The development of efficient new chemical processes has an impact on a wide array of disciplines that require the synthesis of organic compounds (e.g., biological chemistry, pharmaceutical chemistry, and biology). Catalysts can provide access to unique modes of reactivity, and they can furnish less expensive and more environmentally friendly methods for creating new molecules. During the next grant period, this program will explore the development of enantioselective processes catalyzed by planar-chiral derivatives of 4-(dimethylamino)pyridine (DMAP) and by chiral phosphines. A diverse array of reactions (e.g., kinetic resolutions of alcohols and amines, annulations, couplings of ketenes with acylating agents, and 3 additions) will be examined. Achieving the objectives of this program will facilitate access to important families of compounds in highly enantioenriched form. Mechanistic studies will play a significant role in this project. This research area offers an exciting opportunity to have a substantial impact on synthetic chemistry, as well as to enrich our understanding of chemical reactivity.

Public Health Relevance

In order to probe many biological questions and to develop new therapeutic compounds, there is a need to be able to synthesize organic molecules efficiently and to control the chirality (""""""""handedness"""""""") of the target compounds. This proposal is directed at addressing both of these challenges.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM057034-17
Application #
8403054
Study Section
Special Emphasis Panel (ZRG1-BCMB-B (03))
Program Officer
Lees, Robert G
Project Start
1998-01-01
Project End
2013-12-31
Budget Start
2013-01-01
Budget End
2013-12-31
Support Year
17
Fiscal Year
2013
Total Cost
$366,111
Indirect Cost
$134,135
Name
California Institute of Technology
Department
Chemistry
Type
Schools of Engineering
DUNS #
009584210
City
Pasadena
State
CA
Country
United States
Zip Code
91125
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
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
Kalek, Marcin; Fu, Gregory C (2015) Phosphine-Catalyzed Doubly Stereoconvergent γ-Additions of Racemic Heterocycles to Racemic Allenoates: The Catalytic Enantioselective Synthesis of Protected α,α-Disubstituted α-Amino Acid Derivatives. J Am Chem Soc 137:9438-42
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 α-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 γ-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-β-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: γ Additions of Aryl Thiols to Allenoates Catalyzed by a Chiral Phosphepine. Chem Sci 2:2196-2198
Bachovchin, Daniel A; Mohr, Justin T; Speers, Anna E et al. (2011) Academic cross-fertilization by public screening yields a remarkable class of protein phosphatase methylesterase-1 inhibitors. Proc Natl Acad Sci U S A 108:6811-6

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