1
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
123.702 Organic Chemistry
2
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)
123.702 Organic Chemistry
3
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 R
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
123.702 Organic Chemistry
4
Enolate formation and geometry III
• The selectivity observed can be explained via chair-like transition state
• In ketones cis-enolate favoured if R is large but trans-enolate favoured if R is small
if R is large, this TS‡ is
destabilised by R–Me
interaction and cis
predominates
i-Pr
O
H
N
Li
i-Pr
O
i-Pr
Me
Li
H
R
O
Me
R
OLi
N
R
H
R
Me
Me R = large
i-Pr
cis
H
LDA
i-Pr
if R is small, 1,3-diaxial
interaction is important as it
destabilises this TS‡ and
trans predominates
Me
O
Li
N
i-Pr
O
i-Pr
H
R
H
N
Li
OLi
i-Pr
H
R
H
R = small
R
Me
trans
Me
• 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
Me
Li
N
i-Pr
H
O
X
OLi
Me
MeO
cis
H
LDA
i-Pr
O
Me
H
N
Li
H
O Me
OLi
i-Pr
predominates
MeO
trans
Me
123.702 Organic Chemistry
5
Enolate formation and geometry IV
i-Pr
O
Et
O
Me
Et2N
H
OLi
N
Li
i-Pr
Et2N
H
N
Me
Me
trans
Et
LDA
i-Pr
O
Me
Li
N
OLi
i-Pr
H
R
Me
Et2N
predominates
cis
H
• 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
123.702 Organic Chemistry
6
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
123.702 Organic Chemistry
7
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...
123.702 Organic Chemistry
8
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
123.702 Organic Chemistry
9
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
123.702
Organic Chemistry
10
The aldol reaction II
O
O
OLi
H
R
X
Me
X
OH
R
Me
syn aldol
cis-enolate
O
OLi
O
H
X
Me
trans-enolate
OH
R
X
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‡
• You must learn to draw chair-like conformation of 6-membered rings
123.702 Organic Chemistry
11
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
123.702 Organic Chemistry
12
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
123.702 Organic Chemistry
13
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
123.702 Organic Chemistry
14
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
123.702 Organic Chemistry
15
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
123.702 Organic Chemistry
16
Substrate control in total synthesis I
Me
Me
C10
OBn
Cy2BCl
Et3N
Me
OBCy2
Me
Me
O
C9
C13 Me
Me
O
C1
O
Me
BnO
Me
C10
Me
OR
Me
B
Cy
OH
O
93%
97% d.e.
OBn
C13
trans-enolate gives
anti-aldol product
HH
R
O
O
Me
H
disfavoured
lone-pair interaction?
Mg
R
O OR1
Me
C13
OH
83%
93% d.e.
Cy Me
Cy
O
C9
O
Me
O
B
OR
Me
Me
C9 C10
Cy
O
Me
Me
Oleandomycin aglycon
(R=H but should be a sugar)
Me
R
Me
H
re-face favoured
versus
O
C7
OH
BnO
HH
C9
CHO
Me
OBn
C13
O
Me
O
R1
O
L
Mg
Me
H H
Me
Me
H
Me
O
Me
MeMgBr
CH2Cl2
Me
Me
O
H
H
H
O
123.702 Organic Chemistry
17
Substrate control in total synthesis II
Me
BnO
H
H
Sn
O
O
TfO
Me
Me
C4
O
Me
C1
Sn(OTf)2
Me
OBn Et3N
C7
O
Sn
H
R
Me
C5
CHO
Me
re-face attack
favoured
versus
OBn
H
OTf
H
Me
Me
C5 C4
C7
OH
Me
O
90%
93% d.e.
Me OBn
H
Sn
O
OTf
O
OBn
C1
cis-enolate gives
syn-aldol product
R
Me
• Seen oleandomycin earlier
• Here see the opportunities offered
by the aldol reaction
• It creates 1 C–C bond and 2
•
stereogenic centres per reaction
Ian Paterson, Roger D. Norcross,
Richard A. Ward, Pedro Romea
and M. Anne Lister, J. Am. Chem.
Soc., 1994,116, 11287
Me
C7
Me
stereogenic
centres setup by
aldol reaction
C13
Me
C–C bonds
formed by aldol
reaction
O
C9 O
OH
O
Me
O C
1
Me
OR
OR
Me
123.702 Organic Chemistry