Iterative Synthesis of Deoxypropionate Units: The Inductor Effect in Acyclic Conformation Design

Abstract

Conjugate addition of lithium dimethylcuprate to acyclic alpha,beta-unsaturated esters of varying lengths bearing terminal alkyl or phenyl groups leads to a preponderance of syn 1,3-adducts when one methyl is already present. Conversion to enoates, and iteration of cuprate additions also favors syn adducts to give contiguous deoxypropionate units in a growing chain. The effect of end-group variation (Me, i-Pr, phenyl, tert-butyl) in conjunction with the nature of the ester group (Me, tert-butyl, etc.) on the diastereoselectivity of syn and anti products was studied. The results are rationalized in terms of inductor effects related to the minimization of the 1,5-pentane interactions in energetically favored folded conformations and corroborated by homodecoupling NMR studies.