Organocatalysed conjugate addition reactions of aldehydes to nitroolefins with anti selectivity

Abstract

Catalytic reactions that enable access to different diastereoisomers are important but often difficult to achieve. One long-standing unsolved challenge is the anti-selective conjugate addition reaction between aldehydes and nitroolefins. This organocatalytic transformation is a versatile method for the synthesis of γ-nitroaldehydes and downstream compounds such as pyrrolidines and γ-butyrolactams, which are key moieties in bioactive molecules. Numerous amine catalysts have been developed for this transformation, but all provide syn-configured products. Here, we present a tripeptide as a general catalyst for the synthesis of anti-configured γ-nitroaldehydes. Key to the anti selectivity is the installation of substituents at Cδ of the reactive pyrrolidine of proline to enable the formation of s-cis enamine intermediates. The peptidic catalyst converts different aldehyde and nitroolefin combinations into the products in high yields and stereoselectivities. Conformational and mechanistic studies revealed a Curtin–Hammett scenario for the catalytic system. The strategy provides long-sought-after access to anti-configured γ-nitroaldehydes and a guide for reversing the diastereoselectivity of amine-based organocatalysts. The organocatalysed addition of aldehydes to nitroolefins is an extremely well-studied reaction that almost exclusively provides the syn-configured products. Here a general method to reverse the diastereoselectivity is reported, whereby a tripeptide catalyst consistently provides the anti product with high selectivity.