Thursday, November 21, 2024 11/21/2024

Next-generation C-H functionalization methods for organic synthesis and their applications to biological inquiry

Award Number: R35GM122473
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY/ABSTRACT Catalytic C-H bond functionalization has emerged as a powerful approach in synthetic organic chemistry for the discovery and production of new pharmaceuticals. The next generation C-H bond functionalization methods described in this proposal will enable the rapid assembly of pharmaceutically relevant compounds from simple and readily available inputs. In one program, we will access complex molecular architectures in a single step from simple precursors by the sequential three-component coupling of a C-H bond and two different types of coupling partners. Because many different coupling partners are effective for conventional C-H bond additions to one coupling partner, sequential three-component reactions utilitizing different combinations of coupling partners should provide access to an enormous diversity of motifs relevant to drug and natural product synthesis. Preliminary results obtained with MIRA funding have established the feasibility and utility of this approach. In a second program, we will apply reversible light-mediated C-H bond activation to obtain the most stable from the most accessible heterocycle stereoisomer. Saturated heterocycles such as piperidines, morpholines, piperazines, and lactams are prevalent in drugs and drug candidates but are often most efficiently prepared as the less stable stereoisomer. However, light-mediated processes can enable their highly stereoselective conversion to the more stable stereoisomer as we recently demonstrated for piperidines with MIRA funding. In a third program, we will broadly develop nitrogen heterocycle synthesis by imidoyl C-H functionalization. Imines derived from readily available aldehydes and primary amines are centrally important intermediates in organic synthesis. With MIRA funding, we developed a new approach for the efficient preparation of purine bioisosteres by imidoyl C-H activation of imines followed by in situ annulation with different coupling partners. Purine bioisosteres are found in large numbers of drugs and drug candidates, especially those that interact with biomolecular targets that have purine recognition motifs such as receptors, kinases, and mRNA. We will leverage our methods for the synthesis of purine bioisosteres to target the transcriptome and will apply imidoyl C-H activation and annulation to prepare other important heterocycles. With MIRA funding we advanced new enzyme inhibitor discovery approaches and potent and selective inhibitors to challenging enzyme targets. In proposed research, we will directly apply C-H functionalization to biological inquiry. For example, our methods for the synthesis and elaboration of dihydropyridines enable the rapid preparation of amine-containing structures with three-dimensional display of functionality and stereoselective introduction of multiple stereogenic centers, features increasingly sought after in medicinal chemistry endeavors. These approaches will be applied to the discovery of potent and selective ligands to challenging biomolecular targets relevant to the treatment of unmet medical conditions, including the identification of CNS penetrant, highly selective ligands to aminergic GPCRs.


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 = $0 )
2025	2024	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Biomedical Research and Research Training	000	8	11/7/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $785,135 )
2024	2024	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Biomedical Research and Research Training	000	8	4/9/2024	NON-COMPETING CONTINUATION	$680,342
2024	2024	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Biomedical Research and Research Training	002	8	8/5/2024	NON-COMPETING CONTINUATION	$75,594
2024	2024	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Biomedical Research and Research Training	001	8	4/10/2024	SUPPLEMENT FOR EXPANSION	$29,199
														Subtotal = $785,135

Issue Date FY: 2023 ( Subtotal = $968,763 )
2023	2023	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Biomedical Research and Research Training	002	7	4/10/2023	NON-COMPETING CONTINUATION	$755,936
2023	2023	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Biomedical Research and Research Training	004	7	5/29/2023	SUPPLEMENT FOR EXPANSION	$125,237
2023	2023	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Biomedical Research and Research Training	003	7	4/11/2023	SUPPLEMENT FOR EXPANSION	$87,590
2023	2022	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Biomedical Research and Research Training	001	6	11/22/2022	COMPETING CONTINUATION	$0
2023	2021	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Biomedical Research and Research Training	000	5	11/22/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $968,763

Issue Date FY: 2022 ( Subtotal = $814,327 )
2022	2022	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Biomedical Research and Research Training	001	6	8/29/2022	SUPPLEMENT FOR EXPANSION	$58,391
2022	2022	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Biomedical Research and Research Training	000	6	4/5/2022	COMPETING CONTINUATION	$755,936
														Subtotal = $814,327

Issue Date FY: 2021 ( Subtotal = $739,409 )
2021	2021	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Biomedical Research and Research Training	000	5	4/13/2021	NON-COMPETING CONTINUATION	$739,409
														Subtotal = $739,409

Issue Date FY: 2020 ( Subtotal = $818,938 )
2020	2020	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Biomedical Research and Research Training	001	4	6/9/2020	SUPPLEMENT FOR EXPANSION	$79,529
2020	2020	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Biomedical Research and Research Training	000	4	4/10/2020	NON-COMPETING CONTINUATION	$739,409
														Subtotal = $818,938

Issue Date FY: 2019 ( Subtotal = $739,409 )
2019	2019	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Biomedical Research and Research Training	000	3	4/8/2019	NON-COMPETING CONTINUATION	$739,409
														Subtotal = $739,409

Issue Date FY: 2018 ( Subtotal = $739,409 )
2018	2018	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Biomedical Research and Research Training	000	2	4/20/2018	NON-COMPETING CONTINUATION	$739,409
														Subtotal = $739,409

Issue Date FY: 2017 ( Subtotal = $484,233 )
2017	2017	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Biomedical Research and Research Training	000	1	4/28/2017	NEW	$484,233
														Subtotal = $484,233

Grand Total All Awards = $6,089,623

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Next-generation C-H functionalization methods for organic synthesis and their applications to biological inquiry

Award Number: R35GM122473

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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