Date of Award

Spring 2022

Project Type

Dissertation

Program or Major

Chemistry

Degree Name

Doctor of Philosophy

First Advisor

Charles K Zercher

Second Advisor

Erik B Berda

Third Advisor

Roy P Planalp

Abstract

The zinc-mediated chain extension reaction has been previously developed to incorporate alkyl or aryl substituents at the β position of the chain-extended product. The incorporation of heteroatom functionality at the β position of the chain-extended product was demonstrated through the use of a functionalized zinc carbenoid species. Silyl ether-functionalized geminal diiodides were used in the chain extension reaction with low to modest yields. Optimization of the chain extension reaction was performed by modification of solvent, reaction temperature, reaction time, and addition of diiodide. The chain extension reaction was performed on several different substrates, such as β-keto esters, β-keto amides, and β-keto phosphonates. Removal of the silyl group from γ-keto esters led to products which contained a cis-fused tetrahydrofuran-γ-lactone ring system. This new methodology is useful for the synthesis of β-functionalized γ-keto carbonyls. The methodology allows for the formation of the cis-fused tetrahydrofuran-γ-lactone ring system in two steps from commercially available β-keto esters.

Heliotridane is a natural product and a member of the pyrrolizidine alkaloid family. Heliotridane is a common target molecule for synthetic approaches, due to its simple structure. The formal synthesis of heliotridane and pseudoheliotridane was completed through the use of a zinc-mediated chain extension approach. Several different synthetic approaches were attempted, most of which encountered challenges during chain extension. A phthalimide protecting group was used to circumvent these challenges. The formal synthesis of heliotridane and pseudoheliotridane was accomplished in four steps, in 12% overall yield. This synthesis broadens the array of applications of the zinc-mediated chain extension reaction in natural product synthesis.

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