This program will explore the development of enantioselective processes catalyzed by planar-chiral derivatives of 4-(dimethylamino)pyridine (DMAP) and by chiral phosphines. The investigation will focus primarily on their application as nucleophilic catalysts;in addition, a recently discovered dimension of the chemistry of the DMAP derivatives, their use (in protonated form) as Bronsted acid catalysts, will be pursued. A diverse array of reactions (e.g., Staudinger synthesis of beta-lactams, kinetic resolutions of alcohols and amines, annulations, and halogenations) will be examined. Achieving the objectives of this program will facilitate access to important families of compounds in highly enantioenriched form. Relevance: Due to the """"""""handedness"""""""" of the molecules of life (proteins, DMA, RNA, sugars, etc.), the two mirror- image versions (""""""""enantiomers"""""""") of a particular compound often display quite different biological activity. As a result, there is a tremendous need to selectively generate just one of the two mirror-image compounds (nine of the Top 10 pharmaceutical drugs have """"""""handed"""""""" active ingredients, seven of which are single-handed (enantiopure)). Enantioselective catalysis, the focus of this research program, is a particularly attractive strategy for achieving this objective.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM057034-12
Application #
7544463
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Schwab, John M
Project Start
1998-01-01
Project End
2010-02-28
Budget Start
2009-01-01
Budget End
2010-02-28
Support Year
12
Fiscal Year
2009
Total Cost
$363,707
Indirect Cost
Name
Massachusetts Institute of Technology
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
001425594
City
Cambridge
State
MA
Country
United States
Zip Code
02139
Ziegler, Daniel T; Fu, Gregory C (2016) Catalytic Enantioselective Carbon-Oxygen Bond Formation: Phosphine-Catalyzed Synthesis of Benzylic Ethers via the Oxidation of Benzylic C-H Bonds. J Am Chem Soc 138:12069-72
Lee, Sarah Yunmi; Fujiwara, Yuji; Nishiguchi, Atsuko et al. (2015) Phosphine-catalyzed enantioselective intramolecular [3+2] annulations to generate fused ring systems. J Am Chem Soc 137:4587-91
Kalek, Marcin; Fu, Gregory C (2015) Phosphine-Catalyzed Doubly Stereoconvergent ?-Additions of Racemic Heterocycles to Racemic Allenoates: The Catalytic Enantioselective Synthesis of Protected ?,?-Disubstituted ?-Amino Acid Derivatives. J Am Chem Soc 137:9438-42
Kramer, Søren; Fu, Gregory C (2015) Use of a new spirophosphine to achieve catalytic enantioselective [4 + 1] annulations of amines with allenes to generate dihydropyrroles. J Am Chem Soc 137:3803-6
Ziegler, Daniel T; Riesgo, Lorena; Ikeda, Takuya et al. (2014) Biphenyl-derived phosphepines as chiral nucleophilic catalysts: enantioselective [4+1] annulations to form functionalized cyclopentenes. Angew Chem Int Ed Engl 53:13183-7
Lee, Sarah Yunmi; Neufeind, Stefan; Fu, Gregory C (2014) Enantioselective nucleophile-catalyzed synthesis of tertiary alkyl fluorides via the ?-fluorination of ketenes: synthetic and mechanistic studies. J Am Chem Soc 136:8899-902
Lundgren, Rylan J; Wilsily, Ashraf; Marion, Nicolas et al. (2013) Catalytic asymmetric C-N bond formation: phosphine-catalyzed intra- and intermolecular ?-addition of nitrogen nucleophiles to allenoates and alkynoates. Angew Chem Int Ed Engl 52:2525-8
Lee, Sarah Yunmi; Murphy, Jaclyn M; Ukai, Atsushi et al. (2012) Nonenzymatic dynamic kinetic resolution of secondary alcohols via enantioselective acylation: synthetic and mechanistic studies. J Am Chem Soc 134:15149-53
Zuhl, Andrea M; Mohr, Justin T; Bachovchin, Daniel A et al. (2012) Competitive activity-based protein profiling identifies aza-?-lactams as a versatile chemotype for serine hydrolase inhibition. J Am Chem Soc 134:5068-71
Fujiwara, Yuji; Sun, Jianwei; Fu, Gregory C (2011) Enantioselective Carbon-Sulfur Bond Formation: ? Additions of Aryl Thiols to Allenoates Catalyzed by a Chiral Phosphepine. Chem Sci 2:2196-2198

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