Vinblastine: Synthetic and mechanistic studies

A brief summary of studies providing a first generation and second generation asymmetric total synthesis of vindoline based on the implementation of a powerful [4+2]/[3+2] cycloaddition cascade of 1,3,4-oxadiazoles will be presented along with its extension to the preparation of a series of key analogs. The development of a single-step biomimetic Fe(III)-promoted coupling of vindoline with catharanthine and subsequent in situ oxidation to provide vinblastine, its extension to the total synthesis of related natural products and key analogs, and new mechanistic insights into the reactions will be presented. Use of this work in key studies addressing the structural features of vinblastine contributing to its tubulin binding and antitumor properties, and the synthesis, evaluation, and discovery of potent analogs will be discussed.