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Mechanistically Guided Cross-Electrophile Coupling Approaches to Useful Csp2-Csp2 and Csp2- Csp3 Bonds

Award Number: R01GM097243
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 Rapid advancements in biological and computational tools to find new therapeutic targets have outstripped available synthetic tools to synthesize drug candidates. Many proposed molecules are not tested because of the synthetic and time constraints of medicinal chemistry, where lead cores must be rapidly diversified in a modular fashion using robust, well-established methods, such as palladium-catalyzed cross-coupling and Grignard reactions. The major hurdles are the limited accessibility of carbon nucleophiles and the limited tolerance of most methods for the broad range of functional groups and reactivity present in drug candidates. We propose to develop collections of cross-electrophile coupling reactions that address these challenges and are adapted to modern parallel synthesis. Cross-electrophile coupling leverages the increased diversity of carbon electrophiles compared to nucleophiles (100 to 1000 times more commercially available derivatives); but achieving selectivity for cross-coupled product over dimeric products can be challenging and the factors that govern successful coupling remain unclear. This program's long-term goals are the development of methods for the selective cross-coupling of every major class of electrophile and the discovery of the fundamental properties that control selectivity and reactivity. In the proposed grant, a team of graduate students and postdocs will build upon the advances of the previous grant period to develop fourteen new cross-electrophile coupling reactions, explore new ways to utilize the largest substrate pools (organic chlorides, alcohols, amines, and carboxylic acids), and shed light on the reactive nickel intermediates that govern these processes. Our guiding hypothesis is that these challenges can be addressed by a combination of mechanistic studies, mechanism-guided design of new electrophiles, and an optimization approach that focuses on a collection of substrates rather than a single substrate pair. The specific aims of this proposal are to: (1) improve Csp2–Csp3 cross-electrophile coupling by the development of methods to engage new electrophiles, new combinations of old electrophiles, and by tailoring our optimization to the needs of medicinal chemistry; (2) address challenging Csp2–Csp2 cross-couplings by developing new, universal routes to challenging di(hetero)aryl ketones and bi(hetero)aryls; (3) shed light on the principles that govern nickel- catalyzed reactions by using electrochemical methods to study otherwise inaccessible reaction intermediates. The approach is innovative because cross-electrophile coupling is less studied than other cross-coupling methods and the proposed mechanistic studies will shed light on these little-understood processes. The proposed research is significant because the chemistry is increasingly important to industrial and academic chemical synthesis and the development of nickel chemistry has outpaced our understanding.


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 = $575,058 )
2023	2023	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Biomedical Research and Research Training	002	14	5/31/2023	SUPPLEMENT FOR EXPANSION	$176,379
2023	2023	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Biomedical Research and Research Training	001	14	5/19/2023	SUPPLEMENT FOR EXPANSION	$71,799
2023	2023	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Biomedical Research and Research Training	000	14	5/18/2023	NON-COMPETING CONTINUATION	$326,880
														Subtotal = $575,058

Issue Date FY: 2022 ( Subtotal = $380,729 )
2022	2022	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Biomedical Research and Research Training	000	13	5/13/2022	NON-COMPETING CONTINUATION	$326,880
2022	2022	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Biomedical Research and Research Training	001	13	9/9/2022	SUPPLEMENT FOR EXPANSION	$53,849
														Subtotal = $380,729

Issue Date FY: 2021 ( Subtotal = $406,799 )
2021	2021	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	Biomedical Research and Research Training	002	12	8/18/2021	SUPPLEMENT FOR EXPANSION	$80,000
2021	2021	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	Biomedical Research and Research Training	000	12	5/12/2021	NON-COMPETING CONTINUATION	$326,799
2021	2019	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Biomedical Research and Research Training	001	10	6/12/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $406,799

Issue Date FY: 2020 ( Subtotal = $334,891 )
2020	2020	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	Biomedical Research and Research Training	000	11	7/22/2020	COMPETING CONTINUATION	$334,891
														Subtotal = $334,891

Issue Date FY: 2019 ( Subtotal = $311,643 )
2019	2019	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	Biomedical Research and Research Training	000	10	4/15/2019	NON-COMPETING CONTINUATION	$311,643
														Subtotal = $311,643

Issue Date FY: 2018 ( Subtotal = $311,645 )
2018	2018	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	Biomedical Research and Research Training	002	9	4/23/2018	NON-COMPETING CONTINUATION	$311,645
2018	2017	UNIVERSITY OF ROCHESTER	500 JOSEPH C WILSON BLVD	ROCHESTER	NY	14627	MONROE	USA	Biomedical Research and Research Training	000	7	3/6/2018	NON-COMPETING CONTINUATION	-$4,940
2018	2017	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	Biomedical Research and Research Training	001	8	3/6/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$4,940
														Subtotal = $311,645

Issue Date FY: 2017 ( Subtotal = $314,472 )
2017	2017	UNIVERSITY OF ROCHESTER	500 JOSEPH C WILSON BLVD	ROCHESTER	NY	14627	MONROE	USA	Biomedical Research and Research Training	003	7	8/22/2017	NON-COMPETING CONTINUATION	-$208,949
2017	2017	UNIVERSITY OF ROCHESTER	601 ELMWOOD AVE	ROCHESTER	NY	14642	MONROE	USA	Biomedical Research and Research Training	001	7	4/11/2017	NON-COMPETING CONTINUATION	$293,676
2017	2017	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	Biomedical Research and Research Training	004	8	8/23/2017	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$197,113
2017	2017	UNIVERSITY OF ROCHESTER	500 JOSEPH C WILSON BLVD	ROCHESTER	NY	14627	MONROE	USA	Biomedical Research and Research Training	002	7	6/15/2017	NON-COMPETING CONTINUATION	$32,632
2017	2015	UNIVERSITY OF ROCHESTER	500 JOSEPH C WILSON BLVD	ROCHESTER	NY	14627	MONROE	USA	Biomedical Research and Research Training	000	5	10/27/2016	NON-COMPETING CONTINUATION	$0
														Subtotal = $314,472

Issue Date FY: 2016 ( Subtotal = $376,704 )
2016	2016	UNIVERSITY OF ROCHESTER	1325 MOUNT HOPE AVE, SUITE 260	ROCHESTER	NY	14642	MONROE	USA	Biomedical Research and Research Training	001	6	4/25/2016	COMPETING CONTINUATION	$321,491
2016	2016	UNIVERSITY OF ROCHESTER	1325 MOUNT HOPE AVE, SUITE 260	ROCHESTER	NY	14642	MONROE	USA	Biomedical Research and Research Training	002	6	8/1/2016	SUPPLEMENT FOR EXPANSION	$55,213
2016	2015	UNIVERSITY OF ROCHESTER	910 GENESEE STREET SUITE 200	ROCHESTER	NY	146113847	MONROE	USA	Biomedical Research and Research Training	000	5	4/20/2016	NON-COMPETING CONTINUATION	$0
														Subtotal = $376,704

Issue Date FY: 2015 ( Subtotal = $309,542 )
2015	2015	UNIVERSITY OF ROCHESTER	1325 MOUNT HOPE AVE, SUITE 260	ROCHESTER	NY	14642	MONROE	USA	Biomedical Research and Research Training	000	5	6/25/2015	NON-COMPETING CONTINUATION	$309,542
														Subtotal = $309,542

Issue Date FY: 2014 ( Subtotal = $341,519 )
2014	2014	UNIVERSITY OF ROCHESTER	1325 MOUNT HOPE AVE, SUITE 260	ROCHESTER	NY	14642	MONROE	USA	Biomedical Research and Research Training	000	4	4/22/2014	NON-COMPETING CONTINUATION	$293,550
2014	2014	UNIVERSITY OF ROCHESTER	1325 MOUNT HOPE AVE, SUITE 260	ROCHESTER	NY	14642	MONROE	USA	Biomedical Research and Research Training	001	4	4/30/2014	SUPPLEMENT FOR EXPANSION	$47,969
														Subtotal = $341,519

Issue Date FY: 2013 ( Subtotal = $283,276 )
2013	2013	UNIVERSITY OF ROCHESTER	1325 MOUNT HOPE AVE, SUITE 260	ROCHESTER	NY	14642	MONROE	USA	Biomedical Research and Research Training	000	3	4/26/2013	NON-COMPETING CONTINUATION	$264,195
2013	2013	UNIVERSITY OF ROCHESTER	1325 MOUNT HOPE AVE, SUITE 260	ROCHESTER	NY	14642	MONROE	USA	Biomedical Research and Research Training	001	3	6/19/2013	NON-COMPETING CONTINUATION	$19,081
														Subtotal = $283,276

Issue Date FY: 2012 ( Subtotal = $290,236 )
2012	2012	UNIVERSITY OF ROCHESTER	1325 MOUNT HOPE AVE, SUITE 260	ROCHESTER	NY	14642	MONROE	USA	Biomedical Research and Research Training	000	2	4/10/2012	NON-COMPETING CONTINUATION	$290,236
														Subtotal = $290,236

Issue Date FY: 2011 ( Subtotal = $281,952 )
2011	2011	UNIVERSITY OF ROCHESTER	1325 MOUNT HOPE AVE, SUITE 260	ROCHESTER	NY	14642	MONROE	USA	Biomedical Research and Research Training	000	1	6/14/2011	NEW	$281,952
														Subtotal = $281,952

Grand Total All Awards = $4,518,466

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Mechanistically Guided Cross-Electrophile Coupling Approaches to Useful Csp2-Csp2 and Csp2- Csp3 Bonds

Award Number: R01GM097243

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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