Date of Award

May 2020

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

Advisor(s)

John D. Chisholm

Subject Categories

Physical Sciences and Mathematics

Abstract

Alkaloids containing a hexahydropyrrolo[2,3-b] indole (pyrroloindoline) core constitute a sizeable group of natural products. In these systems the most common functionality at the C3a position is perhaps the hydroxyl group. In this work oxoammonium salt 4-acetamido-2,2,6,6-tetramethyl-1-oxopiperidinium tetrafluoroborate (Bobbitt’s salt) rapidly reacts with tryptamine and tryptophan derivatives to provide the C3a oxygenated pyrroloindolines. These conditions exclude the use of expensive transition metal catalyst, LED lamps and long reaction times. This new method wasa then utilized in a synthetic study on the natural product pestalazine A.

1,1′-diaryl ethanes are an important functionality in many biologically active compounds. A pioneering study was done to access these systems by displacement of tricholoracetimidates with stoichiometric amounts of alkylmetal reagent (trimethylaluminium). Most benzylic substrates except the electron poor substrates undergo ready displacement. In case of an enantiopure imidate, a significant racemization was observed, implicating the formation of a cationic intermediate in the transformation.

The success of trimethylaluminium was further extended with allyltributylstannane to synthesize 1, 1’-diarylbutyl. The 1,1’-diarylbutyl group is a common structural motif found in many pharmaceutically active compounds. Commonly a strong base, transition metal catalyst, Brønsted acid or Lewis acid promoter is required to affect the displacement of diarylmethyl leaving groups. However, in this work simply heating diarylmethyl trichloroacetimidates with the allyltributylstannane gives easy access to these systems. Electron rich benzylic trichloroacetimidate systems gave the best results, where excellent yields are achieved just by refluxing the reactants together in nitromethane. Mechanistic studies conducted suggests both cationic and radical pathways may be active in this transformation.

Application of trichloroacetimidates for the synthesis of esters under mild conditions in the absence of an exogenous promoter is explored in this study. These conditions avoid the undesired decomposition of substrates with sensitive functional groups. With heating, these reactions have been extended to benzyl esters without electron donating groups.

Ghrelin is a peptide hormone which plays a key role in regulating hunger and energy balance within the body. Inhibition of ghrelin O-acyltransferase (GOAT), which catalyzes an essential octanoylation step in ghrelin maturation, offers a potential target for controlling ghrelin signaling. Through screening a small molecule library by our collabrators, a class of synthetic triterpenoids (CDDO) was identified that efficiently inhibit ghrelin acylation. To verify which functional group was responsible for hGOAT activity, some minimally functionalized steroid derivatives were synthesized in this project. These compounds act as covalent reversible inhibitors, providing the first evidence of the involvement of a nucleophilic cysteine residue in hGOAT catalysis. The Michael acceptor group plays the most important role in inhibition. This study may lead to a viable treatment for diabetes and obesity in future.

Access

Open Access

Available for download on Sunday, August 15, 2021

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