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Nickel Cross-Coupling Cascades with α-Heteroatom Radicals to Prepare Sterically Hindered Alcohols and Amines

Award Number: F32GM146357
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 02/15/2023
PERIOD OF PERFORMANCE END DATE: 04/11/2025

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Nickel Cross-Coupling Cascades with α-Heteroatom Radicals to Prepare Sterically Hindered Alcohols and Amines - Project Summary The overarching theme of this proposal is to apply robust and reliable reaction mechanisms to improve the efficiency of forming C–C bonds adjacent to alcohol or amine functionality. Among the most common strategies to these products is the addition of a Grignard reagent (or other carbon nucleophile) to a ketone or ketimine electrophile, but the broad applicability of these methods is limited by (1) the poor compatibility of organometallic nucleophiles with many functional groups common to drug scaffolds and (2) significant limitations inherent to migratory insertion mechanisms, such as sluggish or undesired reactivity. The central hypothesis of this proposal is that α-heteroatom radical generating processes can be implemented in tandem with nickel cross-coupling for C–H functionalization to install hindered stereocenters. The emergence of nickel catalyzed cross-electrophile coupling strategies has provided novel and complementary reactivity to traditional cross-couplings and the controlled generation of organic free radicals is central to the development of new methods in this area. Intramolecular hydrogen atom transfer (HAT) mechanisms proceed at a higher rate than nickel capture of alkyl radicals, and should be an appropriate approach to generate the radical. The Specific Aims of this proposal are: (1) development of a 1,5-HAT and nickel C–C bond forming cascade to synthesize tertiary alcohols from readily available secondary alcohols and a traceless auxiliary group; (2) a strategy in which α-heteroatom radicals formed through 1,5-HAT are intercepted for nickel facilitated C–C bond formation to prepare functionalized amino alcohols and amino acids; and (3) an approach for Csp3–Csp3 coupling of α-heteroatom radicals to primary radicals is presented, in which cross-selectivity should be driven by radical stability differences. All three of these Aims can be adopted into enantioconvergent reactions by employing chiral ligands to generate stereocenters, which is highly desirable in the context of pharmaceutical and natural product synthesis. The development and synthesis of drug candidates is limited by the reactions available to make them, and the strategies described in this proposal will facilitate Csp2–Csp3 and Csp3–Csp3 bond formation at α-heteroatom carbon centers, an important motif found in pharmaceuticals and bioactive natural products. The continued improvement of catalytic conditions that employ a large pool of coupling partners to prepare sterically congested alcohols and amines will be of significant interest to both academia and industry, and will enable broader chemical space accessible in future drug discovery endeavors.


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 = $16,568 )
2025	2025	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Biomedical Research and Research Training	000	3	3/5/2025	NON-COMPETING CONTINUATION	$76,756
2025	2025	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Biomedical Research and Research Training	001	3	6/3/2025	NON-COMPETING CONTINUATION	-$60,188
														Subtotal = $16,568

Issue Date FY: 2024 ( Subtotal = $74,284 )
2024	2024	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Biomedical Research and Research Training	001	2	6/26/2024	NON-COMPETING CONTINUATION	$4,784
2024	2024	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Biomedical Research and Research Training	000	2	1/9/2024	NON-COMPETING CONTINUATION	$69,500
														Subtotal = $74,284

Issue Date FY: 2023 ( Subtotal = $69,080 )
2023	2023	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Biomedical Research and Research Training	000	1	1/30/2023	NEW	$67,174
2023	2023	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Biomedical Research and Research Training	002	1	2/14/2023	NEW	$1,906
2023	2023	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Biomedical Research and Research Training	001	1	1/30/2023	NEW	$0
														Subtotal = $69,080

Grand Total All Awards = $159,932

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Nickel Cross-Coupling Cascades with α-Heteroatom Radicals to Prepare Sterically Hindered Alcohols and Amines

Award Number: F32GM146357

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 02/15/2023

PERIOD OF PERFORMANCE END DATE: 04/11/2025

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