Cram’s Rule

C X
* diastereomeric
faces
X = C, O, N

stereogenic
center How
does this center control
The direction of attack at
The trigonal carbon?
 S O
M
L R

Less steric effects LR

Nu: Nu:
S M
O

L L
Nu R R Nu
S M S M
OH OH
Major product Minor product
 The interpretation of Felkin and Anh

S O
M This is the important
L R interaction that must be
S R R M minimized. Thus, in this
approach the carbonyl
L L substituent plays the majo
role.
M O O S
Favored Conformer
for Attack
Houk computational view:
Obtuse attack trajectory
minimizes unfavorable
Nu interactions between these
orbitals
109°
Bürgi-Dunitz
trajectory p*
R
C O
S M

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 R

Preferred conformation. In this coformer, an

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

Donor Carbon s* of nucleophile

Nu: donor
s-bond
O
 Cases for Modification of the Models
Compare the "normal" situation with the influence of
a sterically bulky Lewis acid
Lewis acid Lewis acid

O O
M As the bulk of the M

L S
Lewis acid increases
L
S H H :Nu
Nu:

This gives the This gives the

Cram product "anti-Cram" product
 Dipolar Model
often described as the Cornforth model

H O H R"
R R"M R OH

Cl R' Cl R'

O O
X 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.

S R S Preferred
L R direction
of attack
Het O L
M Het
O
Het = heteroatom
M = metal Ph M
Cl H
Cl O
Ti
Cl O
Cl Me
R
Predict a product from the following
reaction

Me Me Ph
Ph MeMgI S H3O +
S Me O
Me O
O Me O
Me
Mg
I Me
A potentially useful extension of Cram's rule is the asymmetric
induction provided by a remote ester (Prelog's rule):

O
R'MgX
O L
R

O S M

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 Me
OH H
Me O Me Me
H H OH
G H H

H H H

G Ratio

NaBH4 5 : 1
Sia2 BH 1 : 10