Theoretical Study On The Reaction Mechanism Of Chiral Phosphoric Acid Catalyzed Asymmetric Synthesis Of Chiral Aromatics/Olefins

The asymmetric catalysis plays an important role in modern organic chemistry and industrial synthesis.It is one of the most important research fields in the development of chemistry to obtain single chiral compounds.Designing and synthesizing high-efficiency,green,and atom-economic chiral catalyst are crucial for developing new asymmetric reactions.Quantum chemistry theoretical research can screen the optimal catalyst at a high-precision level and predict the optimal path of the reaction,thereby reducing the consumption of manpower and material resources.In this thesis,we choose two representative types of chiral phosphoric acid catalysts（CPA and its derivatives）to explore the preferred activation model and origin of enantioselectivity by studying the reaction mechanism of asymmetric synthesis of four axial chiral aromatics/olefin compounds.We found that the catalyst backbone and functional group can regulate the binding mode with substrates to achieve a more preferred activation model and further determine the sign of enantioselectivity（positive or negative ee value）.Meanwhile,the favorable noncovalent interactions induced by functional group of substrates and catalyst may further affect the activation model and enantioselecivity.The main research contents are as follows:In order to clarify the influence of the two backbones（BINOL or SPINOL）of chiral phosphoric acid on the enantioselectivity of the reaction,the DFT method is used to analyze the structure of the CPA backbone.The orientation of functional groups can be induced by axial chiral backbone.Therefore,a hypothesis is proposed that the BINOL and SPINOL skeletons with different axis chirality can change the binding mode between the substrate and the catalyst by controlling the orientation of the phosphoric acid functional group,and regulate the sign of enantioselectivity.In order to verify our hypothesis,three asymmetric arylation reactions catalyzed by two types of CPA with different backbones are selected for in-depth mechanism study.The results show that although the high enantioselectivity of the three case reactions is due to the favorable C-H···O interaction,deformation energy between the catalyst and the substrate,and electrostatic interaction in the preferred transition state,the sign of enantioselectivity also follows our hypothesis.For the chiral phosphoric acid-derived catalyst,in order to study the role of its central functional group in controlling the activation model and determining the enantioselectivity,we chose the Pinacol and Acyloin rearrangement reaction catalyzed by N-triflylphosphoramides to explore the reaction mechanism.Our calculations reveal that the P（=NTf）OH tautomer of N-triflylphosphoramides is an active catalyst form for the rearrangement reaction,differing from previous proposed model involving P（=O）NHTf group.This can be ascribed to the additional C-F···πinteraction between the CF₃ group of catalyst and the migration group of substrate in the preferred activation model.Furthermore,we found that the CF₃ substituent on the central functional group effectively assisted the bifunctional activation and improved catalytic activity of N-triflylphosphoramides catalyst.The results of this study are beneficial to broaden the application range of chiral N-triflylphosphoramides and can be applied to catalyze other related asymmetric reactions.In order to study the effect of substrate substituents on the activation model and enantioselectivity for the chiral phosphoric acid catalyzed reaction,the enantioselective direct arylation reactions of iminoquinones and naphthylamines or naphthols are used to explore the above issues.Our calculations reveal that substrate naphthylamines or naphthols prefer enantioselective aminal formation model or 1,4-addition model,respectively,which is reverse to Tan’s and Xu’s model.The different reaction sites created by-OH/-NH₂ will lead to different combination modes and change the noncovalent and steric interactions between catalyst and substrates in these transition states.We further investigated the effect of SPINOL-based CPAs on the enantioselectivity and found that the more rigid skeleton and a smaller binding pocket lead to lower enantioselectivity as compared with that of BINOL-based CPA.In order to study the effect of substrate substituents on the activation model and enantioselectivity for the chiral phosphoric acid catalyst derivatives catalyzed reaction,the asymmetric synthesis of C-C and C-S bonds formation reactions are used for theoretical research.Our calculation shows that the free hydroxyl substituent can slightly enhance the enantioselectivity through contributing relative favorable distortion energy as compared to the methyl substituted case.And the oxygen activated model[O^-···H-Nu]is more effective than nitrogen activated model[N^-···H-Nu]for N-triflylphosphoramides catalysis.The different chiral electrostatic environment of the chiral pocket controlled by the patterns of charge distribution for functional group may distinguish the preferred activation model by creating associate noncovalent interactions,which is also responsibility for the enantioselectivity in the title reaction.The research findings not only reveal the effective activation model for N-triflylphosphoramides catalyst,but also guide the design and synthesis of such high-efficiency asymmetric organic catalysts.