Brandeis University

Li Deng

Jianfeng Hang

Liang Tang

Yongwei Wu

Hongming Li

Yonggang Chen

Shikai Tian

Xiao Zhou

Shi-Kai Tian

Yi Wang

Xiaofeng Liu

Fanghui Wu

Provided herein are cinchonium betaine catalysts and methods of promoting asymmetric butenolide isomerization reactions using the same.

Catalysts for olefin isomerization

Provided herein are cinchonium betaine catalysts and methods of promoting asymmetric imine isomerization reactions using the same.

Cinchonium betaine catalysts and methods of using same

The present invention includes certain conchinine-derived phase-transfer catalysts of formula (I), compositions comprising the same, and methods of promoting asymmetric addition reactions using the same. 

Cinchonine-derived catalysts and methods of using same

One aspect of the present invention relates to quinine-based and quinidine-based catalysts. Another aspect of the present invention relates to a method of preparing a chiral, non-racemic compound from a prochiral electron-deficient alkene, comprising the step of: reacting a prochiral electron-deficient alkene with a nucleophile in the presence of a catalyst; thereby producing a chiral, non-racemic compound; wherein said catalyst is a derivatized quinine or quinidine.

Conjugate addition reactions using bifunctional cinchona-alkaloid-based catalysts

In certain embodiments, the present invention relates to methods for asymmetric Friedel-Crafts alkylation catalyzed by bifunctional cinchona alkaloids. In certain embodiments, the catalyst is a 6'-OH cinchona alkaloid. In certain embodiments, the electrophile is an &#x3b1;-ketoester or aldehyde. In certain embodiments, the nucleophile is an aromatic heterocycle. In certain embodiments, the nucleophile is an aromatic N-containing heterocycle. In certain embodiments, the nucleophile is an indole. In certain embodiments, the methods of the invention are relatively insensitive to concentration, temperature, air and moisture.

Asymmetric friedel-crafts alkylations catalyzed by bifunctional cinchona alkaloids

One aspect of the present invention relates to asymmetric catalytic nitroaldol (Henry) reactions with ketones as the electrophilic component. In one embodiment, the present invention relates to asymmetric nitroaldol reactions with &#x3b1;-keto esters catalyzed by a new C6'-OH cinchona alkaloid catalyst. In certain embodiments, this reaction is operationally simple and affords high enantioselectivity as well as good to excellent yield for an exceptionally broad range of &#x3b1;-keto esters.

Asymmetric aldol additions using bifunctional cinchona-alkaloid-based catalysts

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The instability of carbamate-protected alkyl imines has greatly hampered the development of catalytic asymmetric Mannich reactions suitable for the synthesis of optically active carbamate-protected chiral alkyl amines. A highly enantioselective Mannich reaction with in situ generation of carbamate-protected imines from stable &#x3b1;-amido sulfones catalyzed by an organic catalyst has been developed. This reaction provides a concise and highly enantioselective route converting aromatic and aliphatic aldehydes into optically active aryl and alkyl &#x3b2;-amino acids.

Cinchona alkaloid-catalyzed asymmetric mannich reactions

One aspect of the present invention relates to a method for the kinetic resolution of racemic and diastereomeric mixtures of chiral compounds. The critical elements of the method are: a non-racemic chiral tertiary-amine-containing catalyst; a racemic or diastereomeric mixture of a chiral substrate, e.g., a cyclic carbonate or cyclic carbamate; and a nucleophile, e.g., an alcohol, amine or thiol. A preferred embodiment of the present invention relates to a method for achieving the kinetic resolution of racemic and diastereomeric mixtures of derivatives of &#x3b1;- and &#x3b2;-amino, hydroxy, and thio carboxylic acids. In certain embodiments, the methods of the present invention achieve dynamic kinetic resolution of a racemic or diastereomeric mixture of a substrate, i.e., a kinetic resolution wherein the yield of the resolved enantiomer or diastereomer, respectively, exceeds the amount present in the original mixture due to the in situ equilibration of the enantiomers or diastereomers under the reaction conditions prior to the resolution step.

Kinetic resolutions of chiral 2-  and 3-substituted carboxylic acids

One aspect of the present invention relates to quinine-based and quinidine-based catalysts. In certain embodiments, the quinine-based and quinidine-based catalysts contain a hydroxy group at the 6' position. In certain embodiments, the quinine-based and quinidine-based catalysts contain an O-aryl group or an O-aroyl group at the C9 position. In certain embodiments, the quinine-based and quinidine-based catalysts contain an optionally substituted O-diazene group or an optionally substituted O-benzoyl group at the C9 position. In certain embodiments, the quinine-based and quinidine-based catalysts contain a thiourea at the C9 position. In certain embodiments, the quinine-based and quinidine-based catalysts contain an NH(&#x2550;S)NH-aryl group at the C9 position. Another aspect of the present invention relates to a method of preparing a chiral, non-racemic compound from a prochiral electron-deficient alkene or prochiral imine, comprising the step of: reacting a prochiral alkene or imine with a nucleophile in the presence of a catalyst; thereby producing a chiral, non-racemic compound; wherein said catalyst is a derivatized quinine or quinidine. In certain embodiments, the nucleophile is a malonate or &#x3b2;-ketoester. In certain embodiments the nucleophile is an alkyl or aryl or aralkyl 2-cyano-2-alkylacetate. In certain embodiments the nucleophile is an alkyl or aryl or aralkyl 2-cyano-2-alkylacetate. Another aspect of the present invention relates to a method of kinetic resolution, comprising the step of: reacting a racemic aldehyde or racemic ketone with a nucleophile in the presence of a derivatized quinine or quinidine, thereby producing a non-racemic, chiral compound. In certain embodiments, the kinetic resolution is dynamic.

Asymmetric carbon-carbon-bond-forming reactions catalyzed by bifunctional cinchona alkaloids

One aspect of the present invention relates to cinchona-alkaloid-based catalysts. A second aspect of the invention relates to a method of preparing a derivatized cinchona alkaloid catalyst by reacting a cinchona-alkaloid with base and a compound that has a suitable leaving group. Another aspect of the present invention relates to a method of preparing a chiral, non-racemic compound from a prochiral cyclic anhydride or a meso cyclic anhydride, comprising the step of: reacting a prochiral cyclic anhydride or a meso cyclic anhydride with a nucleophile in the presence of a catalyst; wherein said prochiral cyclic anhydride or meso cyclic anhydride comprises an internal plane of symmetry or point of symmetry or both; thereby producing a chiral, non-racemic compound; wherein said catalyst is a derivatized cinchona-alkaloid. Yet another aspect of the present invention relates to a method of kinetic resolution, comprising the step of: reacting a racemic cyclic anhydride with an alcohol in the presence of a derivatized cinchona-alkaloid catalyst.

Cinchona-alkaloid-based catalysts, and asymmetric alcoholysis of cyclic anhydrides using them

One aspect of the present invention relates to quinine-based and quinidine-based catalysts. Another aspect of the invention relates to a method of preparing a derivatized quinine-based or quinidine-based catalyst comprising 1) reacting quinine or quinidine with base and a compound that has a suitable leaving group, and 2) converting the ring methoxy group to a hydroxy group. Another aspect of the present invention relates to a method of preparing a chiral, non-racemic compound from a prochiral electron-deficient alkene or azo compound or prochiral aldehyde or prochiral ketone, comprising the step of: reacting a prochiral electron-deficient alkene or azo compound or prochiral aldehyde or prochiral ketone with a nucleophile in the presence of a catalyst; thereby producing a chiral, non-racemic compound; wherein said catalyst is a derivatized quinine or quinidine. Another aspect of the present invention relates to a method of kinetic resolution, comprising the step of: reacting racemic chiral alkene with a nucleophile in the presence of a derivatized quinine or quinidine.

Asymmetric Michael and Aldol additions using bifunctional cinchona-alkaloid-based catalysts

One aspect of the present invention relates to a method for the catalytic asymmetric cyanosilylation of ketones, aldehydes, thioketones, thioaldehydes, imines and hydrazones. The critical elements of the method are: a non-racemic chiral tertiary-amine-containing catalyst; a substrate selected from the group consisting of ketones, aldehydes, thioketones, thioaldehydes, imines and hydrazones; and a silyl cyanide, e.g., trimethylsilyl cyanide. In preferred embodiments, the substrate is a ketone or aldehyde. A preferred embodiment of the present invention relates to practicing the method in a halocarbon solvent, e.g., chloroform. Another preferred embodiment of the present invention relates to practicing the method in an ester solvent, e.g., ethyl acetate. In certain embodiments, the methods of the present invention produce a silyl cyanohydrin with an enantiomeric excess greater than about 80%. In certain embodiments, the methods of the present invention produce a silyl cyanohydrin with an enantiomeric excess greater than about 90%.

Catalytic asymmetric cyanosilylation of ketones, aldehydes, thioketones, thioaldehydes, imines and hydrazones

The present invention relates to methods for the synthesis of chiral non-racemic products, e.g., enantiomerically-enriched hemiesters, from prochiral starting materials, e.g., meso anhydrides. The present invention also relates to catalysts for the aforementioned methods, and methods for synthesizing these catalysts.

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Waltham, MA, United States of America

Li Deng