Date of Award

2019

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Chemistry

First Advisor

Amos B. Smith

Abstract

Malaria currently remains a worldwide pandemic responsible for the death of over 400,000 people annually. The current frontline treatment protocol for malaria is artemisinin combination therapy (ACT). Artemisinin combination therapy has been responsible for a nearly 50% decrease in malaria responsible mortality over the past 20 years. However, antibiotic resistance to ACT has led to high treatment failure rates in some regions to as many as four of the five ACTs recommended by the World Health Organization. As such, novel therapeutics for the treatment of malaria will become more urgent as resistance to ACT continues to spread.

In 2015, Professor William Gerwick and coworkers at Scripps Institution of Oceanography published on the isolation of a novel antimalarial compound, (-)-bastimolide A, which displayed nanomolar activity against ACT resistant strains of P. falciparum. The Smith group began collaboration with Gerwick to synthesize (-)-bastimolide A and related congeners, the structure of some of which have not been fully elucidated. (-)-Bastimolide A is a 40 membered polyol macrolide, and was envisioned to be an ideal target for chemical synthesis via a series of Type I Anion Relay Chemistry (ARC) reactions.

A highly convergent route towards (-)-bastimolide A was developed featuring two complex Type I ARC reactions to unify three epoxide containing fragments that represent the full C1-C41 carbon skeleton of (-)-bastimolide A. Two of these three fragments were also envisioned to be constructed via a Type I ARC reaction.

Current synthetic studies have resulted in the synthesis of all three epoxide fragments for (-)-bastimolide A. Additionally, these three fragments have been successfully coupled via a Type I ARC reaction. The product of the ARC reactions utilized to construct the C1-C28 fragment of bastimolide represents the largest fragment ever assembled via an ARC process. The entire C1-C41 carbon skeleton, including all ten stereocenters featured in (-)-bastimolide A were able to be assembled in just 14 steps longest linear sequence from the starting material, (R)-epichlorohydrin. Current work is focusing on completing the total synthesis of (-)-bastimolide A, which is proposed to take 5 additional steps.

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Available to all on Tuesday, January 10, 2023

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