Organocatalytic Enantioselective Michael‐Addition of Malonic Acid Half‐Thioesters to β‐Nitroolefins: From Mimicry of Polyketide Synthases to Scalable Synthesis of γ‐Amino Acids

Abstract

Abstract Highly enantioselective biomimetic Michael addition reactions of malonic acid half thioesters (MAHTs) to a variety of nitroolefins, affording the optically active γ‐amino acid precursors, were developed by employing the Cinchona ‐based squaramides (up to >99% ee ). Remarkably, this biomimetic process is enantioconvergent, a highly desirable feature of a catalytic asymmetric reaction, whereby E / Z ‐isomers of the nitroolefins afford the same product enantiomer. The synthetic utility of this organocatalytic protocol was also demonstrated in the formal synthesis of pharmaceutically important γ‐amino acids such as baclofen. Moreover, a quantum chemical analysis of the catalyst‐substrate complexes is shown to give a detailed and instrumental insight into the origin of the observed catalytic activity.