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Build-and-Couple Synthesis of Functional Amines

Award Number: R35GM138114
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: 08/01/2020
PERIOD OF PERFORMANCE END DATE: 03/31/2031

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Build-and-Couple Synthesis of Functional Amines - Project Summary The incorporation of nitrogenic functionality into organic small molecules has a profound effect on chemical structure, properties, and bioactivity. Current methods to install nitrogen rely on substrate pre-functionalization or elaboration of nitrogen-containing starting materials and confront synthetic limitations that prevent systematic amine derivatization. Efforts to develop nitrene transfer catalysis provide mechanisms to install nitrogen in place of C–H bonds and olefins, but also confront limitations: Namely, structural diversification at nitrogen, which is critical to modulating molecular function, are often incompatible with the nitrogen sources needed for nitrene transfer chemistry. The central hypothesis of this proposal is that a new build-and-couple synthetic paradigm will powerfully enable the synthesis, validation, and optimization of nitrogen-containing bioactive small molecules. Build-and-couple chemistry is inherently compatible with activity-based protein profiling for the identification and optimization of small molecule ligands for novel protein targets. This proposal specifically aims to develop reductive cross-electrophile coupling reactions that leverage the reductive lability of N-aminopyridinium salts for C–N bond construction. Extension to in situ amine activation ¾ via phenothiazine redox chemistry ¾ will unlock direct functionalization of the native amine functionality of bioactive scaffolds, complex molecules, and molecular therapeutics. We further seek to advance the synthetic chemistry of N-pyridinium aziridines as lynchpin intermediates for proteomics experiments. N-Pyridinium aziridines display atypical chemoselectivity towards the proteome, selectively functionalizing glutamate and aspartate sites. To unlock the potential of this atypical selectivity to develop small molecule ligands against “undruggable” protein targets, we advance a suite of novel N-functionalization methods. Finally, fragment coupling strategies, to introduce new pharmacophores in fully elaborated molecular scaffolds, are described. Together, the described program in build-and-couple synthetic chemistry introduces new disconnections, new molecular scaffolds, and new mechanisms of action for the discovery and optimization of nitrogen-containing amines.


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 = $419,993 )
2026	2026	TEXAS A & M UNIVERSITY	400 HARVEY MITCHELL PKY S STE 300	COLLEGE STATION	TX	77845	BRAZOS	USA	Biomedical Research and Research Training	001	6	3/4/2026	COMPETING CONTINUATION	$419,993
2026	2024	TEXAS A & M UNIVERSITY	400 HARVEY MITCHELL PKY S STE 300	COLLEGE STATION	TX	77845	BRAZOS	USA	Biomedical Research and Research Training	000	5	2/25/2026	TERMINATION	$0
														Subtotal = $419,993

Issue Date FY: 2024 ( Subtotal = $363,288 )
2024	2024	TEXAS A & M UNIVERSITY	400 HARVEY MITCHELL PKY S STE 300	COLLEGE STATION	TX	77845	BRAZOS	USA	Biomedical Research and Research Training	000	5	7/16/2024	NON-COMPETING CONTINUATION	$363,288
														Subtotal = $363,288

Issue Date FY: 2023 ( Subtotal = $363,288 )
2023	2023	TEXAS A & M UNIVERSITY	400 HARVEY MITCHELL PKY S STE 300	COLLEGE STATION	TX	77845	BRAZOS	USA	Biomedical Research and Research Training	000	4	7/3/2023	NON-COMPETING CONTINUATION	$363,288
														Subtotal = $363,288

Issue Date FY: 2022 ( Subtotal = $363,288 )
2022	2022	TEXAS A & M UNIVERSITY	400 HARVEY MITCHELL PKY S STE 300	COLLEGE STATION	TX	77845	BRAZOS	USA	Biomedical Research and Research Training	000	3	7/18/2022	NON-COMPETING CONTINUATION	$363,288
														Subtotal = $363,288

Issue Date FY: 2021 ( Subtotal = $351,944 )
2021	2021	TEXAS A & M UNIVERSITY	400 HARVEY MITCHELL PKY S STE 300	COLLEGE STATION	TX	77845	BRAZOS	USA	Biomedical Research and Research Training	000	2	7/20/2021	NON-COMPETING CONTINUATION	$351,944
														Subtotal = $351,944

Issue Date FY: 2020 ( Subtotal = $349,658 )
2020	2020	TEXAS A & M UNIVERSITY	400 HARVEY MITCHELL PKY S STE 300	COLLEGE STATION	TX	77845	BRAZOS	USA	Biomedical Research and Research Training	000	1	7/17/2020	NEW	$349,658
														Subtotal = $349,658

Grand Total All Awards = $2,211,459

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Build-and-Couple Synthesis of Functional Amines

Award Number: R35GM138114

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: 08/01/2020

PERIOD OF PERFORMANCE END DATE: 03/31/2031

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