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Synthesis of Partially Saturated Nitrogen Heterocycles Through Stereo- And Regioselective Dearomatization of Heteroarenes

Award Number: R35GM147244
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Synthesis of partially saturated nitrogen heterocycles through stereo- and regioselective dearomatization of heteroarenes. Nitrogen-containing heterocycles are important in multiple areas of chemistry including pharmaceutical, agrochemical and materials science due to their chemical properties and biological significance. These heterocycles are often grouped as aromatic and non-aromatic heterocycles. Aromatic heterocycles are widely available and recent advances in various cross coupling and C-H activation chemistry have further improved the access to these heterocycles. On the other hand, methods for the synthesis of non-aromatic heterocycles which often contain stereogenic centers at sp3 hybridized carbon centers are less developed. Our long-term goal is to develop new chemical transformations that will regio-, and stereoselectively introduce functionality into the heteroarenes to enable synthesis of partially saturated nitrogen heterocycles. Partially saturated heterocycles are excellent precursors to both aromatic and non-aromatic azaheterocycles. For example, dihydropyridines can be functionalization or reduced to yield tetrahydropyridines and piperidines and they can be oxidized to yield pyridines. The current proposal addresses the regioselective, stereoselective and catalytic addition of nucleophiles and electrophiles to the heteroarenes for the synthesis of partially saturated six- membered azaheterocycles. Specifically, we propose methodologies supported by significant preliminary results and literature precedents for the transition metal catalyzed dearomatization reactions of heteroarenes focusing on the regioselective dearomatization of six-membered heteroarenes containing one or two nitrogen atoms. Dearomatization approaches proposed by us include Rh, Pd, Ni and Cu catalyzed addition of boron nucleophiles as well as addition of organometallic nucleophiles to activated N-alkyl and N-acyl heteroarenes. In addition to coupling of nucleophiles, we propose dearomative coupling of heteroarenium salts with electrophiles using Ni-photoredox system. Catalyst design approaches for controlling the regio- and stereoselectivity of the addition reactions will also be explored. Methods described by us are innovative as they involve previously unexplored approaches, coupling partners and catalysts. The results obtained from these studies will be significant as the saturated and partially saturated heterocycles are common structural motifs in bioactive natural products and pharmaceuticals.


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: 2023 ( Subtotal = $374,061 )
2023	2023	AUBURN UNIVERSITY	321-A INGRAM HALL	AUBURN	AL	36849	LEE	USA	Biomedical Research and Research Training	000	2	6/5/2023	NON-COMPETING CONTINUATION	$374,061
														Subtotal = $374,061

Issue Date FY: 2022 ( Subtotal = $374,162 )
2022	2022	AUBURN UNIVERSITY	107 SAMFORD HALL	AUBURN	AL	36849	LEE	USA	Biomedical Research and Research Training	000	1	7/27/2022	NEW	$374,162
														Subtotal = $374,162

Grand Total All Awards = $748,223

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Synthesis of Partially Saturated Nitrogen Heterocycles Through Stereo- And Regioselective Dearomatization of Heteroarenes

Award Number: R35GM147244

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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