Asymmetric Total Synthesis of Vindoline and Novel Analogues

Skepper, Colin

Abstract

Vinblastine and vincristine are members of the Vinca alkaloid family originally isolated from the leaves of the Madagascan periwinkle Catharanthus roseus (L.) G. Don.1 Both compounds have been used clinically for over 40 years and represent one of the most important contributions that the field of natural products chemistry has made to cancer chemotherapy.2 In the clinic, vinblastine is used in curative combination regimens for the treatment of Hodgkin's and non-Hodgkin's lymphomas, bladder cancer and breast cancer. Vincristine, meanwhile, finds use in the treatment of leukemia, lymphomas and small cell lung cancer. Unfortunately, widespread use has led to the emergence of cancers with resistance that is imparted primarily by the action of the transmembrane protein phosphoglycoprotein (Pgp, also known as MDR1).4 The broad goal of this research project is to develop an efficient second-generation asymmetric chemical synthesis of vindoline, which constitutes the """"""""lower"""""""" subunit of vinblastine and vincristine. The proposed synthetic route features, as the key step, a transannular [4+2]/[3+2] cycloaddition cascade reaction that establishes four rings and six stereocenters with complete diastereoselectivity. This reaction constitutes an extension of methodology previously developed in the Boger lab involving an intramolecular variant of the cascade.10d The proposed synthetic route to vindoline will also allow for the construction of vinblastine and vincristine analogues that are not accessible by modification of the parent drug structure. All new analogues will be tested for activity against both wild-type and resistant cancer cells with the ultimate goal being identification of an analogue with activity against resistant cell lines superior to that of the parent drugs.

Public Health Relevance

This project aims to develop an efficient synthesis of vindoline and, subsequently, novel analogues of the cancer drugs vinblastine and vincristine. Analogues prepared through these efforts will be screened for anticancer activity in the search for a candidate with enhanced cytotoxicity against resistant cell lines.