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Authors: Cooper, Simon Joynson
Advisors: Hyster, Todd K
Contributors: Chemistry Department
Keywords: Asymmetric Catalysis
Catalytic Promiscuity
Hydrogen Atom Transfer
Synthetic Methodology
Subjects: Organic chemistry
Issue Date: 2020
Publisher: Princeton, NJ : Princeton University
Abstract: The work disclosed herein is encompassed by the common theme of leveraging the excited electronic states of enzyme-bound photoactive catalysts and cofactors to effect the selective formation of reactive radical intermediates within the confines of a chiral enzyme active site. By using photonic energy to localize the formation of radicals within the protein environment, some of the first examples of non-natural asymmetric radical reactivity in enzymatic systems are reported. First, discovery of asymmetric hydrodeacetoxylation activity in a nicotinamide adenine dinucleotide phosphate-dependent double bond reductase is described, wherein addition of a photosensitive dye enables the double bond reductase from the tobacco plant to catalyze a previously unknown asymmetric hydrogen atom transfer reaction capable of creating stereogenic centers at the α-position of a variety of aromatic ketones under irradiation with green light. Second, excitation of donor-acceptor complexes formed between α-chloroamides and fully reduced flavin mononucleotide in old yellow enzymes causes a reductive single electron transfer event that allows for selective α-amide radical generation. Radicals formed in this way can participate in enantioselective intramolecular C−C bond formations with a tethered alkene in 5- exo, 6-exo, and 7-exo trig cyclizations to form β-substituted butyro-, valero-, and caprolactams. Alternatively, enantioselective hydrogen atom transfer from flavin occurs in 5-endo and 8-endo trig cyclizations to yield γ-substituted butyrolactams and azocan-2-ones, respectively. Additionally, 5-exo trig cyclizations onto trisubstituted olefins may combine the stereoselectivities of C−C and C−H bond formation to control the creation of two stereogenic centers in a single operation, yielding γ-substituted butyrolactams containing an additional exocyclic stereogenic center. Remarkably, this reactivity has also been found to extend to the intermolecular coupling of simple α-chloroamides such as N,N-dimethylchloroacetamide and 1,1-disubstituted olefins, with control over the γ stereocenter possible through enzyme controlled hydrogen atom transfer from flavin. Taken collectively, these results demonstrate the ability of nicotinamide and flavoprotein photobiocatalysis to address longstanding challenges in synthetic radical chemistry.
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Type of Material: Academic dissertations (Ph.D.)
Language: en
Appears in Collections:Chemistry

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