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Chapter 34 Diastereoselectivity
- The Felkin-Ahn model for carbonyl conformations and
diastereoselective nucleophilic attack- The effect of electronegative atoms on carbonyl conformation
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Carbonyl chelation and stereoselectivity---------------------------------------------------------------------
- The aldol reactions chair-like transition state and
stereoselective formation of syn and anti isomers- Selective production of cisand transenolates of ketones
- Stereospecificity vs. stereoselectivity (and a pre-midterm
review of reactions)
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The conformations of acyclic carbonyls
The Felkin-Ahn model for carbonyl conformations
PhO
eclipsed
HO
eclipsed
nothing eclipsed,largest substituentperpendicular
Alpha-substituted carbonyls assume conformations that:
1) avoid all eclipsed interactions
2)
have the largest substituent perpendicular to the plane ofthe carbonyl
PhH
O
Me
O
H
Ph
Me H
H
HH
O
Ph Me
O
H
H
Ph Me
O
H
Ph
Me
H
H
O
Ph
Me
H
O
H
Ph
H
Me
H
O
Ph
H
Me
O
R
L
M
S
L R
O
M S
O
R
L
S
M
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Nucleophilic attack on a Felkin-Ahn conformation 1.
The most stable conformation will be attacked by the nucleophile from the least
hindered trajectory. What trajectory?
remember Brgi and Dunitz!
O
H
Ph
H
Me
O
H
Ph
Me
HHindered
by Ph
Hindered
by Ph
Hindered
by Me
Hindered
by H
This is the easiest approach for the nucleophile
?Ph
H
O
Me
EtMgCl
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Nucleophilic attack on a Felkin-Ahn conformation 2.
O
H
PhMe
HEt
H
PhMe
H
Et
OH
PhEt
Me
OH
PhH
O
Me
EtMgClPh
Et
Me
OH
Major (Minor)
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Another example
Unstable
conformer
Stable
conformers
Product
Redrawing the product Newman projection into a Newman projection
with the main substituents (Me, tBu in this case) opposite to each otheroften makes it easier to translate back into a normal zig-zag structure
Me
O
EtNaBH4
O
Me H
tBu
Et
O
Me
tBu
Et
H
O
Me
tBu
H
Et
H
Me
tBu
Et
H
OH
H
OHtBu
Et
HH
Me
Me
Et
OH
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Electronegative -substituents occupy the perpendicular
position because of *#
* alignment
O
X
O
X
!*
"*O
X
O
X
"*
!*
X = halogen,
NR2, OR
EWG have low-energy "* orbitals that can
conjugate to the neighbouring carbonyl !* orbitalONLY when the alignment is right (i.e. only when
the EWG is perpendicular to the carbonyl plane)
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Electronegative -substituents occupy the
perpendicular position: example
Homework: Check which product would have formed if you put
R in the perpendicular position instead of NBn2
O
H
NBn2
O
H
NBn2
R
H
O
H NBn2
R
H
R
O
H
Bn2N
H
R
OMe
OLi
Nu
OH
H
NBn2
R
H
Nu
OH
H
R
H
Bn2N
Nu
O
OMeOH
NBn2
NuR
OH
NBn2Nu =
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Chelation-controlled carbonyl conformations
Alpha substituents with lone pairs can coordinate divalent (or higher valency) metalions together with the carbonyl lone pairs.
The chelation ring becomes the dominant factor in determining the conformation,
and gives VERY high selectivity for nucleophilic attack.
Common chelating metals:
Zn2+, Cu2+, Ti4+, Ce3+, Mg2+(MgCl+ is not as good)
Non-chelating metals:
Li+
, Na+
, K+
.
O
R'
OR
O
R'
NR2
O
R'
SR
O
R'L
M2+
O
R' Et
L
H
M2+
M2+
or or
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Chelation control can reverseselectivity
O
R'
OR
O
R'RO
M2+O
R'
RO
Et
H
M2+ O
R' Et
RO
H
M2+
R'
RO
Et
H
O
Nu O
R' Et
RO
H
M2+
Nu
Nu Nu
R'
OR
HO Nu
R'
OR
Nu OH
Reaction in presence of a
chelating metal
Reaction in absence of a
chelating metal
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Chelation control can reverseselectivity: example
Ph
O
OMePh
OMe
H OH
Ph OMe
HO HNaBH4
73% 27%
Ph
O
OMePh
OMeMe OH
Ph OMe
HO MeMe2Mg
1% 99%
Work these problems to make sure you can predict the right products
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Attack on -substituted carbonyls: summary
Your choices for predicting the reactive conformation:
1. Normal Felkin-Ahn model (No #-heteroatoms)
2. Electronegative heteroatom perpendicular
3. Electonegative heteroatom chelated and in the plane of the carbonyl
(p. 895, CGWW)
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Aldol reactions are stereoselective!!!
(so no more wiggly bonds)
transenolate
cisenolate
antialdol
synaldol
O OLi OO
H
OHLDA, 78 C
()
O OH
()
Ph
O
Ph
OLi
Ph
O
O
H OHLDA, 78 C
()
Ph
O OH
()
synaldol
antialdol
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Explaining cis-enolatesyn-aldol product
selectivity using a cyclic chair-like T.S.
O
R
Me
H
Li
O
H
Ph
O
O
H
Ph
R
Me
H
Li
R
OLi
Me
O
PhH R
O
Me
Ph
OH
R
OLi
O
PhH
()
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Explaining trans-enolateanti-aldol product
selectivity using a chair-like T.S.
O
R
Me
Li
O
H
Ph
H
O
O
H
Ph
R
H
Me
Li
R
OLi
Me
O
PhH R
O
Me
Ph
OH
()
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Selective production of cis and trans ketone enolates
1. Cyclic ketones must make trans enolates
2. Bulky R groups can drive cisenolate formation
3. Treatment with bulky boron reagents that attach to the enolate oxygen atom
drives formation of a transboron enolate
O OLiOLiLDA, 78 C
2 % 98 %
H Ph
O O
Ph
OH
()
Ph
O
Ph
O
O
H
Et3N,
Ph
O OH
()
B
Cl
B
O
LDA, 78 C
OLi
H
OO OH
()
