Document Type

Dissertation

Degree

Doctor of Philosophy

Major

Chemistry, Organic

Date of Defense

9-3-2020

Graduate Advisor

Prof. Christopher D. Spilling

Committee

Prof. James S. Chickos

Prof. Alexei V. Demchenko

Prof. Michael R. Nichols

Abstract

This dissertation work is divided into two parts. The first part is focused in the development of methodology for the synthesis of phostones and phosphonosugars and advancement thereof. The second part is focused in the development of affinity probes based on analogs of natural products cyclophostin and the cyclipostins.

Phostone (3) and phosphonosugars are cyclic phosphonates. The anomeric carbon of sugar is replaced by a phosphorus atom. The synthesis of phostones has been achieved starting form the key intermediate, γ,δ-epoxy vinyl phosphonate (1). The palladium catalyzed ring opening of γ,δ-epoxy vinyl phosphonates by a nucleophile results in the formation of δ-hydroxy phosphonates (2), which on further reduction and cyclization yields phostones (3). Various primary alcohols have been used as the nucleophiles for the opening of γ,δ-epoxy vinyl phosphonate (1).

The synthesized phostones have been further functionalized and submitted to test their potency as LPS antagonists. Sugar-based methylene phosphonates have been prepared and tested as well.

Cyclophostin (4) and the cyclipostins (5) are bicyclic organophosphates. Previously published studies of analogs of cyclophostin (4) and the cyclipostins (5) have shown that they inhibit the growth of Mycobacterium tuberculosis either in infected macrophage or in a broth medium. This suggests that these analogs could represent a new class of multi-target inhibitors. To assist in the study of the mode of action and the target identification, two series of compounds were synthesized as the affinity probes. The synthesized compounds were submitted to collaborators to study their activity against Mycobacterium tuberculosis.

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