Efforts Toward a Total Synthesis of Acutumine

Abstract

The evolution of our synthetic strategy toward a total synthesis of acutumine is described in this thesis. The first chapter provides background information on several topics: (1) the isolation, structure determination, and biological activity of acutumine; (2) Barton's biosynthetic proposal and the synthetic work carried out by the Matoba and Wipf research groups in an attempt to experimentally validate aspects of this proposal; (3) biochemical studies on the biosynthesis of acutumine; (4) biohalogenation; and (5) the synthetic work carried out by the Castle research group during their successful total synthesis of acutumine. A synthetic strategy that utilized the oxygenated six-membered ring as its foundation to advance aromatic and quinone intermediates into highly functionalized [4.3.0] bicyclic systems that provided critical information about the acutumine system is described in the second chapter. The third chapter presents our evolved strategy to address the acutumine architecture from the vantage of the heterocycle, and how this new strategy led to a synthesis of the propellane-like [4.3.3.0] fused tricyclic core of acutumine in only seven transformations from a known and readily available pyrrolidine derivative. The final chapter describes our further efforts toward a total synthesis of acutumine, including the proposal to utilize a chloronium ion-induced semipinacol rearrangement to introduce both the spirocycle and the chlorine atom in short order from intermediates described during our synthesis of the tricyclic core of acutumine.