Date of Award

2013

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Chemistry

First Advisor

Amos B. Smith

Abstract

The dissertation herein presents the first total synthesis of (-)-irciniastatin B in conjunction with the design and synthesis of analogues. Chapter One details the isolation and biological data of two potent cytotoxins (+)-irciniastatin A and (-)-irciniastatin B by Pettit and Crews. Also outlined in Chapter One are selected total syntheses and endgame strategies for (+)-irciniastatin A and reported structure activity relationship studies of the irciniastatin family of natural products.

The synthetic strategy toward the construction of (-)-irciniastatin B is outlined in Chapter Two. A chemoselective deprotection/oxidation sequence was proposed to install the requisite oxidation state at C(11). To this end, a late-stage alcohol from the earlier Smith synthesis of (+)-irciniastatin A was employed. However, protection of the late-stage alcohol as an orthogonal SEM ether resulted in unexpected degradation. A modified protecting group strategy employing robust 3,4-dimethoxybenzyl ethers successfully led to the first total synthesis of (-)-irciniastatin B. This strategy also led to the construction of (+)-irciniastatin A from (-)-irciniastatin B, confirming the structural relationship of these two secondary metabolites.

The design and synthesis of irciniastatin analogues are detailed in Chapter Three. Our synthetic strategy permits modification at C(11), which has been suggested to be a key structural element for the potent biological activity observed with the irciniastatins. Biological evaluation of C(11)-irciniastatin analogues will aid in the elucidation of the biological mode of action of the irciniastatin family of natural products.

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