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Atom-swapping reaction sequences enabled by decarbonylation and decarboxylation

Award Number: R35GM146854
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: 07/05/2022
PERIOD OF PERFORMANCE END DATE: 05/31/2027

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Atom-swapping reaction sequences enabled by decarbonylation and decarboxylation - The constant search for new chemical entities to address unmet medical needs compels the continued invention of new molecular editing approaches to derivatize complex small molecules. Single atom changes in a molecule alter the electronic properties of the molecule without extensive accompanying structural changes and are known to dramatically alter its biological activity. However, methods that enable substitutions of atoms embedded in the carbon framework of a molecule remain sparse. Substitution of a single atom – “atom swapping” – in the core structure of a molecule, rather than on the periphery, is challenging to execute because it involves multiple bond- breaking and bond-forming events. The conventional approach for introducing single atom changes in a molecule is thus to re-design synthesis routes to access atom-swapped derivatives. We challenge this long-standing practice by presenting a general strategy for atom swapping that proceeds in two stages – oxidation and transition metal-catalyzed carbon-extrusion reactions. The proposed research encompasses carbon-to-oxygen and carbon-to-nitrogen substitutions, and the conversion of lactones to lactams or cycloalkenes. The key step in all the proposed transformations is a transition metal-catalyzed decarbonylation or decarboxylation reaction. We will focus our efforts on the discovery and development of catalysts that promote decarbonylation and decarboxylation reactions on core motifs native to natural products and pharmaceuticals. These proposed reactions require that the catalyst be able to: 1) activate inert amide or ester bonds yet promote challenging carbon-heteroatom reductive eliminations; and 2) undergo site-selective oxidative addition. To identify catalysts that fulfil both criteria, we will examine ligand effects in each step of the catalytic cycle to enable rational ligand design and optimization. We will then interface the newly developed catalytic systems with well-documented C- H oxidation and rearrangement reactions to directly modify the carbon framework of cyclic natural products and pharmaceuticals. Realization of the goals of this proposal will circumvent tedious de novo synthesis for a single atom change and bring to fruition a highly desired transformation in the pharmaceutical industry.


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 = $363,348 )
2025	2025	IOWA STATE UNIVERSITY OF SCIENCE AND TECHNOLOGY	1350 BEARDSHEAR HALL	AMES	IA	50011	STORY	USA	Biomedical Research and Research Training	000	4	7/22/2025	NON-COMPETING CONTINUATION	$363,348
														Subtotal = $363,348

Issue Date FY: 2024 ( Subtotal = $364,121 )
2024	2024	IOWA STATE UNIVERSITY OF SCIENCE AND TECHNOLOGY	1350 BEARDSHEAR HALL	AMES	IA	50011	STORY	USA	Biomedical Research and Research Training	000	3	5/16/2024	NON-COMPETING CONTINUATION	$364,121
														Subtotal = $364,121

Issue Date FY: 2023 ( Subtotal = $364,862 )
2023	2023	IOWA STATE UNIVERSITY OF SCIENCE AND TECHNOLOGY	515 MORRILL RD, 1350 BEARDSHEAR HALL	AMES	IA	50011	STORY	USA	Biomedical Research and Research Training	000	2	7/6/2023	NON-COMPETING CONTINUATION	$364,862
														Subtotal = $364,862

Issue Date FY: 2022 ( Subtotal = $313,600 )
2022	2022	IOWA STATE UNIVERSITY OF SCIENCE AND TECHNOLOGY	515 MORRILL RD, 1350 BEARDSHEAR HALL	AMES	IA	50011	STORY	USA	Biomedical Research and Research Training	000	1	7/5/2022	NEW	$313,600
														Subtotal = $313,600

Grand Total All Awards = $1,405,931

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Atom-swapping reaction sequences enabled by decarbonylation and decarboxylation

Award Number: R35GM146854

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: 07/05/2022

PERIOD OF PERFORMANCE END DATE: 05/31/2027

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