Theoretical Study Of Organophosphorus Compound In Asymmetric Catalysis

Recently,chiral organocatalysis have become a research hotspot in the field of asymmetric catalysis owing to the mild reaction conditions,high atom economy,and high product yield,play an increasingly important role in the synthesis of bioactive natural products and important pharmaceutical molecules.Owing to increasing demands for higher stereoselectivity,this thesis focuses on how to improve the stereoselectivity of chiral organocatalysis.In theoretical calculations,we mainly study the following two key strategies that could control stereoselectivity: steric interactions and noncovalent interactions.Based on the advantages of theoretical calculations,we have systematically investigated the stereoselectivity of asymmetric reactions,by using different control strategies.Moreover,new catalysts were designed to afford higher selectivity.Research results show that these control strategies can effectively improve the stereoselectivity of asymmetric reactions.Details are as followings:Steric interactions mediated catalytic stereoselectivity of asymmetric reactions.We investigated the chiral phosphine catalyzed intramolecular [3 + 2] cycloaddition reaction,and chiral phosphoric acids catalyzed epoxide sulfuration with DFT calculations.We first explored the mechanism of chiral phosphine catalyzed asymmetric intramolecular [3+2] cycloaddition reaction.The computational results revealed that this reaction proceeds through nucleophilic addition of the phosphine catalyst to the allene,which yields a zwitterionic phosphonium intermediate.The subsequent stepwise [3 + 2]annulation process,determines the enantioselectivity of the reaction.Theoretical predictions of the enantioselectivity for various phosphine catalysts were consistent with experimental observations,and 2D contour maps shows that the enantioselectivity originates from the steric interactions between the reactant and the catalyst.Moreover,on the basis of our theoretical study,new chiral phosphine catalysts were designed by using steric interactions control strategies,which are expecting to afford higher enantioselectivity in this cycloaddition reaction.To further understand the organophosphorus catalysts how to control the enantioselectivity by using steric interactions,we explored the chiral phosphoric acids catalyzed epoxide sulfuration.The computational results revealed that the catalytic cycle involves two main steps of thioketal formation and amide elimination.The enantioselectivity-determining step is CPA-assisted SN2 ring-opening attack of the epoxide by the thiolactam.The axial projections of the reactant and catalyst are overlaid,this clearly reveals that the enantioselectivity originates from the steric interactions between the reactant and the catalyst.Bulky ortho substituents on the phenyl group of the chiral phosphoric acids were found to be important to restrict the position of the epoxide in the key transition states for the enantioselectivity-determining step.In addition,modification of the size of the para substituents can significantly improve the enantioselectivity of the reaction by using steric interactions.According to this prediction model,a series of chiral phosphoric acids molecules that provide better enantioselectivity was designed.Noncovalent interactions mediated catalytic stereoselectivity of asymmetric reactions.We investigated the chiral phosphoric acid catalyzed asymmetric allylation with α‐vinyl allylboron reagents,and chiral phosphoric acid catalyzed enantioselective synthesis of chiral tetraarylmethanes by combining experiments with DFT calculations.We first cooperated with Ming Chen group and reported a dual function asymmetric catalysis by a chiral phosphoric acid catalyst that controls both enantioselective addition of an achiral α-vinyl allylboronate to aldehydes and pseudo axial orientation of theα-vinyl group in the transition state.To understand better the origins of the observed enantioselectivity of the reaction,we performed a distortion/interaction analysis of the enantio-determining transition states,the preference for the enantioselectivity is the result of the hydrogen bonding interactions between the catalyst and substrates.Therefore,noncovalent interactions play a major role in the observed enantioselectivity.To further understand the chiral phosphoric acid catalysts how to control the enantioselectivity by using noncovalent interactions,we cooperated with Jianwei Sun group and disclosed the first catalytic enantioselective synthesis of chiral tetraarylmethanes with high enantioselectivity and efficiency.Computational studies showed that the enantio-determining step is the nucleophilic attack of pyrrole on the para-QM intermediate.The multiple weak hydrogen bonding interactions with well-designed tags constitutes the key elements to success.Control experiments and computational calculations provided strong support on hydrogen bonding interactions as the key elements to successful stereocontrol.Based on theoretical calculation and experiment,the noncovalent interaction control strategy could provide a basis for achieving higher enantioselectivity in asymmetric reactions,and has important guiding significance.