The Research Of Double Axially Chiral Br(?)nsted Acid Catalyzed Enantioselective Pictet-spengler Reaction

Alkaloids are an important class of natural products that are widely distributed innature and produced by a large variety of organisms. They have a wide spectrum ofbiological activity and for many years were used in folk medicine. The importance ofthese natural products in inspiring drug discovery programs is proven and, therefore,their continued synthesis is of significant interest. Pictet–Spengler reaction is a directway to synthesize chiral complex Alkaloids. In this thesis, we synthesized a series ofnew double axially chiral bisphosphorylimide Br nsted acid catalysts and appliedthem to three types of asymmetric Pictet–Spengler reaction. We got good results inthe work.First, we synthesis catalysts.(R)-BINOL phosphoryl chlorides were synthesizedvia a MOM protection, halogenation, coupling, and acylation sequence from(R)-BINOL. Further synthesis to obtain (R)-BINOL derived phosphoryl amide.(R)-BINOL phosphoryl chloride reacted with (R)-BINOL phosphoryl amide to get thedouble axially chiral bisphosphorylimide Br nsted acid catalysts. The catalysts werecharacterized by melting point, optical rotation,1H NMR,13C NMR,31P NMR, IR,HRMS.Second, the six double axially chiral bisphosphorylimide catalysts derived from (R)-BINOL,(R)-VAPOL and (R)-H8BINOL were applied to catalytic asymmetricPictet–Spengler reaction of indolyl aniline and pyruvate. The effect of several factors,such as the activity and dosages of catalysts, solvent, temperature of this reactionwere investigated. Under the optimal conditions17examples of asymmetricPictet–Spengler reaction were obtained in high enantioselectivities (up to98%ee)with high yields (up to97%). There are three characteristics of this P–S reactionshould be underlined:1) the catalytic reaction generate enantiomeric excess of DHIQproduct containing a quaternary stereogenic center;2) a very small amount ofcatalyst(2mol%) is used in the recation;3) a wide range of indolyl aniline bearingeither electron-withdrawing or electron-donating groups or aromatic group on theindole ring furnished the resulting DHIQ with high yields and excellentenatioselectivities in all cases. Futher more, experiments were performed on gramscales between2-(3-methyl-1H-indol-1-yl)aniline and phenyl pyruvate, the reactioncan still be carried out smoothly without loss of enantioselectivity and yield.; Whenmethylindolyl aniline and furaldehyde were employed as the substrates, DHIQs4pwhich discovered as a new HIV-1inhibitor in vitro were obtained with with highyield and good enantioselectivity.Third,3,5-(CF3)2-phenyl-substituted H8-BINOL catalyst was applied to catalyticasymmetric Pictet–Spengler reaction of2-(Ar-1H-pyrrol-1-yl)aniline and pyruvate. Agood ability of enantioselectivity control was shown in the reaction. The effect ofseveral factors, such as the dosages of catalysts, solvent, temperature of this reactionwere investigated. Under the optimal conditions,9kinds of2-(Ar-1H-pyrrol-1-yl)anilines were investigated and the reaction were obtained inhigh enantioselectivities (88–98%ee) with high yields (89–7%).3-Phenylpyrrolylsubstrates were tested, and the more crowded C-2position of the pyrrole ring attackedtheir intramolecular imine intermediates and produced3-PDHPQ containing acrowded quaternary chiral carbon center with a remarkable enantioselectivities (98%ee). The absolute configuration of the product was established by single-crystal X-ray structure analysis. The product could also be obtained through gram-scale reactionwithout any loss of chemo-and stereoselectivity.Fourth, a) asymmetric Pictet–Spengler reaction of2-(indolin-1-yl)anilines andpyruvates were tested. The effect of several factors, such as the active and dosages ofcatalysts, the kind of pyruvate, solvent, temperature of this reaction were investigated.Under the optimal conditions,6examples of asymmetric Pictet–Spengler reactionwere obtained in high enantioselectivities (77–97%ee) with high yields (87–95%). b）The asymmetric P–S reactions between1-phenylindolin-7-amines and pyruvates werealso examined and got good result.1-naphthyl-substituted H8-BINOL catalyst wasapplied in the reaction. Under the optimal conditions,7examples of asymmetricPictet–Spengler reaction were obtained in high enantioselectivities (84–99%ee) withhigh yields (72–97%). There are some characteristics of the two kinds of P–S reaction.In the two reaction, the phenyl ring attacked their intramolecular imine intermediatesand produced benzodiazepines containing a quaternary chiral carbon center withremarkable enantioselectivities.Overall, three kind of double axially chiral bisphosphorylimide catalysts wereapplied to catalytic three types of asymmetric Pictet–Spengler reaction.42catalyticasymmetric P–S reaction instances were investigated. Via the researching work of thisdissertation, it can provide experimental data for the application of the double axiallychiral bisphosphorylimide catalysts. And we got different complex alkaloid skelectonswith high enantioselectivities through asymmetric P–S reaction. We hope that it canprovide some new ideas for asymmetric organic synthesis.