Slides Ch34 Diastereoselectivity (Felkin-Ahn)

Chapter 34 Diastereoselectivity
- The Felkin-Ahn model for carbonyl conformations and

diastereoselective nucleophilic attack
- The effect of electronegative atoms on carbonyl conformation
- Carbonyl chelation and stereoselectivity
--------------------------------------------------------------------- The aldol reactions chair-like transition state and
stereoselective formation of syn and anti isomers
- Selective production of cis and trans enolates of ketones
- Stereospecificity vs. stereoselectivity (and a pre-midterm
review of reactions)
The conformations of acyclic carbonyls

O
Ph
Me
Me H
Ph
Ph Me
Ph
O
H
O
H
H
H
Me O
Ph
PhO
eclipsed
Me
H
Me
O H
Ph
Me
Ph
HH
HO
eclipsed
Ph
H Me
nothing eclipsed,
largest substituent
perpendicular
The Felkin-Ahn model for carbonyl conformations

O
L
M
Alpha-substituted carbonyls assume conformations that:

R
1) avoid all eclipsed interactions
2) have the largest substituent perpendicular to the plane of

the carbonyl
MO
O S
L
SR
L
RM
Nucleophilic attack on a Felkin-Ahn conformation 1.
O
Ph
EtMgCl
H
Me
The most stable conformation will be attacked by the nucleophile from the least
hindered trajectory. What trajectory?
remember Brgi and Dunitz!
Me O
O H
Ph
Ph
HH
H Me
Hindered
by Ph
Hindered
by Me
Hindered
by H
Hindered
by Ph
This is the easiest approach for the nucleophile
Nucleophilic attack on a Felkin-Ahn conformation 2.

Major
O
Ph
EtMgCl
H
Me O
Ph
Et
OH
Ph
Et
Me
Me
HH
(Minor)
Me OH
Ph
Et
H H
OH
Ph
Et
Me
Another example
Et
Et
NaBH4
Me
Me
OH
H
Et
Me H
O
tBu
Unstable
conformer
Me Et
H Me
tBu
tBu
Et O
O H
Stable
conformers
Et
Me
H
H
H
Me
tBu
Et
OH
tBu OH
Product
Redrawing the product Newman projection into a Newman projection

with the main substituents (Me, tBu in this case) opposite to each other
often makes it easier to translate back into a normal zig-zag structure
Electronegative -substituents occupy the perpendicular

position because of ** alignment
X
X
X
*
*
O
X = halogen,
NR2, OR
X
O
EWG have low-energy * orbitals that can
conjugate to the neighbouring carbonyl * orbital
ONLY when the alignment is right (i.e. only when
the EWG is perpendicular to the carbonyl plane)
Electronegative -substituents occupy the

perpendicular position: example
OMe
NBn2
Nu =
NBn2
OLi
Nu
O
R
OH
Nu
NBn2
NBn2
H H
H
NBn2
R O
O
R
Nu
R
H
NBn2
OH
Bn2N
Nu
H
H
R
OH
H R
Bn2N
O H
Homework: Check which product would have formed if you put

R in the perpendicular position instead of NBn2
O
OH OMe
Chelation-controlled carbonyl conformations
O
R'
OR
or
M2+
O
R'
NR2
or
M2+
R'
SR
M2+
L
L
O
R'
H
R'
Alpha substituents with lone pairs can coordinate divalent (or higher valency) metal
ions 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+.
Et
Chelation control can reverse selectivity

M2+
O
O Et
R'
RO
M2+
M2+
RO
R'
R' H
OR
RO
O
O
H
Et
R'
Nu
Nu
M2+
HO Nu
R'
OR
RO
R'
Et
Nu
Nu
OR
Reaction in absence of a
chelating metal
OH
R'
RO
Nu
H R'
O
Et
Reaction in presence of a
chelating metal
Chelation control can reverse selectivity: example

O
OMe
Ph
NaBH4
OH
HO
OMe
Ph
Ph
OMe
Me2Mg
Me
Ph
1%
OMe
Ph
73%
27%
OH
HO
OMe
Me
OMe
Ph
99%
Work these problems to make sure you can predict the right products
Attack on -substituted carbonyls: summary
(p. 895, CGWW)
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
Aldol reactions are stereoselective!!!

(so no more wiggly bonds)
O
LDA, 78 C
OLi
OH
OH
H
()
trans enolate
()
anti aldol
syn aldol
O
O
Ph
OLi
LDA, 78 C
Ph
OH
Ph
anti aldol
OH
Ph
()
cis enolate
()
syn aldol
Explaining cis-enolatesyn-aldol product

selectivity using a cyclic chair-like T.S.
Li
Me
O
H
Ph
OH
Ph
Me
Li
O
Ph
H
O
H
Ph
Me
()
Li
O
Li
O
Ph
Me
Explaining trans-enolateanti-aldol product

selectivity using a chair-like T.S.
Li
O
H
Ph
Ph
Me
Me
H
O
Me
Ph
()
OH
Li
Me
O
Li
O
Ph
H
Selective production of cis and trans ketone enolates

1. Cyclic ketones must make trans enolates
O
OLi
LDA, 78 C
OH
H
()
2. Bulky R groups can drive cis enolate formation

O
LDA, 78 C
OLi
OLi
O
H
Ph
OH
Ph
2%
()
98 %
3. Treatment with bulky boron reagents that attach to the enolate oxygen atom
drives formation of a trans boron enolate
Et3N,
Cl
B
O
Ph
O
Ph
OH
Ph
()

Slides Ch34 Diastereoselectivity (Felkin-Ahn)

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Chapter 34 Diastereoselectivity

- The Felkin-Ahn model for carbonyl conformations and

The conformations of acyclic carbonyls

The Felkin-Ahn model for carbonyl conformations

Alpha-substituted carbonyls assume conformations that:

1) avoid all eclipsed interactions

2) have the largest substituent perpendicular to the plane of

Nucleophilic attack on a Felkin-Ahn conformation 1.

This is the easiest approach for the nucleophile

Nucleophilic attack on a Felkin-Ahn conformation 2.

Redrawing the product Newman projection into a Newman projection

Electronegative -substituents occupy the perpendicular

Electronegative -substituents occupy the

Homework: Check which product would have formed if you put

Chelation-controlled carbonyl conformations

Chelation control can reverse selectivity

Chelation control can reverse selectivity: example

Attack on -substituted carbonyls: summary

(p. 895, CGWW)

Your choices for predicting the reactive conformation:

Normal Felkin-Ahn model (No -heteroatoms)

Electronegative heteroatom perpendicular

Electonegative heteroatom chelated and in the plane of the carbonyl

Aldol reactions are stereoselective!!!

Explaining cis-enolatesyn-aldol product

Explaining trans-enolateanti-aldol product

Selective production of cis and trans ketone enolates

2. Bulky R groups can drive cis enolate formation

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