Asymmetric induction in methyl ketone aldol additions to alpha-alkoxy and alpha,beta-bisalkoxy aldehydes: a model for acyclic stereocontrol.

A systematic study of methyl ketone aldol additions under nonchelating conditions with alpha-alkoxy and alpha,beta-bisalkoxy aldehydes is described. Additions to aldehydes containing a single alpha-alkoxy stereocenter generally provide the product diastereomers in accord with the Cornforth/polar Felkin-Anh models for carbonyl addition. Vicinal asymmetric induction is sensitive to the aldehyde alpha-alkyl substituent, but is relatively insensitive to the nature of the alkoxy protecting group. Aldehyde pi-facial selectivity in additions to substrates containing an additional beta-alkoxy-substituted stereocenter exhibits a striking dependence on the relative configuration of the alpha- and beta-stereocenters. Aldehydes with the alpha- and beta-alkoxy substituents in an anti relationship in most cases exhibit good diastereoselectivity, while aldehydes with the alpha- and beta-alkoxy substituents in a syn relationship unexpectedly give product mixtures. A stereochemical model based on Cornforth-like transition-state arrangements is proposed.