Theoretical Study On The Lewis Base-catalyzed [n+4](n=2,3) Cyclizations Of Carbonyl Compounds And Alkenyl Ketone/hydrazone

Organometallic catalysis,enzyme catalysis,and organocatalysis are three powerful ways to achieve asymmetric reactions.Among them,organocatalysis reactions have attracted more and more attention because of their economic,practical and environmentally friendly advantages.In the organocatalysis reaction,the catalysts include Lewis acid,Lewis base,Br?nstde acid,and Br?nstde base.The reactions involved in this paper are the Lewis base promoted reactions,i.e.,the isothiourea-catalyzed asymmetric[2+4]annulation of phenylacetic acid with alkylidene pyrazolone,N-heterocyclic carbene-catalyzed[3+4]annulation reactions of 2-bromoenals with N-Ts hydrazones,and DABCO-catalyzed ring expansion of cyclopropyl ketone.The first chapter mainly introduces the theoretical calculation method and several commonly used Lewis bases.The second chapter is the theoretical study on the[2+4]cyclization of phenylacetic acid and alkylidene pyrazolone catalyzed by isothiourea.The computed results revealed that the reaction contains several steps,including complexation of isothiourea with substrate,dissociation of the t-BuCO₂^-group,?-C–H deprotonation of the acyl ammonium intermediate,stepwise[2+4]cycloaddition processes,and the dissociation of isothiourea.The C–C bond formation involved in the[2+4]cycloaddition process was identified as the stereoselectivity-determining step.The pathway associated with the RR configurational isomer was calculated to be most energetically favorable,which is consistent with the experimental observations.The origin of stereoselectivity was further studied through analyses of distortion/interaction and non-covalent interaction?NCI?,and the role of isothiourea was discovered to enhance the nucleophilicity of phenylacetic acid by analyzing the global reaction index?GRI?and Parr functions.By analyzing the activity of different isothiourea catalysts,it was found that a stronger nucleophilicity of the center N atom of the isothiourea catalysts would result in a lower energy barrier of the reaction.The third chapter is the theoretical study of the[3+4]cyclization of2-bromoenal and N-Ts hydrazone catalyzed by NHC.Our calculated results indicate that the C–C bond formation involved in the stepwise[3+4]process is the rate-and stereoselectivity-determining step,and the SR-isomer is the predominant product,which is consistent with the experiment.Non-covalent interaction analysis discovers that the strong C–H···O and C–H···?interactions should be the key for controlling the stereoselectivity in the reaction.The local reactivity index analysis shows that the reaction prefers to proceed via the[3+4]annulation reaction rather than the[3+2]annulation reaction.It is noteworthy that further analysis indicates that the main role of the NHC in this kind of reaction is to activate the C–Br bond,which is different from the umpolung role in the NHC-catalyzed annulation reactions of enals.In the fourth chapter,the reaction mechanism and chemical selectivity of1,4-diazabicyclo[2.2.2]octane?DABCO?catalyzedring-openingreactionof cyclopropyl ketone were studied in theory.Two reaction steps are contained in the favorable path:?1?nucleophilic addition of DABCO to cyclopropyl ketone coupled with three-membered ring opening;?2?five-membered ring closure process.Moreover,global reactivity index and non-covalent interaction analyses were performed to disclose the role of catalyst and explain the chemoselectivity.By analysing of the efficiency of different catalysts?i.e.,tricyclohexylphosphine?PCy₃?,triphenylphosphine?PPh₃?,tributylphosphine?PBu₃?,4-dimethylaminopyridine?DMAP?,and 1,8-diazabicyclo[5.4.0]undec-7-ene?DBU??,it was found that the stronger nucleophilicity of amine catalyst would be corresponding to the lower energy barrier of the ring expansion reaction.The fifth chapter is a summary of the above work,and the following research contents are prospected.