Cinchonium Betaines as New and Powerful Catalysts for Asymmetric Proton Transfer Catalysis: The Development of a Practical Enantioselective Isomerization of Trifluoromethyl Imines (Brandeis Ref. 1299 and 2017-050)

Chiral organic catalysts containing both hydrogen bond donor and acceptor could facilitate biomimetic 1,3-proton transfer catalysis to promote highly enantioselective olefin and imine isomerizations. These enantioselective isomerizations provide new access to valuable chiral building blocks such as α, β-unsaturated butenolides, α-amino acids, α, β-unsaturated cyclohexenones and trifluoromethylated amines. Among these studies, the realization of the first highly enantioselective isomerization of trifluoromethyl imines with DHQ-a stands as a conceptually significant progress as DHQ-a achieved efficient catalytic chiral recognition of nonenolate carbanions for asymmetric reactions. The invention discloses a new class of cinchonium betaine catalysts bearing both a base moiety and an aromatic moiety. These cinchonium betains were found to promote proton transfer catalysis with 1000-5000 turnovers per 24 hours, thereby enabling us to realize highly efficient enantioselective isomerization of trifluoromethyl imines to provide a practical access to optically active trifluoromethylated amines. Notably the catalyst QD-9c promoted an unprecedented isomerization of α, β-unsaturated imine in excellent enantioselectivity and yield. It is noteworthy that the reaction proceeded without the formation of the 1,3-proton transfer product. The scope of the reaction was readily extended to aryl trifluoromethyl imines. The invention’s studies of cinchonium betaines have led to the discovery of a new class of catalysts for enantioselective proton transfer catalysis. These new catalysts afforded a remarkably high catalyst turnover rate for the promotion of asymmetric isomerizations of trifluoromethyl imines. Consequently, abroad range of alkyl, alkenyl, and aryl trifluoromethyl imines could be converted in a highly enantioselective manner into either enantiomer of the corresponding optically active trifluoromethylated amines with typically 0.02 to 0.10 mol % of the cinchonium betaines. With a mechanistically distinct mode of catalysis, this reaction should provide a complementary approach to existing methods for the asymmetric synthesis of trifluoromethylated amines. Rong Zhou zhourong@brandeis.edu 7817368753

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