On the role of β-silyloxy- and β-alkoxyaldehyde protecting groups in Mukaiyama aldol 1,3-diastereocontrol

Abstract

Longstanding paradigmatic studies have noted anti-1,3-diastereocontrol in Mukaiyama aldol reactions with β-silyloxy- and β-alkoxyaldehydes. In our efforts to exploit this stereocontrol, we found that an aldehyde of this type that lacks branching at the γ-carbon led to eroded diastereoselectivity that was restored upon changing the β-protecting group. This suggested the hypothesis that 1,3-anti selectivity in these cases is inversely dependent on the size of the β-protecting group. In testing this hypothesis, Mukaiyama aldol reactions of several analogs of unbranched β-silyloxy- and β-alkoxyaldehydes, varying only the protecting group, showed improved selectivity with smaller silyl and alkyl groups. These results will aid synthetic design as well as provide experimental benchmarks for computational studies.