Catalytic Asymmetric Tandem Cyclization Of 2-indolylmethanols With Three-atom Building Blocks

Heterocyclic compounds containing indole nucleus are widely present in many pharmacologically active molecules and natural products with potential biological activity.The simple and efficient synthesis of compounds containing indole nucleus has important research significance.As a synthetic building block with multiple reactive sites,indolylmethanol can be used to synthesize indole derivatives simply and efficiently.This thesis mainly focuses on the tandem cyclization reaction involving 2-indolylmethanol.In the first chapter,we introduce the background of 2-indolylmethanol-involved substitution and cyclization reactions.Simultaneously,the goal and the contents of this dissertation were also introduced.In the second chapter,we realize the regio-and enantioselective [3+3]cycloaddition of nitrones with 2-indolylmethanols is accomplished by the cooperative catalysis of hexafluoroisopropanol(HFIP)and chiral phosphoric acid(CPA).Using this approach,a series of indole-fused six-membered heterocycles are synthesized in high yields(up to 98% yield),with excellent enantioselectivities(up to 96% ee)and exclusive regiospecificity.This approach enables not only the first organocatalytic asymmetric [3+3] cycloaddition of nitrones but also the first C3-nucleophilic asymmetric [3+3] cycloaddition of 2-indolylmethanols.More importantly,theoretical calculations elucidate the role of the cocatalyst HFIP in helping CPA control the reactivity and enantioselectivity of the reaction,demonstrating a new mode of cooperative catalysis.In the third chapter,a new class of axially chiral aryl-alkene-indole frameworks have been designed,and the first catalytic asymmetric construction of such scaffolds has been established by the strategy of organocatalytic(Z/E)-selective and enantioselective [4+3] cyclization of 3-alkynyl-2-indolylmethanols with 2-naphthols or phenols(all >95:5 E/Z,up to 98% yield,97% ee).This reaction also represents the first catalytic asymmetric construction of axially chiral alkene-heteroaryl scaffolds,which will add a new member to the atropisomeric family.This approach has not only confronted the great challenges in constructing axially chiral alkene-heteroaryl scaffolds but also provided a powerful strategy for the enantioselective construction of axially chiral aryl-alkene-indole frameworks.At the same time,a new type of alleneimine intermediate is discovered through theoretical calculations,which promotes the development of indolylmethanol chemistry.