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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
- 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
()