Total Synthesis of (-)- and ent-(+)-4-Desacetoxy-5-desethylvindoline

A concise synthesis of (-)-and ent-(+)-4-desacetoxy-5desethylvindoline (2), a key analogue of vindoline, is disclosed enlisting an intramolecular tandem [4+2]/[3+2] cycloaddition cascade of 1,3,4-oxadiazole (5) to assemble the pentacyclic skeleton of 2 in a single step that forms three new rings, four C-C bonds, and sets all five key stereocenters.The subsequent efforts on the elaboration of 6 to 2 revealed two subtle features key to our recent total syntheses of vindoline, vindorosine, and related natural products based on this strategy.Vinblastine and vincristine constitute the most widely recognized members of the class of bisindole alkaloids as a result of their clinical use as antineoplastic drugs (Figure 1). 1 Originally isolated in trace quantities from Cantharanthus roseus (L.) G. Don, 2 their biological properties were among the first to be shown to arise from inhibition of microtubule formation and mitosis that today is still regarded as one of the more successful drug targets for the treatment of cancer. 3Recently, we reported full details of the development of an usually concise total synthesis of (-)-and ent-(+)-vindoline (1), a major alkaloid of Cantharanthus roseus that constitutes the most complex half of vinblastine.It and related alkaloids were prepared by a route in which the pentacyclic skeleton complete with all substituents and stereocenters is created in a single step by a tandem intramolecular [4+2]/[3+2] cycloaddition cascade of a 1,3,4-oxadiazole that was inspired by the natural product structure. 4key analogue of vindoline that we anticipate synthetically incorporating into a vinblastine analogue is 4-desacetoxy-5-desethylvindoline (2) which is lacking both the C4-acetoxy and C5-ethyl groups.The C4-acetoxy substituent, which lies at the external and solvent exposed face of the vinblastine-tubulin † We would like to dedicate this work to Professor Y. Kishi, an inspirational scientist, on the occasion of his 70 th birthday.