Theoretical Study Of Photo-Mediated Nickel/Copper Synergistic Catalysis Asymmetric Cross-Coupling Reactions

Chiral compounds,as important intermediates in various drugs,are widely found in natural products and bioactive molecules.However,asymmetric synthesis faces many disadvantages,such as harsh experimental conditions,low yield and difficult separation of enantiomers,which brings great challenges to researchers in the preparation of chiral compounds.In recent years,a breakthrough has been made in the synthesis of chiral compounds through asymmetric C-C or C-X（X=O,N,S）coupling reactions by the dual catalysis of photocatalyst with transition-metal catalyst.However,it is difficult for the current experimental instruments to accurately and comprehensively capture the relevant active intermediates during the reaction process.Therefore,the determinants of such reaction mechanism and enantioselectivity are still controversial.At present,computations have become essential to investigate the reaction mechanisms,electronic processes,and kinetic properties.Therefore,the reaction mechanism and essence of synergistic effect between photocatalysts and transition metal catalysts have been revealed by modeling the catalysis using computational programs in this thesis.The intrinsic relationship between chiral ligand structure and the enantioselectivity of the reaction was in-depthly analyzed.These works will provide theoretical basis and guidance for understanding and improving asymmetric synergistic catalytic systems with high efficiency.This knowledge helps to further design novel synergistic catalytic systems and promote the development of C-C/C-X coupling reactions in asymmetric synthetic chemistry.In this thesis,using density functional theory（DFT）,mechanisms of asymmetric C-C/C-X coupling reactions catalyzed by inexpensive transition metals（copper,nickel）with/without light irradiation.The thesis consists of seven chapters:the first chapter is an introduction including catalysis and synergetic catalysis,significance and method of chiral compounds synthesis,and the application of synergistic catalysis of light-mediated chiral catalysts for the synthesis of asymmetric compounds.The second chapter is theoretical basis and calculation method.The third to the seventh chapters are the main content of the thesis:1.The reversal CuH-catalyzed asymmetric hydroamination ofβ-aryl substitutedα,β-unsaturated olefins was theoretically investigated using DFT.The results show that the reaction mainly consists of three major processes:olefin insertion,single-electron transfer,and radical group cross coupling.The radical-radical cross coupling occurs at the singlet potential energy surface of the open-shell,which is not only the enantio-determining step but also the rate-determining step of the catalytic cycle.In addition,（1）the regioselectivity of the reaction was rationally explained.We found that the reaction proceeds via a radical participation pathway to produceβ-substituted product andα-substituted product,the former has a lower energy barrier than the latter.Therefore,theβ-substituted product is the target product,which is consistent with the experimental fact.（2）The origin of enantioselectivity was clarified.Through steric effect analysis,it is found that the transition state of the R-type product is more stable than that of the S-type product,because it has stronger hydrogen-bonding interaction and smaller spatial repulsion.It is worth noting that,based on the above novel single-electron reaction mechanism,we designed and discovered the possibility of using（E）-β-phenyl substituted trifluoromethyl olefins to prepare chiralα-tertiary alkylamines withβ-fluorine functional groups.Finally,chiralβ-fluoroalkylamines with high regioselectivity and excellent enantioselectivity were successfully synthesized,which further confirmed the accuracy of the current calculation results.In conclusion,this work proposes a method to construct chiral C-N bond using asymmetric radical through a novel single-electron reaction mechanism,which rationally explains the experimental phenomenon.This work brings into play the accuracy and foresight of theoretical calculations,and realizes the precise synthesis of experiments guided by theoretical calculations.2.The mechanism of photoinduced Cu^Ⅰ-catalyzed asymmetric C-O cross-coupling of 1,3-dienes and oxime esters was investigated using DFT.The calculation results show that the reaction mainly undergoes the following processes:First,the initial catalyst Cu^Ⅰ is photoexcited and transformed into an excited state*Cu^Ⅰ.Then,the single electron oxidation of the*Cu^Ⅰ by oxime esters obtain the ground state Cu^Ⅱ cation[Cu^Ⅱ]²⁺and radical oxime ester anion.Followed by N-O bond cleavage,β-C-C bond cleavage and radical addition to of 1-phenylbutadiene provide the allyl radical.Finally,the allyl radical was captured by Cu^Ⅱ for C-O reductive elimination to generate the target product.It is clarified by calculation that the C-O reductive elimination is not only the regio-determining step but also the enantio-determining step of the catalytic cycle.Cu^Ⅱ captures the allyl radical（C2’/C4’）at different positions and undergoes C-O reductive elimination to generate 1,2-adducts with kinetic favorable of 2.9 kcal/mol.At the same time,Cu^Ⅱ captures the C2’position of allyl radical from different chiral faces through C2’-O reductive elimination to generate the R-type product with the advantage of 4.2 kcal/mol.The qualitative analysis of steric effect shows that the interaction between allyl radical and chiral ligand determines the enantioselectivity of chiral products.Detailed theoretical studies are helpful to understand the light-mediated bifunctional copper catalyzed（copper is both used as photocatalyst and transition metal catalyst）asymmetric reaction system.Such knowledge will provide theoretical foundation for further experimental research.3.The mechanism of Ir^Ⅲ/Cu^Ⅰ-metallaphotoredox catalyzed asymmetric radical decarboxylative cyanation was systematically investigated using DFT.The radical mechanism of the reaction merging oxidative quenching（Ir^Ⅲ-*Ir^Ⅲ-Ir^Ⅳ-Ir^Ⅲ）and copper catalytic（Cu^Ⅰ-Cu^Ⅱ-Cu^Ⅲ-Cu^Ⅰ）cycles is favourable.The reaction mainly consists of five major processes:single-electron oxidation of*Ir^Ⅲ by N-hydroxy-phthalimide（NHP）esters followed by decarboxylation to generate benzyl radical,oxidation of Cu^Ⅰby Ir^Ⅳ via a SET process,cyanide exchange,radical capture by Cu^Ⅱ,and C-CN reductive elimination from Cu^Ⅲ.It is clarified by calculation that cyanide exchange is the rate-determining step,whereas the C-CN reductive elimination is the enantio-determining step of the reaction.At the same time,it is revealed that the transition state of the R-type product is more stable than that of the S-type product,because it has a larger intramolecularπ-πinteraction.Therefore,it is more favorable to lead to the formation of R-type product.4.The mechanism of Ir^Ⅲ/Ni^Ⅱ-metallaphotoredox catalyzed enantioselective decarboxylative arylation ofα?amino acids was systematically investigated using DFT.In the presence of Cs₂CO₃,an oxidation state modulation mechanism of oxidative quenching（Ir^Ⅲ-*Ir^Ⅲ-Ir^Ⅳ-Ir^Ⅲ）or a radical mechanism of reductive quenching（Ir^Ⅲ-*Ir^Ⅲ-Ir^Ⅱ-Ir^Ⅲ）combined with nickel catalytic cycles（Ni^Ⅱ-Ni ^Ⅰ-Ni ^Ⅲ-Ni ^Ⅱ）are both possible.It mainly includes the following processes:the Ni^Ⅱ complex and substrate amino acid participate in the photocatalytic cycle to generate Ni^Ⅰ complex andα-amino radical through SET process,oxidative addition,outer-sphere reductive elimination.It is clarified by calculation that oxidative addition is the rate-determining step,whereas the triplet outer-sphere electrophilic attack is the enantio-determining step of the reaction.The transition state of the R-type product has larger spatial repulsion between substrate and chiral ligand than the transition state of the S-type product by steric effect analysis,resulting in more favorable formation of the S-type product.The outer-sphere electrophilic attack mechanism proposed in this work successfully explains the experimental phenomenon and provides a theoretical basis for the rational design of more efficient such synergistic catalytic asymmetric systems.5.4Cz IPN/Ni⁰-metallaphotoredox catalyzed enantioselective desymmetrization of cyclic meso-anhydrides was chosen to illuminate the ambiguous mechanism of such dual catalytic system using DFT.A radical mechanism merging reductive quenching（PC-*PC-PC^--PC）and nickel catalytic cycles（Ni⁰-Ni ^Ⅱ-Ni ^Ⅲ-Ni ^Ⅰ-Ni⁰）is favourable.It consists of seven major processes:single-electron reduction of*PC by benzyl trifluoroborates to generate benzyl radical,ligand exchange,oxidative addition,radical addition,reductive elimination,SET,and ion exchange.The oxidative addition is not only the enantio-determining step but also the rate-determining step of the catalytic cycle.In terms of steric effect,the transition state of the R-type product is more stable than that of the S-type product,because it has stronger hydrogen-bonding interaction and smaller spatial repulsion.Therefore,it is more favorable to lead to the formation of R-type product.In addition,by comparing the reaction mechanisms with Ni⁰ and Ni^Ⅱas initial catalysts,we found that the two undergo different reaction paths and correspond to different energy barriers,which explains the reason for their different reactivity.Detailed theoretical studies will provide theoretical foundation to exploit novel and inexpensive photoredox-mediated synergistic catalytic asymmetric systems.