Addition of heteroatom nucleophiles to ketene dimers

Abstract

An investigation of the reaction of heteroatom nucleophiles with ketene dimers, with an emphasis on a discussion of diastereoselectivity where applicable, is described. During this study we focused on the reaction of nitrogen-centred nucleophiles (Weinreb amine, lithiated Weinreb amide, and an amino acid derivative), and oxygen-centred nucleophiles (alkoxides). Simple Weinreb amide derivatives of ketene heterodimers were formed in moderate to excellent yield (up to 89%) and excellent retention of chirality (ee up to 91%), albeit with poor diastereoselectivity. The 2-pyridone-catalysed amine ring-opening was also applied to the asymmetric synthesis of a cinnabaramide A intermediate. Finally, the use of amide and alkoxide ring-opening nucleophiles enabled the development of a sequential one-pot reaction with benzaldehyde to afford -lactones in moderate yields (up to 47%) but with good diastereoselectivity (dr up to 24:1).