Theoretical Study On Organocatalytic Construction Of Axially/Centrally Chiral Molecular Reactions

Transition-metal catalysis,enzyme catalysis,and organocatalysis are the three pillars in the field of asymmetric catalytic synthesis.Among them,organocatalysis is an important strategy for the efficient construction of chiral molecules.It has the advantages of economic efficiency,green-and safe-concept,and easy recovery of raw materials,and is widely used in organic synthesis.However,it is difficult to clearly reveal the detailed mechanism and the origin of stereoselectivity in experiments.Therefore,it is necessary to explore the existing questions in the field of organocatalysis through theoretical calculations.In this thesis,density functional theory(DFT)has been employed to theoretically study chiral sulfide/selenidecatalyzed thiolation of alkynes and BINOL-catalyzed insertion of carbene into C-B bond.The detailed mechanism,the origin of stereoselectivity,and the role of catalysts are studied,and the electronic structure changes along the intrinsic reaction coordinate(IRC)of key transition states are illustrated using electron localization function(ELF)analysis.In addition,ONIOM(QM/MM)calculation method has been employed to study the mechanism of 1-H-3-hydroxy-4-oxoquinaldine 2,4-dioxygenase(HOD)catalyzed ring-opening of N-heteroaromatic substrate.The first chapter of this thesis is the introduction,which introduces the basic knowledge of computational chemistry,and the employed theoretical methods.Then,chiral sulfide-catalyzed thiolation of alkynes reactions,BINOL-catalyzed insertion of carbene into C-B bond reactions and several cofactor-free enzymes,were briefly introduced in this part.The second chapter to the fourth chapter is the main research content.In the second chapter,the detailed mechanism,the role of the catalyst and the origin of stereoselectivity of sulfide/selenide-catalyzed thiolation of alkynes reaction were investigated theoretically.In the third chapter,we explored the detailed mechanism and the origin of stereoselectivity of BINOL-catalyzed insertion of carbene into C-B bond,and revealed the energy difference of BINOL-catalyzed different substrates.In the fourth chapter,the mechanism of HOD-catalyzed ring-opening of Nheteroaromatic substrate is studied,and a new mechanism for the activation of O2 by proton-coupled electron transfer(PCET)is proposed.The following is a brief description of the contents from the second chapter to the fourth chapter:In the second chapter of this thesis,we used the DFT method to systematically investigate the mechanism of chiral sulfide/selenide-catalyzed electrophilic thiolation of alkynes,and proposed two possible pathways for the construction of axially chiral products(paths a and b).Among them,the energetically favorable pathway(path a)includes four steps:(1)the catalyst activates the electrophilic sulfur reagent to form a cation intermediate;(2)the cation intermediate undergoes electrophilic addition to alkyne to form a thiiranium ion intermediate;(3)ring-opening of thiiranium ion intermediate to form vinylidene quinone methide(VQM)intermediate;(4)an intramolecular dehydrogenation coupled with cyclization reaction occurs to dissociate axially chiral product and the catalyst.ELF analysis revealed the electronic structure of for the formation of thiiranium ion intermediate,and explained the regioselectivity of the cleavage of C-S bond.In the exploration of the stereoselectivity step,the energy barrier of S-configurational isomer pathway is lower than that of the R-configurational isomer pathway,which is consistent with experimental observation.Further noncovalent interaction(NCI)and quantitative atoms-in-molecules(AIM)analyses show that the N-H…O,C-H…O and C-H…F interactions are responsible for determining the enantioselectivity.Moreover,the volume of the R substituents is the important factor for the maintenance of the high axial chirality in the product,and there is a positive correlation between the volume and the energy barrier of racemization.Further frontier molecular orbital(FMO)overlap mode and ELF analyses give a deep understanding of the general mechanism of chiral sulfide/selenide-catalyzed electrophilic carbothiolation of alkynes,and thus provide valuable insights for the rational design on efficient organocatalytic strategies for construction of axially chiral compounds with high stereoselectivity.In the third chapter of this thesis,the origin of stereoselectivity for BINOLcatalyzed insertion into the C(sp2)-B bond of alkylboronic ester by carbene has been investigated using DFT method.The most energetically favorable pathway includes the following processes:Firstly,two transesterification processes occur between the BINOL catalyst and alkylboronic ester to form the chiral vinyl-boronate ester.Secondly,the dissociation of N2 from CF3CHN2 is coupled with the carbene insertion into the C(sp2)-B bond of vinyl-boronate ester.Thirdly,the BINOL catalyst is regenerated and dissociated at the end of the catalytic cycle.The calculation results show that the carbene insertion is identified as the stereoselectivity-determining step.The AIM analyses suggest that the C-H…X(X=I,Br)hydrogen bond interactions are the key factors for determining enantiomeric outcome and finally leads to the Sconfigurational pathway is more energetically favorable than the R-counterpart.The fourth chapter is to study the detailed catalytic mechanism of HOD enzyme by using ONIOM method.The HOD-catalyzed activation of O 2 and the cleavage of Nheteroaromatic substrate consists of four steps:(1)The deprotonation of 1-hydro-3hydroxy-4-oxoquinidine(QND),along with an electron transfer from the substrate to the oxygen molecule to form triplet double radicals(O2·-and QND·);(2)It is a diradical(superoxide anion radical O2·-and QND·)recombination process to form a peroxide intermediate.(3)The ring-closure process occurs to form a bicyclic ring structure;(4)It is the dissociation of CO.The dissociation of CO is rate-determining step in the entire reaction.Our calculated energy barrier(14.9 kcal/mol)for the ratedetermining step of the HOD-catalyzed reaction is close to the experimentally estimated energy barrier(15.5 kcal/mol),indicating that our calculated results are reasonable and reliable.The mechanism obtained from this work contributes to the understanding of other cofactor-free dioxygenase-catalyzed reactions using oxygen as the oxidant.The fifth chapter of this thesis is a summary of the calculated results on the researched topics and prospected future theoretical research.