Studies On New Asymmetric Reaction Of Ketonitrones

Asymmetric catalytic reaction involving nitrone is one of the most important methods to synthesize chiral 1,2-oxazo heterocycles and chiral hydroxylamine compounds,which has been extensively studied over the past decades.However,the exploration of ketonitrones in asymmetric catalytic reactions remains undeveloped.In this context,this thesis focuses on the development of asymmetric catalytic reactions using simple ketonitrones as the substrate,and realized the asymmetric cycloaddition and nucleophilic addition reactions involving simple ketonitrones for the first time,which includes following research work:1)A highly diastereoselective[3+3]cycloaddition spirocyclopropyl oxindoles with nitrone was established,by installing an electron-withdrawing N-protecting group on the nitrogen atom of spirocyclopropyl oxindoles to activate low-activity donor-acceptor cyclopropanes.The reactions of spirocyclopropyl oxindoles with p-toluidine,2,5-dihydroxy-1,4-dithiane or p-chlorobenzaldehyde could also be realized by using the same activation strategy.On this basis,a highly diastereoselective one-pot sequential[3+3]dipolar cycloaddition reaction of aldehyde/ketone,hydroxylamine and spirocyclopropyl oxindole was achieved,allowing facile construction of spirocyclic oxindole-tetrahydro-1,2-oxazines in sufficient structural diversity.Bioactive studies indicated that the thus obtained spirocyclic oxindoles were promising therapeutic agents for prostate cancer.By employing Box/Ni?OTf?₂ complex as catalyst,a highly enantioselective[3+3]cycloaddition and kinetic resolution of N-diethoxyphosphoryl spirocyclopropyl oxindoles and nitrone was developed,enabled the facile synthesis of optically active oxindole-based spirocyclic tetrahydro-1,2-oxazines and spirocyclopropyl oxindoles.It was worth mentioning that this represented the first asymmetry reaction involving spirocyclopropyl oxindoles.On this basis,the asymmetric cycloaddition of simple ketonitrones and spirocyclopropyl oxindoles was also realized,and a series of spirocyclic tetrahydro-1,2-oxazines bearing consecutive four-substituted carbon chiral centers could be efficiently synthesized with high stereoselectivity.This was the first asymmetric cycloaddition reaction involving simple ketonitrones.Furthermore,the asymmetry version of one-pot sequential cycloaddition of aldehyde,hydroxylamine and spirocyclopropyl oxindole could also be developed by a slightly modificated reaction condition.2)By employing Me₂?CH₂Cl?SiCN as cyanide reagent and Box/Cu?OTf?₂ complex as catalyst,a highly enantioselective Strecker reaction of ketonitrones was developed to synthesize the optically active N-hydroxyl-?-cyanamide of wide application.At the same time,functional group conversions of the products were also explored for the synthesis of optically active hydroxylamine compounds with a chloromethyl ketone or aminomethyl moiety.NMR study revealed the interaction existed between ketonitrones and Me₂?CH₂Cl?SiCN,we thus believed that ketonitrones could activate Me₂?CH₂Cl?SiCN,and the two reagents probably form larger sterically hindered cyanide reagent,which might be conducive to the enantioselectivity control of the reaction;This was also confirmed by control experiments,because the larger sterically hindered cyanide reagent Me₂?CH₂Cl?SiCN obtained better enantioselectivity than TMSCN in the aforementioned reaction.Meanwhile,the E/Z ratio of ketonitrones has a great influence on the enantioselectivity of the reaction,the high enantioselectivity could only be obtained when ketonitrones with high E/Z ratio were used.