Date of Award

Winter 12-22-2021

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

Advisor(s)

Chisholm, John D

Subject Categories

Chemistry | Organic Chemistry | Physical Sciences and Mathematics

Abstract

Pyrroloindolines and related systems are present in a large number of complex natural products. These core structures have generated considerable synthetic interest, as many of the compounds possess challenging, elaborate structures and interesting biological properties. Recently we have focused on using trichloroacetimidates for the synthesis of these fascinating molecules. Trichloroacetimidates can be used an electrophilic source of an alkyl group to form the pyrroloindoline directly from tryptamine derivatives. In this manner trichloroacetimidates provide a flexible solution to accessing highly functionalized pyrroloindoline core structures, needing only a catalytic amount of a Lewis acid to effect the requisite transformations.

Isatin (1H-indol-2,3-dione) based structures are commonly found in molecules of medicinal interest. These molecules are usually synthesized in multiple steps, with their N-alkylation typically requiring the use of stoichiometric strong base which limits the type of electrophile that can be used and generates stoichiometric waste byproducts. Utilizing trichloroacetimidate electrophiles we have initiated an investigation into the N-alkylation of isatin based molecules with catalytic amounts of Lewis acids, which produce fewer side products and therefore are more environmentally friendly. The method provides a single-step N-alkylation of isatins and is also applicable to hindered electrophiles that do not give high yields under the base mediated conditions.

Similar alkylations with trichloroacetimidates and benzotriazole substrates are also under investigation. Base promoted benzotriazole alkylation yields predominantly the N1-alkylation product, maintaining the aromaticity of the fused ring moiety. The N2-alkylation of benzotriazole which results in their de-aromatization has been explored here. This method can be applied for the synthesis of dearomatized benzotriazoles decorated with bulky functionalities yielding three-dimensional benzotriazole containing scaffolds.

Ghrelin is a peptide hormone that plays a key role in the regulation of appetite and energy within the body. In order to exert its appetite stimulating effects, ghrelin must be post-translationally octanoylated by ghrelin O-acyltransferase (GOAT). Inhibition of GOAT offers an enzymatic target to control appetite, presenting a potential method for the development of small-molecule therapeutics to treat obesity and diabetes. A heterocyclic lead compound has been identified that shows significant inhibition of ghrelin acylation by GOAT. Synthesis of the lead compound and similar molecules to explore structure activity relationships are reported.

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