Addition of Heteroatom Nucleophiles to Ketene Dimers

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 delta-lactones in moderate yields (up to 47%) but with good diastereoselectivity (dr up to 24:1). [GRAPHICS]

Automated summary

The study focused on the reaction of heteroatom nucleophiles with ketene dimers, synthesizing Weinreb amide derivatives with excellent retention of chirality but poor diastereoselectivity. The research also applied to asymmetric synthesis and sequential one-pot reactions successfully.