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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Synthetic and Biological Chemistry B Study Section (SBCB)
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Lees, Robert G
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Brandeis University
Schools of Arts and Sciences
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Li, Zhe; Hu, Bin; Wu, Yongwei et al. (2018) Control of chemoselectivity in asymmetric tandem reactions: Direct synthesis of chiral amines bearing nonadjacent stereocenters. Proc Natl Acad Sci U S A 115:1730-1735
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
Hu, Lin; Wu, Yongwei; Li, Zhe et al. (2016) Catalytic Asymmetric Synthesis of Chiral ?-Amino Ketones via Umpolung Reactions of Imines. J Am Chem Soc 138:15817-15820
Hu, Lin; Lu, Xiaojie; Deng, Li (2015) Catalytic Enantioselective Peroxidation of ?,?-Unsaturated Aldehydes for the Asymmetric Synthesis of Biologically Important Chiral Endoperoxides. J Am Chem Soc 137:8400-3
Zheng, Yang; Deng, Li (2015) Catalytic Asymmetric Direct Aldol Reaction of ?-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
Lu, Xiaojie; Deng, Li (2014) Catalytic asymmetric peroxidation of ?,?-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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