ConspectusCatalytic atroposelective syntheses of axially chiral compounds have stimulated extensive interest in multiple communities, such as synthetic chemistry, biochemistry, and materials science, because of the intriguing characteristics of atropisomerism. In particular, atropisomeric indole derivatives, which contain a kind of five-membered heterocyclic framework, are widely distributed in a number of natural alkaloids, biologically relevant compounds, chiral ligands, and chiral organocatalysts. Hence, the catalytic atroposelective synthesis of indole derivatives bearing axial chirality is of considerable importance and has become an emerging focus of research. However, there are substantial challenges associated with the atroposelective synthesis of indole derivatives, including remote ortho-substituents around the chiral axis, a lower barrier for rotation, and a weaker configurational stability than that of atropisomeric six-membered biaryls. Therefore, the development of effective strategies toward the catalytic atroposelective synthesis of indole derivatives has become an urgent task.In order to tackle these challenges and to accomplish the task, our group devised a unique strategy of designing indole-derived platform molecules and developing organocatalytic enantioselective transformations of such platform molecules to synthesize atropisomeric indole derivatives; asymmetric organocatalysis has tremendous advantages and was the research area recognized by the Nobel Prize in Chemistry in 2021. This Account summarizes our endeavors in the organocatalytic atroposelective synthesis of indole derivatives bearing axial chirality. In brief, we devised and developed a series of indole-derived platform molecules, such as indolylmethanols, (hetero)aryl indoles, oxindole-based styrenes, N-aminoindoles, and indole-based homophthalic anhydrides, by introducing different functional groups onto the indole ring to achieve new reactivity and modulate the reactive site of the indole ring. As a result, these indole-derived platform molecules possess versatile and unique reactivity and are capable of undergoing a variety of organocatalytic enantioselective transformations for preparing structurally diversified indole derivatives with axial chirality.We used these strategies to accomplish the atroposelective synthesis of plenty of indole derivatives with axial chirality, including (hetero)aryl indoles, alkene-indoles, oxindole-based styrenes, N-pyrrolylindoles, and isochromenone-indoles. In addition, we gave a thorough and detailed understanding of the designed reaction by investigating the reaction pathway and activation mode. More importantly, we studied the biological activity of some products and performed catalyst design on the basis of atropisomeric indole moieties, which are helpful for disclosing more applications of indole derivatives bearing axial chirality.In the future, the organocatalytic atroposelective synthesis of indole derivatives bearing axial chirality will indubitably remain a frontier topic in the research area of asymmetric catalysis and chiral indole chemistry despite challenging issues, for instance, the atroposelective synthesis of novel indole derivatives bearing an unconventional chiral axis, the development of atropisomeric indole derivatives into powerful catalysts or ligands, and the discovery of atroposelective indole derivatives as potent drug candidates. We hope our efforts summarized in this Account will encourage chemists worldwide to devise innovative strategies toward solving the challenging issues that remain in this field, thus promoting its development to a higher level.

Organocatalytic Atroposelective Synthesis of Indole Derivatives Bearing Axial Chirality: Strategies and Applications.

The first highly atroposelective construction of N-N axially chiral indole scaffolds were established via a new strategy of de novo ring formation. This strategy makes use of the organocatalytic asymmetric Paal-Knorr reaction of well-designed N-aminoindoles with 1,4-diketones, thus affording high yields for N-pyrrolylindoles with excellent atroposelectivities (up to 98% yield, 96% ee). In addition, this strategy is applicable for the atroposelective synthesis of N-N axially chiral bispyrroles (up to 98% yield, 97% ee). More importantly, such N-N axially chiral heterocycles can be converted into chiral organocatalysts with applications in asymmetric catalysis, and some molecules display potent anticancer activities. This work not only provides a new strategy for the atroposelective synthesis of N-N axially chiral molecules but also offers a new member of the N-N atropisomer family with promising applications in synthetic and medicinal chemistry.

Organocatalytic Atroposelective Synthesis of N-N Axially Chiral Indoles and Pyrroles by De Novo Ring Formation.

A new strategy for the enantioselective synthesis of axially chiral 3,3'-bisindoles was devised by the direct coupling of two indole rings. This strategy makes use of the C3-umpolung reactivity of 2-indolylmethanols, which enables the catalytic asymmetric addition reaction of 2-indolylmethanols with rationally designed 2-substituted indoles, thus constructing axially chiral 3,3'-bisindole scaffolds in overall excellent yields (up to 98%) with high enantioselectivities (up to 96 : 4 er). This approach not only has overcome the challenges in constructing axially chiral five-five-membered heterobiaryls, but also represents a new application of the C3-umpolung reactivity of 2-indolylmethanols in asymmetric catalysis. More importantly, this class of axially chiral 3,3'-bisindoles can undergo a variety of post-functionalizations to give axially chiral 3,3'-bisindole-based organocatalysts, which have found their preliminary applications in asymmetric catalysis. Appendix S1: Supporting Information Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. 

Catalytic Asymmetric Synthesis of Axially Chiral 3,3'‐Bisindoles by Direct Coupling of Indole Rings

The axially chiral indole-aryl motifs are present in natural products and biologically active compounds as well as in chiral ligands. Atroposelective indole formation is an efficient method to construct indole-based biaryls. We report herein the result of a chiral phosphoric acid catalyzed asymmetric cycloaddition of 3-alkynylindoles with azonaphthalenes. A class of indole-based biaryls were prepared efficiently with excellent yields and enantioselectivities (up to 98% yield, 99% ee). Control experiment and DFT calculations illustrate a possible mechanism in which the reaction proceeds via a dearomatization of indole to generate an allene-iminium intermediate, followed by an intramolecular aza-Michael addition. This approach provides a convergent synthetic strategy for enantioselective construction of axially chiral heterobiaryl backbones. 

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Organocatalytic cycloaddition of alkynylindoles with azonaphthalenes for atroposelective construction of indole-based biaryls

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The first chiral phosphoric acid (CPA) catalyzed cycloaddition-elimination cascade reaction of 2-naphthol- and phenol-derived enecarbamates with azonaphthalenes has been established, providing the highly atroposelective route to an array of axially chiral aryl-C3-benzoindoles in excellent yields with excellent enantioselectivities. The success of this strategy derives from stepwise process involving CPA-catalyzed asymmetric formal [3+2] cycloaddition and subsequent central-to-axial chirality conversion by elimination of a carbamate. In addition, the practicality of this reaction had been verified by varieties of transformations towards functionalized atropisomers.

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Ru-Xia Zhang

Papers

Organocatalytic cycloaddition–elimination cascade for atroposelective construction of heterobiaryls