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A New General Strategy for Pyridine Functionalization via Dearomatized Intermediates

Award Number: R01GM144591
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: 12/01/2021
PERIOD OF PERFORMANCE END DATE: 11/30/2026

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A New General Strategy for Pyridine Functionalization via Dearomatized Intermediates - Project Abstract. The goal of this project is to introduce a new synthetic strategy to functionalize pyridine heterocycles. Pyridines are the second most common nitrogen heterocycle found in FDA approved drugs, an unsurprising fact because of their propensity for hydrogen bonding and suite of valuable physiochemical properties such as aqueous solubility, net polarity, and resistance to oxidative metabolism. Synthetic methods to directly and selectively functionalize pyridines are critical in drug discovery efforts because drug-developers require variation in positional selectivity, various carbon- and heteroatom bearing groups on the scaffold a wide variance in their steric and electronic properties. However, general approaches to transform pyridine C–H bonds into valuable derivatives are lacking. In this proposal, we outline a dearomatization strategy by converting pyridines into Zincke imine and iminium adducts. In effect, these adducts make pyridines react like a series of alkenes rather than an aromatic system and thus open up the plethora of reactions associated with olefins that were previously ineffective on pyridines themselves. We will show that pyridines can now participate in numerous processes, such as halogenation, reaction with sp2-carbon electrophiles radical reactions that were either not viable or operated under extreme reaction conditions. The processes will occur with exclusive control of regioselectivity for the 3-position of Zincke intermediates and are also switchable to the 5-position based on the Zincke adduct's structure. The ring-opening-functionalization-ring-closing is sequencable into one-pot processes in many cases. We will also use the Zincke platform to access pyridine isotopologs for ADME studies and new methods to form N–oxides. We plan to employ this strategy for simple building block pyridines, drug-like intermediates and for late-stage functionalization of complex pyridine-containing drugs.


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 = $0 )
2026	2025	COLORADO STATE UNIVERSITY	601 S HOWES ST	FORT COLLINS	CO	80521	LARIMER	USA	Biomedical Research and Research Training	000	4	10/10/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $297,474 )
2025	2025	COLORADO STATE UNIVERSITY	601 S HOWES ST	FORT COLLINS	CO	80521	LARIMER	USA	Biomedical Research and Research Training	001	4	8/13/2025	NON-COMPETING CONTINUATION	$29,747
2025	2025	COLORADO STATE UNIVERSITY	601 S HOWES ST	FORT COLLINS	CO	80521	LARIMER	USA	Biomedical Research and Research Training	000	4	11/26/2024	NON-COMPETING CONTINUATION	$267,727
														Subtotal = $297,474

Issue Date FY: 2024 ( Subtotal = $297,068 )
2024	2024	COLORADO STATE UNIVERSITY	601 S HOWES ST	FORT COLLINS	CO	80521	LARIMER	USA	Biomedical Research and Research Training	001	3	6/12/2024	NON-COMPETING CONTINUATION	$29,707
2024	2024	COLORADO STATE UNIVERSITY	601 S HOWES ST	FORT COLLINS	CO	80521	LARIMER	USA	Biomedical Research and Research Training	000	3	11/16/2023	NON-COMPETING CONTINUATION	$267,361
														Subtotal = $297,068

Issue Date FY: 2023 ( Subtotal = $298,143 )
2023	2023	COLORADO STATE UNIVERSITY	601 S HOWES ST	FORT COLLINS	CO	80521	LARIMER	USA	Biomedical Research and Research Training	000	2	11/7/2022	NON-COMPETING CONTINUATION	$268,329
2023	2023	COLORADO STATE UNIVERSITY	601 S HOWES ST	FORT COLLINS	CO	80521	LARIMER	USA	Biomedical Research and Research Training	001	2	2/14/2023	NON-COMPETING CONTINUATION	$29,814
														Subtotal = $298,143

Issue Date FY: 2022 ( Subtotal = $299,141 )
2022	2022	COLORADO STATE UNIVERSITY	601 S HOWES ST	FORT COLLINS	CO	80521	LARIMER	USA	Biomedical Research and Research Training	000	1	11/25/2021	NEW	$299,141
														Subtotal = $299,141

Grand Total All Awards = $1,191,826

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A New General Strategy for Pyridine Functionalization via Dearomatized Intermediates

Award Number: R01GM144591

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: 12/01/2021

PERIOD OF PERFORMANCE END DATE: 11/30/2026

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