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Studies Pertaining to Amide Bond Activation, Small Molecule Therapeutics, Cyclic Allenes, and Chemical Education

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This dissertation describes the development of reaction methodologies that utilize unconventional building blocks in chemical synthesis. One major effort involves the nickel-catalyzed net hydrolysis of traditionally inert amide C�–N bonds to give carboxylic acids. Additionally, the development of synthetic routes to afford structurally complex bioactive compounds are reported. Specifically, these include the synthesis of a small library of furanoindoline compounds for structure-activity relationship studies related to the treatment of Alzheimer’s disease and an alternative synthesis of the nucleobase found in the FDA-approved COVID-19 antiviral remdesivir. Finally, investigations into strained heterocyclic allenes are described. These studies have allowed for highly reactive cyclic allene intermediates to be utilized strategically in the regioselective and enantiospecific synthesis of a diverse array of densely functionalized heterocycles. Furthermore, a synthetic approach toward the synthesis of alstilobanine A is reported, where the key step hinges on a cycloaddition of an azacyclic allene intermediate. Each of the new strategies presented are expected to expand the synthetic toolbox by leveraging unique reactivity.

Chapter one describes the development of a nickel-catalyzed net hydrolysis of amides. The methodology strategically employs a nickel-catalyzed esterification using 2-(trimethylsilyl)-ethanol, followed by a fluoride-mediated deprotection in a single-pot operation. The selectivity and mildness of this transformation are demonstrated through competition experiments and the net-hydrolysis of a complex valine-derived substrate. This strategy addresses a limitation in the field with regard to functional groups accessible from amides using transition metal-catalyzed C–N bond activation.

Chapters two and three detail the synthesis of bioactive compounds. Chapter two specifically describes the synthesis of a small library of furanoindoline analogs for structure-activity relationship studies on the inhibition of neutral sphingomyelinase-2 and acetylcholinesterase, enzymes implicated in Alzheimer’s disease. The syntheses employ a key interrupted Fischer indolization reaction where the furanoindoline product is elaborated to generate a number of analogs. Identification of the dual inhibitors represents a promising new therapeutic approach to Alzheimer’s disease. Chapter three describes an alternative approach to the unnatural nucleobase fragment found in remdesivir (Veklury�), an FDA-approved antiviral for the treatment of COVID-19. The route relies on the formation of a cyanoamidine intermediate, which undergoes a Lewis acid-mediated cyclization to yield the desired nucleobase. The approach is strategically distinct from prior routes and could further enable the synthesis of remdesivir and other small-molecule therapeutics.

Chapters four and five are concerned with the investigation of cyclic allene intermediates. Chapter four describes an experimental and computational study of azacyclic allenes, including the synthesis of several substituted azacyclic allene precursors, subsequent allene generation, and trapping in cycloadditions. Additionally, the computational studies performed provide insight into the underlying reasons for the observed regioselectivities and enantiospecificities. Chapter five details experimental studies of oxacyclic. Specifically, the development of a precursor to 3,4-oxacyclohexadiene and subsequent allene trapping in (4+2), (3+2), and (2+2) cycloadditions is disclosed. Additionally, the first asymmetric synthesis of a silyl triflate cyclic allene precursor was achieved, as well as enantiospecific trapping of the allene. These studies highlighted the potential for cyclic allenes to be valuable building blocks the asymmetric synthesis of heterocycles.

Chapter six illustrates the development of an alternative precursor toward strained cyclic allenes and alkynes. Our studies of strained cyclic allenes revealed that, in some cases, silyl triflate precursors were inaccessible. This study shows that silyl tosylates can serve as alternative precursors to strained cyclic allenes and alkynes.

Chapter seven details a strategy for the total synthesis of alstilobanine A, a monoterpene indole alkaloid. Our approach hinges on a key (4+2) Diels–Alder reaction between an acetoxy-substituted azacyclic allene intermediate and a pyrone. This cycloaddition forms two key C–C bonds and sets three of the four stereocenters found in the natural product. Current efforts to synthesize the natural product are detailed. If successful, these studies should provide efficient access to alstilobanine A and demonstrate the utility of cyclic allenes in complex molecule synthesis.

Finally, chapter eight is a contribution to chemical education. The chapter outlines a new course centered around transition-metal catalysis in modern drug discovery. The course was designed to illustrate the central role of organic chemistry in driving small-molecule drug development and was taught by graduate students with mentorship from a faculty member. Additionally, experts in the fields of catalysis and drug discovery served as guest lecturers throughout the duration of the course. This chapter reflects on the experience of creating and developing the course, and aims to motivate the creation of future courses that unify fundamental concepts with applications and career outcomes.

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This item is under embargo until June 1, 2024.