Nitrogen-substituted carbon stereocenters are widely presented in numerous biologically active small molecules and pharmaceuticals. Thus, chiral amines are fundamentally important building blocks for the synthesis of biologically active compounds. Building on a wealth of promising leads and insights revealed in recent preliminary studies, the proposed studies focus on the design and discovery of novel chiral phase transfer catalysts of new activity and selectivity for the development of a series of asymmetric imine umpolung reactions to directly transform prochiral simple and trifluoromethylated imines into the corresponding optically active chiral amines. In contrast to conventional nucleophilic addition reactions where imines serve as an electrophile, these new reactions utilize chiral organocatalysts to activate trifluoromethyl imines and simple imines as nucleophiles to form C-C bonds with a broad range of electrophile to enantioselectively generate the corresponding chiral amines. With a catalyst-induced reversal of the polarity in the reactivity of imines, these reactions are termed as catalytic asymmetric imine umpolung reactions.
The specific aims are: 1)The discovery and development of novel chiral organocatalysts for asymmetric imine umpolung reactions.; 2) The development of C-C bond forming catalytic asymmetric imine umpolung reactions for the asymmetric synthesis of chiral trifluoromethylated amines; 3) The development of C-C bond forming catalytic asymmetric imine umpolung reactions for the asymmetric synthesis of unfunctionalized chiral amines. These catalytic asymmetric imine umpolung reactions allow novel bond disconnections for retrosynthetic design and consequently provide a fundamentally new approach toward chiral amino compounds.

Public Health Relevance

Small molecules constitute one of the most important forms of therapeutic agents and play an increasingly important role in both basic and translational biomedical research. The goal of this work is to develop new synthetic methods that will greatly enhance our ability to rapidly create molecules of diverse structures with defined configuration, thereby providing biomedical researchers with powerful tools for the discovery of small molecules possessing biologically interesting and therapeutically desirable properties. These synthetic methods will also provide the foundation for the development of cost-effective processes for the sustainable manufacturing of therapeutic agents with significant implications to public health.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM061591-15
Application #
8976260
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Lees, Robert G
Project Start
2001-04-01
Project End
2018-11-30
Budget Start
2015-12-01
Budget End
2016-11-30
Support Year
15
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Brandeis University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
616845814
City
Waltham
State
MA
Country
United States
Zip Code
Zhou, Xiao; Wu, Yongwei; Deng, Li (2016) Cinchonium Betaines as Efficient Catalysts for Asymmetric Proton Transfer Catalysis: The Development of a Practical Enantioselective Isomerization of Trifluoromethyl Imines. J Am Chem Soc 138:12297-302
Zheng, Yang; Deng, Li (2015) Catalytic Asymmetric Direct Aldol Reaction of α-Alkyl Azlactones and Aliphatic Aldehydes. Chem Sci 6:6510-6514
Wu, Yongwei; Hu, Lin; Li, Zhe et al. (2015) Catalytic asymmetric umpolung reactions of imines. Nature 523:445-50
Hu, Lin; Lu, Xiaojie; Deng, Li (2015) Catalytic Enantioselective Peroxidation of α,β-Unsaturated Aldehydes for the Asymmetric Synthesis of Biologically Important Chiral Endoperoxides. J Am Chem Soc 137:8400-3
Lu, Xiaojie; Deng, Li (2014) Catalytic asymmetric peroxidation of α,β-unsaturated nitroalkenes by a bifunctional organic catalyst. Org Lett 16:2358-61
Wu, Yongwei; Deng, Li (2012) Asymmetric synthesis of trifluoromethylated amines via catalytic enantioselective isomerization of imines. J Am Chem Soc 134:14334-7
Lee, Jung Hwa; Deng, Li (2012) Asymmetric approach toward chiral cyclohex-2-enones from anisoles via an enantioselective isomerization by a new chiral diamine catalyst. J Am Chem Soc 134:18209-12
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Wu, Yongwei; Singh, Ravi P; Deng, Li (2011) Asymmetric olefin isomerization of butenolides via proton transfer catalysis by an organic molecule. J Am Chem Soc 133:12458-61
Campbell, Nathaniel R; Sun, Bingfeng; Singh, Ravi P et al. (2011) Cinchona alkaloid catalyzed enantioselective amination of α,β-unsaturated ketones: an asymmetric approach to Δ(2)-pyrazolines. Adv Synth Catal 353:3123-3128

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