Enantioselective Total Synthesis of (-)-Mmovincme in Nine Chemical Steps: An Approach to Ketone Activation in Cascade Catalysis

摘要

Since its isolation in 1962, (-)-minovincinef (1, Figure 1) has garnered considerable interest within the chemical synthesis community because of its characteristic spiroindoline framework, a common structural feature found among a number of high-profile natural products derived from the Aspidosperma, Kopsia, and Catharanthus genre. Indeed, this structural core has led to (-)-minovincine being described as a "biogenetic turntable" between the vindolinine and kopsinine classes of isolates, and has provided the impetus over several decades for a number of racemic total syntheses of this biosynthetic linchpin. At the present time, however, no asymmetric total synthesis of (-)-minovincine has been reported, a surprising fact given the range of catalytic technologies which have been developed to forge this broadly represented spiroindoline framework. Herein, we detail the first enantioselective total synthesis of (-)-minovincine in only nine chemical steps using a novel organocascade catalysis transformation which incorporates an enantioselective Diels-Alder cycloaddition/β-elimination/conjugate addition sequence. Central to the development of this new catalysis cascade has been the identification of ketone substrates and amine catalysts which combine to provide direct access to the key functional and architectural elements found in (-)-minovincine.