Asymmetric Induction in Methyl Ketone Aldol Additions to α-Alkoxy and α,β-Bisalkoxy Aldehydes: A Model for Acyclic Stereocontrol

A systematic study of methyl ketone aldol additions under nonchelating conditions with α-alkoxy
and α,β-bisalkoxy aldehydes is described. Additions to aldehydes containing a single α-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 α-alkyl substituent, but is relatively
insensitive to the nature of the alkoxy protecting group. Aldehyde π-facial selectivity in additions to substrates
containing an additional β-alkoxy-substituted stereocenter exhibits a striking dependence on the relative
configuration of the α- and β-stereocenters. Aldehydes with the α- and β-alkoxy substituents in an anti
relationship in most cases exhibit good diastereoselectivity, while aldehydes with the α- and β-alkoxy
substituents in a syn relationship unexpectedly give product mixtures. A stereochemical model based on
Cornforth-like transition-state arrangements is proposed.