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Accessing Carbon-based S(VI) compounds via Sulfur-Fluorine (SuFEx) Exchange Reactions

Award Number: R15GM134457
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: 07/01/2020
PERIOD OF PERFORMANCE END DATE: 07/31/2028

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Accessing Carbon-based S(VI) compounds via Sulfur-Fluorine (SuFEx) Exchange Reactions - S(VI)-based compounds are a critical class of organic molecules with biomedical applications against inflammatory disorders, cancer, and bacterial infections. Approaches to making these carbon-based sulfur(VI) compounds are limited by the commercial availability of starting materials and harsh reactions preventing late-stage functionalization. Sulfur-fluorine exchange (SuFEx) chemistry is a new, promising pathway to synthesize sulfonylated products from sulfur(VI) fluorides and nucleophiles, but the unique stability of sulfur(VI) fluorides compared to other S(VI) halides introduces challenges for synthetic applications. We propose new (SuFEx) reactions to make carbon-based sulfonylated compounds using metals salt and sulfur(VI) fluorides. The proposed work is innovative because it seeks to develop attractive alternatives to induce sulfonylated moieties into organic molecules using affordable Lewis acid catalysts and easy-to-handle metal bases. Successful implementation of the research proposed herein will lead to novel, one-step SuFEx transformations toward S–N and S–C formation, enabling the development of new, diverse libraries for drug discovery. The first aim focuses on the development of calcium-catalyzed activation of sulfonyl, sulfonimidoyl, and sulfondiimidoyl fluorides to make sulfonamides as well as new chiral S(VI) compounds chiral bioisosteres sulfonimidamides, and sulfondiimidamides – critically underdeveloped classes of sulfonylated compounds with high potential as drug targets. The proposed transformations will represent a considerable advance over current methods that rely on starting materials that are challenging to synthesize or isolate. Additionally, these reactions would be the first Lewis acid-catalyzed SuFEx reaction. The second aim focuses on understanding the catalytic Lewis-acid activation mechanism of sulfur(VI) fluorides in SuFEx chemistry. These kinetic and computational studies will provide critical information for understanding key intermolecular interactions that govern the reaction, leading to a new generation of SuFEx reactions. The third aim will focus on developing a two- step, one-pot method to access sulfones and sulfonate esters from sulfonyl fluorides and fluorosulfates using metal enolates. The proposed SuFEx/decarboxylative method would establish the role of enolates as carbon nucleophiles to sulfonylated compounds. This would represent a new avenue in SuFEx chemistry and allow access to complex structures in sulfones and sulfonates esters key to their promise in drug discovery. The PI’s research has enhanced the research environment at Pomona College by engaging undergraduate students in biomedically relevant research with a significant impact on synthesis and medicinal chemistry.


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 = $428,004 )
2025	2025	POMONA COLLEGE	550 N COLLEGE AVE	CLAREMONT	CA	91711	LOS ANGELES	USA	Biomedical Research and Research Training	000	2	7/23/2025	COMPETING CONTINUATION	$428,004
														Subtotal = $428,004

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2020	POMONA COLLEGE	550 N COLLEGE AVE # 244	CLAREMONT	CA	91711	LOS ANGELES	USA	Biomedical Research and Research Training	000	1	9/19/2024	NEW	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2020	POMONA COLLEGE	550 N COLLEGE AVE	CLAREMONT	CA	91711	LOS ANGELES	USA	Biomedical Research and Research Training	000	1	3/31/2023	NEW	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $394,145 )
2020	2020	POMONA COLLEGE	550 N COLLEGE AVE	CLAREMONT	CA	91711	LOS ANGELES	USA	Biomedical Research and Research Training	000	1	4/8/2020	NEW	$394,145
														Subtotal = $394,145

Grand Total All Awards = $822,149

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Accessing Carbon-based S(VI) compounds via Sulfur-Fluorine (SuFEx) Exchange Reactions

Award Number: R15GM134457

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: 07/01/2020

PERIOD OF PERFORMANCE END DATE: 07/31/2028

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