Synthesis Of Bifunctional Chiral Organocatalysts And Their Applications In Asymmetric Imine Addition Reactions

Chiral nitrogen-containing compounds have been found in a variety of natural products and biologically active compounds.Among these compounds,nitrogen-containing structural fragments play important role in their biological activities.Asymmetric additions of imines with different nucleophiles are the most efficient and convenient way to synthesize various chiral nitrogen-containing compounds.Therefore,it is of great significance to develop new catalysts for applications and to expand new asymmetric addition reactions of imines.In this paper,bifunctional asymmetric phase-transfer catalysts bearing multiple hydrogen-bonding donors derived from cinchona alkaloids and?-amino acids were synthesized.These catalysts and other known bifunctional catalysts which are reported in the literatures were successfully applied to asymmetric addition of imines with carbon nucleophiles and nitrogen nucleophiles.The specific work contain the following five parts:1.The new quaternary ammonium type of bifunctional asymmetric phase-transfer catalysts bearing multiple hydrogen-bonding donors derived from?-amino acids were readily prepared and found to be highly efficient in asymmetric nitro-Mannich reactions of amidosulfones.Among them,the catalysts bearing L-phenylglycine or L-phenylalanin as multiple hydrogen-bonding donors all have high catalytic activities.After screening and optimization,the optimal reaction conditions were as follows:5 mol%of catalyst and 5 equiv KOH used as base in CHCl₃ at-20°C.Very broad substrates were observed,and all the adducts were achieved in high enantio-/diasteroselectivities?90->99.9%ee,90:10 to 92:8 dr?.In particular,compared with previous reports,the enantioselectivity of aliphatic amidosulfones have been improved to a high level?91-93%ee?.Control experiment for mechanistic study indicated that both the hydroxy on the phenylglycinol moiety and the quaternary ammonium center were crucial to achieve excellent catalytic activity and stereoselectivity in this asymmetric nitro-Mannich reaction.Optically pure vicinal diamines were synthesized by derivatization.2.A series of bifunctional asymmetric phase-transfer catalysts bearing multiple hydrogen-bonding donors derived from cinchona alkaloids were synthesized,and successfully applied to asymmetric nitro-Mannich of isatin-derived N-Boc ketimines.Among them,the catalyst bearing 3,5-di-tert-butylbenzyl group exhibited excellent catalytic activity.When using LiOH·H₂O as base,significantly increasing enantioselectivity of the adduct could be found,and 10?L water was critical for the reactivity.After screening and optimization,the optimal reaction conditions were as follows:10 mol%of catalyst and 5 equiv LiOH·H₂O used as base in CHCl₃?10?L H₂O?at-40°C.The products 3-substituted 3-amino-oxindoles were constructed in excellent yields?96–99%?and good enantioselectivities?up to 95%ee?.Control experiment for mechanistic study indicated that both the hydroxy on the phenylglycinol moiety and the quaternary ammonium center were crucial to achieve excellent catalytic activity and stereoselectivity in this asymmetric nitro-Mannich reaction.3.Highly diastereo-and enantioselective nitro-Mannich reaction of isatin-derived ketimines with?-aryl nitromethane catalyzed by Cinchona alkaloid-derived phase-transfer catalysts bearing multiple hydrogen-bonding donors has been developed.It was the first metal-free catalytic system used in this reaction.After screening and optimization,the optimal reaction conditions were as follows:1.5equiv aryl nitromethanes in the presence of 10%catalyst and 5 equiv LiOH·H₂O at-40°C in CHCl₃.A series of 3-substituted 3-amino-oxindoles were constructed by this protocol in excellent yields?96-99%?with high enantioselectivities?up to 95%ee?and diastereoselectivities?up to 95:5 dr?.Control experiment for mechanistic study indicated that both the hydroxy on the phenylglycinol moiety and the quaternary ammonium center were crucial to achieve excellent catalytic activity and stereoselectivity in this asymmetric nitro-Mannich reaction.4.Highly diastereo-and enantioselective Mannich reaction of isatin-derived ketimines with oxo-indanecarboxylates catalyzed by chiral thiourea derived from hydroquinidine has been developed.The corresponding adducts containing attached bicyclic linked by a C-C bond are prominent structural features of several classes of natural products,and the stereoselective synthesis of attached rings in which both rings are chiral is highly challenging in organic synthesis.Minor modifications on the catalyst greatly improve the diastereoselectivities of the reaction and still keep good enantioselectivities and yields.Catalyst bearing hydroquinine skeleton gave the best result due to the carbon-carbon bond at C1 position of hydroquinine is easy to rotate which can effectively improve the stereo matching of catalyst and substrate.A series of 3-substituted 3-amino-oxindoles which containing assembled bicyclic linked by a C-C bond were constructed by this protocol in excellent yields?92-99%?with high enantioselectivities?85-99%ee?and diastereoselectivities?up to>99:1 dr?.The scalability and practicability of the reaction were proved by a gram-level reaction,and a possible transition state model to rationalize the stereochemical results of the reaction were proposed on the basis of the stereochemistry of the obtained products.5.Highly enantioselective addition of aryl amines to isatin-derived ketimines catalyzed by chiral urea derived from quinidine has been developed.The asymmetric additions of nitrogen nucleophiles to imines constructed chiral N,N'-acetals which contains two different nitrogen groups on one carbon were less reported due to their potentially sensitive.The potential sensitivity of this structural unit is always mitigated by its incorporation in a ring,thus the synthesis of acyclic N,N'-acetals are even more challenging.By using methyl tert-butyl ether as solvent,the product was obtained in high enantioselectivity.The urea and thiourea derived from quinine and hydrogenated quinine also have excellent catalytic activities.A series of new acyclic N,N'-acetals were constructed by this protocol in high to excellent yields?78-99%?with high to excellent enantioselectivities?76-96%ee?.The stability,expandability and practicability of the reaction were proved by a gram-level experiment.A possible reaction transition state is proposed on the basis of the stereochemistry of the obtained products.