Electronic Theses and Dissertations

Date of Award

1-1-2018

Document Type

Dissertation

Degree Name

Ph.D. in Pharmaceutical Sciences

Department

Biomolecular Sciences

First Advisor

David A Colby

Second Advisor

Jared Delcamp

Third Advisor

Christopher R. McCurdy

Abstract

The significant applications of fluorinated molecules in the pharmaceutical, agrochemical, and material sciences make them attractive synthetic targets. Difluoromethylation methods are of exceptional value and a limited number of techniques are available to perform that transformation. The primary method for introducing CF2 groups is through the use of difluoroenolates. Difluoroenolates can be generated from α-keto pentafluoro gem -diols under mild conditions. The process involves the cleavage of carbon-carbon bond and the release of trifluoroacetate. The release of trifluoroacetate is a versatile method to generate fluorinated molecules. We explored the utility of this method in generating various fluorinated moieties including α,α-difluoroketones, α-deutero-α,α-difluoroketones, α,α-difluoromethyl sulfones, ?-deutero-α,α-difluoromethyl sulfones, monofluoro α-hydroxy ketones and α,α-difluorohalohydrins.

We also endeavored to design and synthesize fluorinated molecules for biological applications. Our efforts were aimed at the use of a novel fluorinated β-hydroxy ketone scaffold developed in our lab to develop new agonists of the GABAB receptor. The value of GABAB agonists as muscle relaxants is well established, and interest in these agonists has been rekindled due to reports of new applications in managing drug and alcohol tolerance. We have developed several new analogues, characterized new structure-activity relationships of the fluorinated ?-hydroxy ketone scaffold, and identified more active agents.

We are also interested in using fluorine as a tag to track anti-body drug conjugates (ADCs). The chemistry of ADC linkers has attracted a lot of interest recently. The cleavage of the linker is essential for the function of ADCs and in addition to this traditional role, linkers can provide a handle for tagging ADCs. The incorporation of fluorine into linkers minimally affects the sterics of the linker owing to the small size of fluorine atom while at the same time provides a tractable tag. A fluorinated ADC linker has been designed and its synthesis was explored.

Concentration/Emphasis

Emphasis: Medicinal Chemistry

Available for download on Thursday, July 23, 2020

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