Asymmetric Total Synthesis of Vindorosine Vindoline and Key Vinblastine Analogues

摘要

Concise asymmetric total syntheses of vindoline (>1) and vindorosine (>2) are detailed based on a unique intramolecular [4+2]/[3+2] cycloaddition cascade of 1,3,4-oxadiazoles inspired by the natural product structures. A chiral substituent on the tether linking the dienophile and oxadiazole was used to control the facial selectivity of the initiating Diels–Alder reaction and set the absolute stereochemistry of the remaining six stereocenters in the cascade cycloadduct. This key reaction introduced three rings and four C–C bonds central to the pentacyclic ring system setting all six stereocenters and introducing essentially all the functionality found in the natural products in a single step. Implementation of the approach for the synthesis of >1 and >2 required the development of a ring expansion reaction to provide a 6-membered ring suitably functionalized for introduction of the Δ^6,7-double bond found in the core structure of the natural products. Two unique approaches were developed that defined our use of a protected hydroxymethyl group as the substituent that controls the stereochemical course of the cycloaddition cascade. In the course of these studies, several analogues of vindoline were prepared containing deep-seated structural changes presently accessible only by total synthesis. These analogues, bearing key modifications at C6–C8, were incorporated into vinblastine analogues and used to probe the unusual importance (100-fold) and define the potential role of the vinblastine Δ^6,7-double bond.