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Development of Flavoproteins as Catalysts for Asymmetric Radical Reactions

Award Number: R01GM127703
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2018
PERIOD OF PERFORMANCE END DATE: 02/28/2027

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Development of Flavoproteins as Catalysts for Asymmetric Radical Reactions - Project Summary The work described in this proposal aims to address the longstanding challenge of controlling the enantioselectivity and regioselectivity of synthetically valuable reactions mediated by radical intermediates. This work will develop novel mechanisms for generating free radical intermediates within protein active sites. Evolution of the protein will be conducted to enhance the chemo-, regio-, and enantioselectivity of the reactions performed within their protein active site. Building on findings in the previous funding period, we will develop couplings reactions between nitronates and alkyl halides. These reactions have two possible products: a redox- neutral reaction to afford chiral 𝛼-tertiary nitroalkanes and a reductive coupling to prepare cross-coupled products. We will design catalysts to favor each outcome. Secondly, we will develop a regioselective coupling of alkyl radicals with arenes. In this project, we will engineer the protein scaffold to favor functionalization at positions that are untouched using existing synthetic methods. Thirdly, we will explore alkene difunctionalization. In one manifold, we will oxidize radical intermediates to form carbocations which can be quenched with various nucleophiles. In a second approach, we will exploit Smiles rearrangements for radical termination. These approaches will enable the rapid synthesis of highly substituted products while also enabling the development of catalysts to precisely control the stereochemistry of stereocenters formed in C–C bond- forming events. In this application, we will also develop a new strategy for radical initiation using oxidative decarboxylation. This activation mode will be applied to the synthesis of secondary amines. Finally, we will create a biocatalytic cross-coupling reaction, where alkylated flavin adducts mimic the reactivity of organometallic intermediates. This method will enable the coupling of carboxylic acids and alkyl halides without using a metalloprotein. Together, these methods and the goals proposed in the Specific Aims have the potential to streamline the synthesis of biological probes and drug targets, creating a significant benefit to human health and associated biomedical sciences.


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: 2025 ( Subtotal = $349,824 )
2025	2025	THE TRUSTEES OF PRINCETON UNIVERSITY	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Biomedical Research and Research Training	001	9	6/5/2025	TERMINATION	$0
2025	2025	THE TRUSTEES OF PRINCETON UNIVERSITY	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Biomedical Research and Research Training	002	10	6/5/2025	NON-COMPETING CONTINUATION	$327,228
2025	2025	THE TRUSTEES OF PRINCETON UNIVERSITY	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Biomedical Research and Research Training	000	9	1/8/2025	SUPPLEMENT FOR EXPANSION	$22,596
														Subtotal = $349,824

Issue Date FY: 2024 ( Subtotal = $346,695 )
2024	2024	THE TRUSTEES OF PRINCETON UNIVERSITY	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Biomedical Research and Research Training	003	9	6/11/2024	NON-COMPETING CONTINUATION	$32,599
2024	2024	THE TRUSTEES OF PRINCETON UNIVERSITY	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Biomedical Research and Research Training	002	9	3/18/2024	NON-COMPETING CONTINUATION	$293,398
2024	2023	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Biomedical Research and Research Training	005	7	8/20/2024	COMPETING CONTINUATION	$0
2024	2023	THE TRUSTEES OF PRINCETON UNIVERSITY	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Biomedical Research and Research Training	001	8	11/21/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$278,143
2024	2023	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Biomedical Research and Research Training	000	7	11/21/2023	COMPETING CONTINUATION	-$257,445
2024	2023	THE TRUSTEES OF PRINCETON UNIVERSITY	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Biomedical Research and Research Training	006	8	8/20/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2024	2022	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Biomedical Research and Research Training	004	6	8/20/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $346,695

Issue Date FY: 2023 ( Subtotal = $318,629 )
2023	2023	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Biomedical Research and Research Training	000	7	2/16/2023	COMPETING CONTINUATION	$318,629
														Subtotal = $318,629

Issue Date FY: 2022 ( Subtotal = $297,504 )
2022	2022	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Biomedical Research and Research Training	000	6	3/3/2022	NON-COMPETING CONTINUATION	$267,754
2022	2022	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Biomedical Research and Research Training	001	6	7/20/2022	NON-COMPETING CONTINUATION	$29,750
														Subtotal = $297,504

Issue Date FY: 2021 ( Subtotal = $219,313 )
2021	2021	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Biomedical Research and Research Training	002	5	6/22/2021	NON-COMPETING CONTINUATION	$298,016
2021	2020	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Biomedical Research and Research Training	004	4	8/10/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$61
2021	2020	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Biomedical Research and Research Training	001	4	6/8/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$46,194
2021	2020	TRUSTEES OF PRINCETON UNIVERSITY, THE	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Biomedical Research and Research Training	003	3	8/10/2021	NON-COMPETING CONTINUATION	-$61
2021	2020	TRUSTEES OF PRINCETON UNIVERSITY, THE	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Biomedical Research and Research Training	000	3	6/8/2021	NON-COMPETING CONTINUATION	-$124,897
														Subtotal = $219,313

Issue Date FY: 2020 ( Subtotal = $310,237 )
2020	2020	TRUSTEES OF PRINCETON UNIVERSITY, THE	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Biomedical Research and Research Training	000	3	2/26/2020	NON-COMPETING CONTINUATION	$310,237
														Subtotal = $310,237

Issue Date FY: 2019 ( Subtotal = $396,323 )
2019	2019	TRUSTEES OF PRINCETON UNIVERSITY, THE	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Biomedical Research and Research Training	000	2	2/21/2019	NON-COMPETING CONTINUATION	$310,237
2019	2019	TRUSTEES OF PRINCETON UNIVERSITY, THE	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Biomedical Research and Research Training	001	2	6/7/2019	SUPPLEMENT FOR EXPANSION	$86,086
														Subtotal = $396,323

Issue Date FY: 2018 ( Subtotal = $300,317 )
2018	2018	TRUSTEES OF PRINCETON UNIVERSITY, THE	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Biomedical Research and Research Training	000	1	4/16/2018	NEW	$300,317
														Subtotal = $300,317

Grand Total All Awards = $2,538,842

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Development of Flavoproteins as Catalysts for Asymmetric Radical Reactions

Award Number: R01GM127703

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 05/01/2018

PERIOD OF PERFORMANCE END DATE: 02/28/2027

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