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Chiral Complexes Designed to Catalyzed Organic Reactions

Award Number: R01GM043214
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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This program is dedicated to the development and elucidation of new principles for stereoselective catalysis, and in the application of those principles to the invention of practical synthetic methods for the preparation of chiral, bioactive compounds. This renewal application is focused on two distinct approaches to the generation and stereocontrolled reaction of highly electrophilic intermediates. Each of the proposed reaction manifolds is based on firm mechanistic hypotheses gleaned from extensive preliminary investigations. The first involves the application of precisely designed chiral ureas, thioureas, and squaramides to catalyze enantioselective reactions via ion-pair intermediates. These dual hydrogen-bond donors can abstract or bind weakly basic anions, such as halides, sulfonates, and carboxylates, to generate chiral ion pairs that remain tightly associated during subsequent selectivity-determining reactions of the prochiral cations. We discovered that the combination of hydrogen-bond donors with achiral Lewis or Brønsted acids generates highly reactive complexes that can promote activation and enantioselective reactions of weakly electrophilic substrates. This new principle is directed to creative new applications including the enantioselective multi-component synthesis of amines from carbonyl compounds and to the asymmetric ring opening of oxetanes. The principle of anion-abstraction catalysis is also applied in a new way to the promotion of enantioselective boronate rearrangements, through a novel chiral recognition mechanism involving discrimination of enantiotopic leaving groups. The boronate rearrangement methodology provides a general approach to the systematic construction of trisubstituted stereocenters from readily available organoboron derivatives. The second distinct approach involves the oxidative fluorofunctionalization of alkenes using hypervalent iodine catalysis. We have discovered that simple C2-symmetric aryl iodides catalyze enantioselective difluorination of simple alkenes via a multistep mechanism involving a highly reactive fluoroalkyl iodane intermediate. That intermediate can be intercepted in a variety of intra- or intermolecular reactions, leading to novel, 1,1-, 1,2-, and 1,3-fluorofunctionalized products in highly enantioenriched form. Efforts are directed toward the mechanistic elucidation of the new reactions, and to their practical enablement through the use of practical fluoride sources.


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 = $723,098 )
2023	2023	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE 5TH FL	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Biomedical Research and Research Training	000	33	12/23/2022	NON-COMPETING CONTINUATION	$650,788
2023	2023	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE 5TH FL	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Biomedical Research and Research Training	001	33	2/13/2023	NON-COMPETING CONTINUATION	$72,310
														Subtotal = $723,098

Issue Date FY: 2022 ( Subtotal = $728,271 )
2022	2022	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE 5TH FL	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Biomedical Research and Research Training	000	32	12/20/2021	NON-COMPETING CONTINUATION	$655,444
2022	2022	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE 5TH FL	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Biomedical Research and Research Training	001	32	5/17/2022	NON-COMPETING CONTINUATION	$72,827
														Subtotal = $728,271

Issue Date FY: 2021 ( Subtotal = $742,419 )
2021	2021	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE 5TH FL	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Biomedical Research and Research Training	002	31	8/12/2021	SUPPLEMENT FOR EXPANSION	$9,021
2021	2021	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE 5TH FL	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Biomedical Research and Research Training	001	31	3/12/2021	NON-COMPETING CONTINUATION	$73,340
2021	2021	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE 5TH FL	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Biomedical Research and Research Training	000	31	12/21/2020	NON-COMPETING CONTINUATION	$660,058
														Subtotal = $742,419

Issue Date FY: 2020 ( Subtotal = $726,880 )
2020	2020	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE 5TH FL	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Biomedical Research and Research Training	000	30	12/12/2019	COMPETING CONTINUATION	$726,880
2020	2020	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE 5TH FL	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Biomedical Research and Research Training	002	30	5/8/2020	COMPETING CONTINUATION	$29,775
2020	2019	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE 5TH FL	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Biomedical Research and Research Training	001	29	5/8/2020	SUPPLEMENT FOR EXPANSION	-$29,775
														Subtotal = $726,880

Issue Date FY: 2019 ( Subtotal = $913,690 )
2019	2019	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE 5TH FL	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Biomedical Research and Research Training	001	29	6/5/2019	SUPPLEMENT FOR EXPANSION	$106,192
2019	2019	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE 5TH FL	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Biomedical Research and Research Training	000	29	12/24/2018	NON-COMPETING CONTINUATION	$807,498
														Subtotal = $913,690

Issue Date FY: 2018 ( Subtotal = $751,108 )
2018	2018	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE 5TH FL	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Biomedical Research and Research Training	001	28	5/23/2018	NON-COMPETING CONTINUATION	$69,472
2018	2018	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE 5TH FL	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Biomedical Research and Research Training	002	28	7/17/2018	SUPPLEMENT FOR EXPANSION	$56,390
2018	2018	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE 5TH FL	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Biomedical Research and Research Training	000	28	12/6/2017	NON-COMPETING CONTINUATION	$625,246
														Subtotal = $751,108

Issue Date FY: 2017 ( Subtotal = $674,584 )
2017	2017	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE 5TH FL	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Biomedical Research and Research Training	000	27	12/21/2016	NON-COMPETING CONTINUATION	$605,112
2017	2017	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE 5TH FL	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Biomedical Research and Research Training	001	27	6/2/2017	NON-COMPETING CONTINUATION	$69,472
														Subtotal = $674,584

Issue Date FY: 2016 ( Subtotal = $694,718 )
2016	2016	HARVARD UNIVERSITY PRESIDENT & FELLOWS	HOLYOKE 466, 1350 MASS AVENUE	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Biomedical Research and Research Training	000	26	12/23/2015	COMPETING CONTINUATION	$694,718
														Subtotal = $694,718

Issue Date FY: 2015 ( Subtotal = $666,932 )
2015	2015	HARVARD UNIVERSITY PRESIDENT & FELLOWS	HOLYOKE 466, 1350 MASS AVENUE	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Biomedical Research and Research Training	001	25	2/18/2015	NON-COMPETING CONTINUATION	$66,694
2015	2015	HARVARD UNIVERSITY PRESIDENT & FELLOWS	HOLYOKE 466, 1350 MASS AVENUE	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Biomedical Research and Research Training	000	25	12/12/2014	NON-COMPETING CONTINUATION	$600,238
														Subtotal = $666,932

Issue Date FY: 2014 ( Subtotal = $666,933 )
2014	2014	HARVARD UNIVERSITY PRESIDENT & FELLOWS	HOLYOKE 466, 1350 MASS AVENUE	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Biomedical Research and Research Training	001	24	3/12/2014	NON-COMPETING CONTINUATION	$66,693
2014	2014	HARVARD UNIVERSITY PRESIDENT & FELLOWS	HOLYOKE 466, 1350 MASS AVENUE	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Biomedical Research and Research Training	000	24	12/16/2013	NON-COMPETING CONTINUATION	$600,240
														Subtotal = $666,933

Issue Date FY: 2013 ( Subtotal = $643,589 )
2013	2013	HARVARD UNIVERSITY PRESIDENT & FELLOWS	HOLYOKE 466, 1350 MASS AVENUE	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Biomedical Research and Research Training	001	23	6/17/2013	NON-COMPETING CONTINUATION	$43,349
2013	2013	HARVARD UNIVERSITY PRESIDENT & FELLOWS	HOLYOKE 466, 1350 MASS AVENUE	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Biomedical Research and Research Training	000	23	12/31/2012	NON-COMPETING CONTINUATION	$600,240
														Subtotal = $643,589

Issue Date FY: 2012 ( Subtotal = $673,942 )
2012	2012	HARVARD UNIVERSITY PRESIDENT & FELLOWS	HOLYOKE 466, 1350 MASS AVENUE	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Biomedical Research and Research Training	000	22	1/30/2012	COMPETING CONTINUATION	$673,942
														Subtotal = $673,942

Issue Date FY: 2001 ( Subtotal = $392,507 )
2001	2001	HARVARD UNIVERSITY PRESIDENT & FELLOWS	HOLYOKE 466, 1350 MASS AVENUE	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Biomedical Research and Research Training	000	11	1/5/2001	NON-COMPETING CONTINUATION	$392,507
														Subtotal = $392,507

Issue Date FY: 2000 ( Subtotal = $381,669 )
2000	2000	HARVARD UNIVERSITY PRESIDENT & FELLOWS	HOLYOKE 466, 1350 MASS AVENUE	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Biomedical Research and Research Training	000	10	12/22/1999	NON-COMPETING CONTINUATION	$381,669
														Subtotal = $381,669

Issue Date FY: 1999 ( Subtotal = $371,097 )
1999	1999	HARVARD UNIVERSITY PRESIDENT & FELLOWS	HOLYOKE 466, 1350 MASS AVENUE	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Biomedical Research and Research Training	000	9	12/17/1998	NON-COMPETING CONTINUATION	$371,097
														Subtotal = $371,097

Issue Date FY: 1998 ( Subtotal = $360,288 )
1998	1998	HARVARD UNIVERSITY PRESIDENT & FELLOWS	HOLYOKE 466, 1350 MASS AVENUE	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Biomedical Research and Research Training	000	8	12/12/1997	COMPETING CONTINUATION	$360,288
														Subtotal = $360,288

Grand Total All Awards = $10,111,725

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Chiral Complexes Designed to Catalyzed Organic Reactions

Award Number: R01GM043214

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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