* Cram’s Rule How does this center control The direction of attack at 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 R Less steric effects L Nu: Nu: S M O L L N u R R N u S M S M O H O H Minor product Major product

The interpretation of Felkin and Anh S O M This is the important interaction that must be minimized. Thus, in this approach the carbonyl substituent plays the major role. L R R R S M L L M S O O Favored Conformer for Attack

Houk computational view: Obtuse attack trajectory minimizes unfavorable interactions between these orbitals N u 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

E 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 Carbon donor s -bond D o n r s * of nucleophile Nu: 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 Cram product This gives the "anti-Cram" product

Dipolar Model often described as the Cornforth model

R S Preferred direction of attack S L R H e t O L M H e t O Chelation Control See: M.T. Reetz, Acc. Chem. Res., (1993), 26, 462. R S Preferred direction of attack S L R H e t O L M H e t O Het = heteroatom M = metal M

Predict a product from the following reaction

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

M e M e M e O H H O M e M e M e H O H H G H H H H H G Ratio N a B H 5 Explain the following trends observed by Midland and coworkers M.M. Midland and Y.C. Kwon, J. Am. Chem. Soc. (1983), 105, 3725. M e M e M e O H H O M e M e M e H O H H G H H H H H G Ratio N a B H 4 5 : 1 S i a 2 B H 1 : 10