DOI

10.17077/etd.2fsxkotb

Document Type

Dissertation

Date of Degree

Spring 2016

Degree Name

PhD (Doctor of Philosophy)

Degree In

Chemistry

First Advisor

Wiemer, David F.

First Committee Member

Gloer, James B.

Second Committee Member

Pigge, F. Christopher

Third Committee Member

Forbes, Tori Z.

Fourth Committee Member

Olivo, Horacio F.

Abstract

Living organisms are capable of producing novel terpenoids with both remarkable ease and great selectivity. Many of these natural products exhibit significant biological activity useful for treatment of human diseases, but isolation of highly sought chemicals often results in only minute quantities. Consequently, extraction of these potential therapeutics from natural sources becomes an unrealistic method for obtaining enough material for a thorough biological evaluation, and so synthesizing these compounds becomes essential. Synthesis of terpenoids as potential therapeutics requires exceptional selectivity, especially when corresponding isomers elicit a contrasting biological response. The necessity for such selective syntheses along with the inherent structural complexities of terpenoids, often presents a number of significant challenges for the synthetic chemist.

Isolation of the terpenoids pawhuskins A–C and petalostemumol from Dalea purpurea was reported by Belofsky in 2004, and of the collected compounds pawhuskin A was found to exhibit the most significant activity in an opioid receptor assay in vitro. Natural pawhuskin A was extracted from “Purple Prairie Clover” in only a 39 mg quantity and therefore syntheses of the natural product along with several analogues were pursued. Two of the synthesized analogues demonstrated greater potency than pawhuskin A, and interestingly these two isomeric derivatives were found to be selective for two different opioid receptors. However, the synthetic route utilized to form these two derivatives was not very selective for either isomer, and thorough purification proved challenging. Ergo, an alternative approach was sought to ensure the purity of these potential therapeutics.

Parallel syntheses affording high selectivity for the key isomeric intermediates as well as a third regioisomer have been developed. The new isomeric intermediate also allowed the synthesis of two new analogues. This work is described in this report along with the formation of additional pawhuskin derivatives. The activity of these analogues as opioid receptor modulators also will be discussed.

Keywords

Halogen Metal Exchange, Opioid Receptor, Pawhuskin, Regioisomers, Suzuki

Pages

xx, 289 pages

Bibliography

Includes bibliographical references (pages 282-289).

Copyright

Copyright © 2016 Kevyn Danielle Gardner

Included in

Chemistry Commons

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