Total Synthesis of a Bicyclo[1.1.0]butane Fatty Acid and Biosynthetically Empowered Investigation of the Biological Activity of Apoptolidin

Abstract

Complex secondary metabolites from diverse life forms play key roles in mediating many biological processes but the exact nature of their function is often unknown. Chemical synthesis can be utilized to access such compounds in high purity and to modify them as chemical probes to understand their specific activity and function in biological systems. Herein are described two projects with these goals. Chapter I details the first project involving the total synthesis of a unique bicyclo[1.1.0]butane fatty acid isolated from the cyanobacteria Anabaena sp. implementing a designed cyclization/epoxidation cascade reaction. A second project is described in chapters II-V that involves the synthesis and utilization of several chemical probes of the polyketide natural product apoptolidin. Specifically, chapter II details previous work resulting in the isolation and preparation of structurally diverse analogues of apoptolidin through chemical synthesis or directed mutasynthesis. Chapter III details experiments aimed at understanding the mechanism of the highly cancer cell selective cytotoxicity of apoptolidin. Chapters IV and V describe the preparation of fluorescent and affinity purification probes from apoptolidin and their use in experiments aimed at understanding the roles of apoptolidin’s deoxysugar moieties and identifying novel biological targets.