The Synthesis Of Chiral Imidodiphosphoric Acids And Their Catalysis Research In Enantioselective Multicomponent Reactions And Kinetic Resolutions

In the field of asymmetric catalysis,organocatalysts have been widely developed and applied in recent years.Among them,the BINOL derived biaxially chiral imidodiphosphoric acid catalysts have been successfully used in many asymmetric reactions since reported in 2012.In this dissertation,based on the BINOL framework,a series of H₈-BINOL derived imidodiphosphoric acids were synthesized and the types of imidodiphosphoric acids were further enriched.Meanwhile,this kind of imidodiphosphoric acids were applied in enantioselective Biginelli reactions,the multicomponent reactions of enantioselective synthesis of 1,4-dihydropyridines,the asymmetric nucleophilic addition to 2H-azirines and kinetic resolution of racemic 2H-azirines.The details are as follows:?1?Firstly we introduced the research progresses of biaxially imidodiphosphoric acids.Next,the asymmetric Biginelli reactions and the multicomponent reactions of enantioselective synthesis of 1,4-dihydropyridines were introduced respectively.At last,we introduced the research progresses of asymmetric synthesis of 2H-azirines and their nucleophilic addition reactions.?2?We introduced our work on the design and synthesis of H₈-BINOL derived imidodiphosphoric acid catalysts.?R?-BINOL was used as the starting material and hydrogenated to produce H₈-BINOL.Then through bromination,coupling,acylation and amidation,finally H₈-BINOL derived phosphoryl chloride reacted with phosphoryl amide under basic conditions and generated imidodiphosphoric acids.We have synthesized five H₈-BINOL derived imidodiphosphoric acid catalysts with different 3,3' position substituents respectively and the total yields were up to 43%.Meanwhile,we used DDQ to oxidate H₈-BINOL derived imidodiphosphoric acids and obtained the corresponding BINOL derived imidodiphosphoric acids.The total yields were up to 30%.Compared with the previous synthetic route,the total yields increased nearly three times.?3?The study of the imidodiphosphoric acids catalyzed enantioselective Biginelli reaction was introduced.BINOL and H₈-BINOL derived imidodiphosphoric acids were used in the multicomponent Biginelli reaction of aromatic aldehydes,thiourea and ethyl acetoacetate.Both of these two kinds of catalysts exhibited high enantioselectivity.After the comprehensive consideration of reaction rate,yield,enantioselectivity and other factors,3,3'-2-naphthyl substituted BINOL derived imidodiphosphoric acid was selected as the optimal catalyst.Under the optimal conditions,we have investigated 24 examples and afforded 3,4-dihydropyrimidin-2-?1H?-thiones with up to 97% yields and up to 96% ee.It should be mentioned that the reaction time is only 12 hours,much shorter than other reported methods which needed reaction times from 2 to 7 days.We also put forward a plausible catalytic cycle mechanism of the reaction.?4?We introduced our study of imidodiphosphoric acids catalyzed multicomponent reactions of ?,?-unsaturated ?-ketoesters,aromatic amines and acetylacetone: the enantioselective synthesis of 1,4-dihydropyridines.The organocatalyzed synthesis of 1,4-dihydropyridines by using unsaturated ketones was realized for the first time.In the reaction,3,3'-phenyl substituted H₈-BINOL derived imidodiphosphoric acid exhibited the highest catalytic activity and stereocontrol ability.Under the optimal conditions,27 examples were examined and provided chiral 1,4-dihydropyridines with up to 61% yields and up to 96% ee.A plausible mechanism of the reaction was proposed and further proved by the synthesis of the intermediate.We also analyzed the structures and causes of the impurities.The application of products 1,4-dihydropyridines were further extended.Chiral 1,4-dihydropyridines could transform into chiral multisubstituted piperidines via hydrogenation and the configuration was not affected by the reaction.The absolute configurations of multisubstituted piperidine and corresponding 1,4-dihydropyridine were established by X-ray crystallography.?5?We introduced the imidodiphosphoric acids catalyzed asymmetric nucleophilic addition of pyrazoles to 2H-azirines and kinetic resolution of racemic 2H-azirines.It is the first time to realize the organocatalyzed asymmetric addition reaction and kinetic resolution of 2H-azirines.H₈-BINOL derived chiral imidodiphosphoric acid with 1-naphthyl and 9-anthracenyl substituents exhibited extremely high catalytic activity and selectivity in the reaction.We have investigated 24 examples of nucleophilic addition reactions and obtained multisubstituted chiral aziridines with up to 98% yields and up to 99.9% ee.The absolute configuration of the product chiral aziridine was determined by X-ray crystallography.Meanwhile,by adjusting the feed ratio,2H-azirines could be recovered with up to 49% yields and up to 99% ee.We also extended the application of chiral 2H-azirines.The nucleophilic addition of resolution product chiral 2H-azirine with pyrazole could afford the enantiomeric aziridine.