| Summary: | Thesis (Ph. D.)--University of Rochester. Department of Chemistry, 2022 Biocatalysis has been covering an increasingly important role for chemical synthesis and manufacturing of drugs, APIs, and other high-value compounds. This trend is driven by enzymes’ potential for high chemo-, regio-, and stereoselectivity, ability to operate under mild conditions, and amenability to adopt new or improved functions through protein engineering. Our group and others have recently explored heme-containing protein scaffolds (i.e. cytochrome P450, myoglobin (Mb), cytochrome c) to carry out abiological carbene and nitrene transfer reactions for the formation of new carbon-carbon, carbon-nitrogen and C-heteroatom bonds with high levels of catalytic efficiency and stereoselectivity. Building upon this work, a first goal of this dissertation was to develop a chemoenzymatic strategy for the stereoselective assembly and structural diversification of cyclopropyl ketones, a highly versatile yet underexploited class of functionalized cyclopropanes. As described in Chapter 2, an engineered variant of sperm whale myoglobin was shown to enable the highly diastereo- and enantioselective construction of these molecules via olefin cyclopropanation in the presence of a diazoketone carbene donor reagent. This biocatalyst was determined to offer a remarkably broad substrate scope, being able to catalyze this reaction with high stereoselectivity across a variety of vinylarene substrates as well as a range of different benzyl diazoketone derivatives. Chemical transformation of these enzymatic products has enabled further diversification of these molecules to yield a collection of structurally diverse cyclopropane-containing scaffolds in enantiopure form, including core motifs found in drugs and natural products as well as novel structures. Extending upon this work, a biocatalytic strategy for the highly diastereo-and enantioselective synthesis of acetal-substituted cyclopropanes was also developed (Chapter 3). In this work. a semi-rational ...
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