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Stereoselective Photoenzymatic O- and N-centered Radical Transformations Mediated by the Pyridoxal 5’-phosphate Cofactor

Award Number: F32GM163376
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 03/15/2026
PERIOD OF PERFORMANCE END DATE: 03/14/2029

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Stereoselective Photoenzymatic O- and N-centered Radical Transformations Mediated by the Pyridoxal 5’-phosphate Cofactor - PROJECT SUMMARY/ABSTRACT Chiral oxygen and nitrogen containing heterocycles are prolific in pharmaceutical agents, natural products, and biologically relevant molecules. The cyclization of heteroatom-centered radicals with alkenes provides a direct and atom-efficient route towards the synthesis of chiral heterocycles. However, this seemingly simple transformation presents substantial challenges due to limited avenues of generating heteroatom-centered radicals and controlling their resultant stereochemistry. Triplet energy transfer (EnT) from an excited state photocatalyst is a growing conceptual strategy for the mild generation of O- and N-centered radicals by direct bond homolysis of oximes and hydrazones but still suffers from a lack of stereocontrol. Photoenzymatic catalysis is an emerging strategy for initiating and controlling radical intermediates with high stereoselectivity. The highly ordered active site of enzymes overcomes selectivity issues by maintaining a strong association between radical intermediates. Non-natural mechanisms of initiating radical generation have mainly taken advantage of the excited state redox properties of the flavin and NADP cofactors, outer sphere electron transfer from exogenous photocatalysts, and metallocofactor-to-ligand charge transfer. Herein, we propose leveraging pyridoxal 5’-phosphate (PLP) dependent enzymes and EnT catalysis as a platform for generating and controlling oxyl-imidyl and amidyl-imidyl biradical pairs for the intramolecular oxy- amination or diamination of alkenes. By taking advantage of a substantial body of known hydroxylamine and hydrazine based PLP inhibitors, we hypothesize the well characterized PLP oxime and hydrazone intermediates are primed for EnT-mediated homolysis for the generation of O- and N-centered radicals. Substrate pre- organization within the PLP bound active site will exert stereocontrol and the rapid rates of heteroatom radical- ene cyclization will limit deleterious side reactions. By developing the stereoselective radical-ene cyclization of O- and N-centered radicals, we would address one of chemistry’s grand challenges and broadly benefit the synthetic community. Thus, our following specific aims are: (Aim 1) Identify PLP-dependent enzymes for oxyl radical cyclization and imidyl recombination for the synthesis of chiral tetrahydrofuryl amines. PLP dependent enzymes are an extremely versatile class of enzymes that facilitate a plethora of biochemical pathways, and we anticipate this will promote the promiscuous reactivity we seek. We will use the oxyl-ene cyclization as a testbed for the development of this novel mechanism within enzymes for the synthesis of valuable alpha-stereogenic tetrahydrofurans. (Aim 2) By expanding reactivity to O-acyl hydroxylamines, hydrazines, and hydrazides we seek to access the stereoselective synthesis of C-C and C-N unsaturated cyclic species which constitute the two most frequently used unsaturated ring systems in FDA approved drugs. Concurrent directed evolution and protein engineering will allow for the optimization of reaction yield, selectivity, and expansion of scope.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $76,300 )
2026	2026	THE TRUSTEES OF PRINCETON UNIVERSITY	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Biomedical Research and Research Training	000	1	1/26/2026	NEW	$75,052
2026	2026	THE TRUSTEES OF PRINCETON UNIVERSITY	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Biomedical Research and Research Training	002	1	4/14/2026	NEW	$0
2026	2026	THE TRUSTEES OF PRINCETON UNIVERSITY	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Biomedical Research and Research Training	001	1	4/14/2026	NEW	$1,248
														Subtotal = $76,300

Grand Total All Awards = $76,300

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Stereoselective Photoenzymatic O- and N-centered Radical Transformations Mediated by the Pyridoxal 5’-phosphate Cofactor

Award Number: F32GM163376

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 03/15/2026

PERIOD OF PERFORMANCE END DATE: 03/14/2029

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