Crams Rule

diastereomeric faces

X = C, O, N

stereogenic center How

does this center control The direction of attack at The trigonal carbon?

M L

O R

Less steric effects LR

Nu:

M L

Nu:

Nu S

R S

Nu

M OH Major product

M OH Minor product

The interpretation of Felkin and Anh

M S R S O R R M

L
M O Favored Conformer for Attack

L
O S

This is the important interaction that must be minimized. Thus, in this approach the carbonyl substituent plays the majo role.

Houk computational view:

Nu Brgi-Dunitz trajectory 109

Obtuse attack trajectory minimizes unfavorable interactions between these orbitals

p*
C M O

R
S s L

The obtuse angle of attack supports the nonpassive role of the R-group in ketones. Not only will there be steric interactions between the S or M groups and the R-group, but also interactions with the incoming nucleophile due to the attack trajectory. In this model one would predict an increase of stereodifferentiation as the size of R increases. This has been found experimentally
O O

R Preferred conformation. Less interaction between the small group and the R-group. Note that this model "feels" the influence of increasing size of R.

R In this coformer, an increased interaction is seen between the medium group and R. Also, there is more interaction with the nucleophile.

A useful orbital approach by Cieplak, suggests that the nucleophile will attack the carbonyl anti to the best donor ligand.
A.S. Cieplak, B.D. Yait and C.R. Johnson, J. Am. Chem. Soc., (1989), 111, 8447 A.S. Cieplak, J. Am. Chem. Soc., (1981), 103, 4548.

E
D onor
O

Nu:

Carbon donor s-bond

s* of nucleophile

Cases for Modification of the Models

Compare the "normal" situation with the influence of a sterically bulky Lewis acid
Lewis acid
M O Lewis acid O M

As the bulk of the L

S

Nu:

S H

Lewis acid increases

:Nu

This gives the Cram product

This gives the "anti-Cram" product

Dipolar Model
often described as the Cornforth model

R Cl

O R'
O

R"M

R Cl

R" OH R'

O L L S

Preferred direction of attack.

S R

X R

favored conformer

Chelation Control

See: M.T. Reetz, Acc. Chem. Res., (1993), 26, 462.

L Het

S O M

R S R L O
Ph Cl Ti Cl O O H Me R

Preferred direction of attack

Het M

Het = heteroatom M = metal

Cl Cl

Predict a product from the following reaction

Me S Me Ph O O Me S Me Mg I Me Ph O O H3O +

Me

MeMgI

Me

A potentially useful extension of Cram's rule is the asymmetric induction provided by a remote ester (Prelog's rule):

R
O

L S M

R'MgX

Why would you think this might not provide as important directing influences?

Explain the following trends observed by Midland and coworkers M.M. Midland and Y.C. Kwon, J. Am. Chem. Soc. (1983), 105, 3725.

Me Me O H G H G

Me Me

OH

Me Me

H H

OH H

H Ratio

NaBH4
Sia2 BH

5
1

:
:

1
10