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Please use this identifier to cite or link to this item: http://arks.princeton.edu/ark:/88435/dsp014f16c574c
Title: VISIBLE LIGHT-PROMOTED, RADICAL-MEDIATED ASYMMETRIC C−C & C−H BOND FORMATIONS IN NICOTINAMIDE & FLAVIN MONONUCLEOTIDE-DEPENDENT OXIDOREDUCTASES
Authors: Cooper, Simon Joynson
Advisors: Hyster, Todd K
Contributors: Chemistry Department
Keywords: Asymmetric Catalysis
BIocatalysis
Catalytic Promiscuity
Hydrogen Atom Transfer
Photocatalysis
Synthetic Methodology
Subjects: Organic chemistry
Biochemistry
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.
URI: http://arks.princeton.edu/ark:/88435/dsp014f16c574c
Alternate format: The Mudd Manuscript Library retains one bound copy of each dissertation. Search for these copies in the library's main catalog: catalog.princeton.edu
Type of Material: Academic dissertations (Ph.D.)
Language: en
Appears in Collections:Chemistry

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