Date of Award

2015

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Chemistry

First Advisor

Amos B. Smith

Abstract

This dissertation describes progress towards the synthesis of spirastrellolide E, a potent cytotoxic marine macrolide. In particular, the synthesis of advanced southern hemisphere fragments is reported. Chapter 1 details the isolation, structural determination, and biological activity of the spirastrellolide family, as well as synthetic efforts towards members of the family. Chapter 2 describes the evolution of the Smith group synthetic strategy towards the spirastrellolides, details the choice of target for a total synthesis effort, and describes a successful first generation approach to a relevant advanced southern hemisphere fragment. Key steps involve a convergent Type I Anion Relay Chemistry (ARC) union and a gold catalyzed directed spiroketalization. Chapter 3 then revises the overall retrosynthetic analysis by proposing a novel strategy for hemisphere union, involving a cross metathesis/epoxidation/epoxide ring opening cascade, and describes the synthesis of more than 500 mg of a revised southern hemisphere fragment. In addition, the mechanism of the key directed gold catalyzed spiroketalization is discussed in detail. A stereochemical rationale for diverging outcomes during spiroketalization is described.

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