Studies of nucleophile ring opening of oxabicyclic systems in highly polar media : application to a total synthesis of antitumor agent, (-)-epothilone B

Abstract

Polyketides constitute an important family of natural products, having a broad spectrum of biological activity such as antitumor, antibiotic, antifungal, or immunomodulatory action.¹ Many of these compounds possess polypropionates (units with alternating hydroxyl and methyl groups), reflecting their common biosynthesis that is found within nature. Their structural complexity and importance of these compounds as therapeutical agents have made them attractive targets for synthetic organic chemists.¹ Excellent chiral propionate reagents have been developed over the years, including many chiral auxiliaries to direct and promote stereoselectivity, but most recent, investigations have focused upon developing metal-catalyzed asymmetric ring opening. To achieve these results, transition metals (Ni, Pd, Pt) have been employed leading to synthetically useful transformations.

This dissertation describes an alternative methodology to the use of transition metal. Ring opening reaction via polar media methodology developed in the Grieco group was extended to the synthesis of polypropionates and the completion of the naturally occurring epothilones. The use of 5.0 M lithium perchlorate in ether as a reaction solvent was required to obtain direct bridgehead opening of oxabicyclic[3.2.1] compound. Many nucleophiles (silyl enol ether and silyl ketene acetal) were tested for ring opening, but minimal diastereoselectivity was achieved. The reaction was improved by changing the O-silyl group of the oxabicyclic[3.2.1]-silyl enol ether (from O-TBS to O-TBDPS). Addition of trimethylsilyl chloride (TMSCl) enhanced reaction when hindered nucleophile was employed. Chiral nucleophiles (silyl enol ether and silyl ketene acetal) were also attempted, but ring opening did not transpire. This thesis explains the conceptual development of direct ring-opening of [3.2.1]-oxabicyclic octene, explorating the scope, and proving the principle by the completion of the epothilones synthesis.