=C
Me H
H
R
OEt
O
Li
Me
R
Me
H
H
OEt
O
≡
Me
R
OEt
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
L
OEt
S H
LDA
OEt
L
S H
OLi
(E)-enolate
trans
L
preferred
approach
H
H
S
OEt
L
OEt
(Z)-enolate
cis
≡
≡
preferred
approach
S
OLi
S H
E
OLi
L
OLi
O
L
OEt
E
OEt
H
• 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
R
OEt
Me
O
LDA
Me Me
H
R
OEt
O
Li
Me
R
H
Me
H
OEt
O
≡
H Me
R
OEt
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
R1
O
R2
Y
R1
X
syn
R2
X
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
O
O
+
R1
M
O
O
O
R1
R3
R1
R3
R3
R2
R2
R2
OH
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
O
OLi
LDA
H
OH
Ph
Ph
H
anti aldol
trans-enolate
O
O
t-Bu
LDA
Me
O
OLi
t-Bu
H
Me
cis-enolate
OH
Ph
t-Bu
Ph
Me
syn aldol
Advanced organic
20
The aldol reaction II
O
O
OLi
H
R
X
Me
X
OH
R
Me
syn aldol
cis-enolate
O
OLi
O
H
OH
R
X
X
Me
trans-enolate
R
Me
anti aldol
• Generally speaking the above guideline sums up aldol chemistry!
• To understand why this happens we need ‡to examine Zimmerman-Traxler TS‡
TS
• So need to be able to draw a chair-like
draw final line
to first
tops should allparallel
be
draw two
level
parallel lines
H
start at one
end of 6-ring
add equatorial substituents
so that they are parallel to
two C–C bonds
H
H
H
HlevelH
H
levelH
H
H
H
H
should have 3 pairs
of parallel lines
bottom should be
level with initial
lines
add axial groups so that they
are vertical and alternate up
& down. Each carbon should
be tetrahedral
new line
parallel to first
add equatorial substituents
so that they are parallel to
add equatorial
two C–C
substituents
bonds
so that they are parallel to
two C–C bonds
Advanced organic
21
Zimmerman-Traxler transition state
1,3-diaxial
interaction
X
R
cis-enolate
M
O
H
O
H
Me
R pseudo-axial
disfavoured
X
H
cis-enolate
M
O
H
R
O
Me
R pseudo-equatorial
• 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
OLi
H
X
R
Me
X
OH
X
H
R
Me
syn aldol
cis-enolate
H
Me
X
X
H
re face of enolate attacks
si face of aldehyde
H
Me
R
H
M
O
O
M
O
H
Me
R
O
M
O
R
O
to ‘see’ relative
stereochemistry
consider S as plane
and see which groups
are above and which
below
Advanced organic
22
Zimmerman-Traxler transition state II
O
O
OLi
H
R
X
Me
X
OH
R
Me
syn aldol
cis-enolate
Me
O
H
O
R
Me
H
Me
O
H
O
R
X
M
H
si face of enolate attacks
re face of aldehyde
O
R
H
X
M
visualising relative
stereochemistry
O
H
X
M
• 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
H
X
OH
R
R
X
Me
trans-enolate
Me
anti aldol
H
O
Me
O
R
H
H
H
O
Me
O
R
X
M
H
re face of enolate attacks
re face of aldehyde
O
R
H
M
visualising relative
stereochemistry
O
Me
X
M
X
• 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
O
LDA
Me
R
OLi
OLi
Me
R
R = t-Bu
R = Et
+
R
Me
98%
30%
2%
70%
• With boron enolates we can select the geometry by altering the boron reagent used
O
O
O
Ph
Me
+
Et3N
B
Cl
bulky
substituents
O
B
H
OH
Ph
Ph
Ph
Me
Ph
Me
trans-enolate
anti aldol (>90% de)
forces enolate to
adopt trans geometry
Advanced organic
25
Enolisation and the aldol reaction II
O
O
O
Ph
Me
Et3N
+
B
TfO
H
O
B
OH
Ph
Ph
Me
Ph
cis-enolate
Ph
Me
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