Mechanistic Insights On The Synthesis Of Chiral Nitrogen/Oxygen Heterocyclic Framework Catalyzed By Two Types Of Br?nsted Acids

Chirality can be encountered at all levels in nature.Chiral molecules play a vital role in the fields of medicine,biocatalysis,chemistry and materials science.Chiral nitrogen/oxygen-containing heterocycles are core scaffolds in many bioactive natural products and pharmaceuticals and they are particularly important in the pharmaceutical field.In recent years,the study for the synthesis of the chiral frameworks has attracted a significant amount of attention and made enormous progress.However,the related theoretical research is relatively lagging behind.Hence,we conduct an in-depth mechanism study on the two representative reactions of constructing nitrogen/oxygen-containing heterocycles under the Br?nsted Acid catalysis conditions based on density functional theory（DFT）.The purpose is to reveal the excellent catalytic activity origin of Br?nsted acid catalyst,its unique activation mode for substrates and the origin of enantioselectivity.Then,it provides a theoretical basis for the realization of high-efficiency catalytic enantioselective synthesis of the two types of Br?nsted acids.The main research contents are as follows:1.DFT calculations were performed to explore the mechanism of the dynamic kinetic asymmetric hydroamination（Dy KAH）of racemic allenes to synthesize chiral nitrogen-containing heterocycles catalyzed by（S/R）-SPINOL-derived chiral phosphoric acids（CPAs）.Computational studies show that the reaction proceeds through a catalytic asymmetric model involving a highly reactiveπ-allylic carbocationic intermediate,generated from a racemic allene through an intermolecular proton transfer mediated by CPA,which also results in the high E/Z selectivity.Moreover,the distortion-interaction,atoms in molecule,electrostatic interactions analyses and space-filling models of key transition states are provided to explain the origins of high enantioselectivity and the signs of enantioselectivity.Our calculations indicate that the enantioselectivity can be mainly ascribed to the favorable electrostatic interactions and non-covalent interactions in the preferential transition states.In addition,the chirality of the SPINOL framework controls the way that the substrate enters the chiral pocket of the catalyst by adjusting the orientation of the phosphate functional group,thereby realizing the adjustment of the enantioselective sign.Therefore,our calculation rationalizes the experimental results and provides valuable insights into the reaction mechanism,which can be used in the design of more selective catalysts for Dy KAHs.2.The reaction mechanism for the allyl ether-tethered ynamides to synthesize chiral oxygen-containing heterocycles catalyzed by HNTf₂ was investigated by DFT calculations.Based on the different rearrangement modes of allyl（the rate-determining step）,two mechanisms M1（[1,3]O→C rearrangement）and M2（[3,3]O→C rearrangement）were studied.According to the difference of the auxiliary NTf₂^-/H₂O and the role of the auxiliary in the rearrangement process,three different pathways were explored in M1/M2 respectively.The calculation results show that the most favorable pathway is the rearrangement process assisted by the O atom on the promoter NTf₂^-in mechanism M2.The preferential mechanistic scenario includes six main processes:catalyst protonated substrate,C-O bond formation,[3,3]O→C rearrangement,water addition,stepwise hydrogen-transfer,C-N bond cleavage with HNTf₂ regeneration.Moreover,the distortion-interaction of the key enantiodetermining transition states are provided to explain the origins of high enantioselectivity.Our calculations indicate that the enantioselectivity can be mainly ascribed to the favorable distortion of the substrate in the preferential transition states.HNTf₂ acts as catalyst.NTf₂^-is the auxiliary in the[3,3]O→C rearrangement process,catalyst to effectively promote the proton transfer and stabilizer.Water molecules act as the reactant,stabilizer,and catalyst to effectively promote the proton transfer.Our results provide a theoretical basis for optimizing the title reaction.