Theoretical Study Of Lewis Base-Catalyzed Cyclization Reactions Of Unsaturated Carbonyl/Alkynyl Compounds For Synthesizing N/O-Heterocyclic Products

Organocatalysis has been developed quickly in the past two decades.During this period,many new and complex cascade reactions have been designed by employing a variety of organocatalysts.Because these kinds of organocatalytic reactions have the advantages of mild reaction conditions and high stereoselectivity,they have great potential applications in the field of asymmetric synthesis.Among them,Lewis base catalysts,such as amines,nucleophilic carbenes,organic phosphines,etc.,occupy an indispensable position in the field of organocatalysis.Their electron-rich atoms,such as sp2 N atom,carbene C atom,sp3 N/P atom,etc.,are prone to nucleophilic attack on electron-deficient allenes,olefins,carbonyl compounds and other substrates,which initiates a variety of organic reactions with special chemoselectivity and high stereoselectivity.However,limited by experimental conditions,the detailed mechanism and the origin of stereo-and chemoselectivity are still unclear in the field of organocatalysis.At the same time,theoretical calculation has become one of the most powerful tools to study the detailed mechanism and selectivity of these catalytic reactions.In this thesis,density functional theory(DFT)was used to study the detailed mechanism as well as origin of chemoselectivity and stereoselectivity of several organocatalytic cyclization reactions for formation of heterocyclic compounds containing nitrogen/oxygen atom.The first chapter of this thesis includes the following aspects:(1)a short introduction to the development background of theoretical computational chemistry,the density functional theory(DFT)and transition state theory;(2)a list of the organocatalysts used in this thesis and some theoretical analysis methods for organocatalytic system;(3)a summary of general mechanism of several representative Lewis base catalyzed cyclization reactions;(4)a brief summary of the main content,research significance,and highlights of this thesis.The second chapter of this thesis is to explore the general mechanism of Lewis base-catalyzed cyclization reaction of Morita-Baylis-Hillman(MBH)carbonates at B3LYP-D3/6-311+G(d,p)/IEF-PCMacetonitrile//B3LYP/6-31G(d)/IEF-PCMacetonitrile level.The origin of chemoselectivity on Lewis bases-catalyzed[3+4]and[3+2]annulations of MBH carbonates were also theoretically explored in this chapter.The calculated results indicate that the energetically favorable pathway contains five steps:(1)nucleophilic addition on α-carbon of MBH carbonates by Lewis base,(2)dissociation of BocO-,(3)deprotonation of α-carbon,(4)Michael addition,and(5)ring-closure coupled with the dissociation of Lewis base.The ring-closure step determines the chemoselectivity for the possible[3+4]and[3+2]annulation reactions.In view of this,the frontier molecular orbital(FMO)theory were used to explain the chemoselectivity of such reactions.The results show that the different overlap modes of FMOs involved in ring-closure transition states control the chemoselectivity.In different[3+4]or[3+2]cyclization transition states,the head-to-head overlap mode of central atoms is suitable for the formation of σ bond to obtain the main product,whereas the significantly distorted shoulder-to-head overlap mode of central atoms is not suitable for the formation of the σ bond.Through global reaction index(GRI)analysis,it is found that the catalyst promotes the reaction by enhancing the nucleophilicity of the reactants in this type of reaction.In the third chapter,the construction mechanism of axial chirality naphthyl-C2indoles via the asymmetric annulation of ortho-alkynylaniline catalyzed by a chiral Br(?)nsted base(cinchonine-thiourea)has been systematically explored by density functional theory(DFT).Several key processes are included in the general mechanism of this kind of reaction through theoretical calculation results,i.e.hydrogen bond adsorption of the ortho-alkynylaniline by catalyst,proton transfer for forming orthoquinone methide(VQM)intermediate,intramolecular cyclization,release of catalyst to generate R-or S-axial-chiral aryl-C2-indole skeletons.The theoretical calculations show that the formation of VQM intermediates and ring-closure process are the stereoselectivity-determining steps,and the calculated results show that the pathway associated with the R-configurational isomer has the lower energy barrier,so the corresponding product should be the main one.Non-covalent interaction and atom-inmolecule analyses indicate that the N-H…O,C-H…π and π…π interactions play the important roles in controlling the stereoselectivity.By constructing and calculating different substituents,it is found that the energy barriers of the racemization reaction of R-configuration products are related to the volume of substituents on both sides of the chiral axis.These obtained insights provide valuable clues for the rational design of highly axially chiral structures in the field of organocatalysis.In the fourth chapter,the detailed mechanism and origin of stereoselectivity of the NHC-mediated cyclization reaction between benzoic acid and o-phthalaldehyde for asymmetric construction of phthalidyl ester,have been deeply investigated using density functional theory(DFT).The most energetically favorable pathway undergoes the following processes:(1)the nucleophilic attack on o-phthalaldehyde by catalyst,(2)the formation of Breslow intermediate,(3)oxidation process,(4)the formation of dual C-O bonds,and(5)the dissociation of catalyst with the product.By systematical calculations,the concerted dual C-O bond formation step was identified as the stereoselectivity-determining step.Moreover,the pathway associated with Rconfigurational isomer product was computed as the dominant one,which is in agreement with the experimental result.Further non-covalent interaction(NCI)and atom-in-molecule(AIM)analyses were employed to qualitatively and quantitatively reveal that the C-H…O hydrogen-bond interactions are the key factors for controlling the stereoselectivity.In the fifth chapter of this thesis,all the above studies were summarized and the upcoming researches were prospected herein.