A breakthrough in 2-indolylmethanol-involved organocatalytic asymmetric reactions

Tan, Wei; Shi, Feng

doi:10.20517/cs.2022.14

Cited by 17 publications

(4 citation statements)

References 7 publications

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“…The first type of indole-based platform molecules we designed for the atroposelective synthesis of indole derivatives with axial chirality are indolylmethanols, which have proven to be competent reactants in catalytic enantioselective transformations . Although the first metal-catalyzed enantioselective synthesis of N -arylindoles with a C–N chiral axis was reported in 2010 by Kitagawa’s group, this research field did not attract substantial interest from chemists until we established the first organocatalytic enantioselective synthesis of 3-arylindoles with a C–C chiral axis in 2017 by using a unique reactivity of 2-indolylmethanols, i.e.…”

Section: Indolylmethanols As Platform Molecules To Synthesize Axially...mentioning

confidence: 99%

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

2022

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Conspectus Catalytic 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...

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Section: Indolylmethanols As Platform Molecules To Synthesize Axially...mentioning

confidence: 99%

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

2022

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“…Specifically, in the presence of a chiral Brønsted acid, this class of 3-alkynyl-2-indolylmethanols transformed into alleneiminium intermediates, which were readily attacked by nucleophiles to undergo 1, 4-addition, thus giving axially chiral alkene-indoles. When using dinucleophiles, the OH group of 2-indolylmethanols undergoes dehydration to give carbocation intermediates [64][65][66][67][68][69][70][71][72] , which subsequently undergo an intramolecular addition reaction to generate axially chiral cyclic alkene-indoles [73,74] . In these previous studies, the t-Bu group, as an aliphatic and bulky group, was detrimental to the delocalization of carbocation, thus making this class of 3alkynyl-2-indolylmethanols unsuitable for Nazarov-type cyclizations.…”

Section: Introductionmentioning

confidence: 99%

Organocatalytic Nazarov-type cyclization of 3-alkynyl-2-indolylmethanols: construction of axially chiral cyclopenta[b]indole scaffolds

Wu¹,

Yan²,

Jiang³

et al. 2023

Chem Synth

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In recent years, it has become an urgent task to design new types of indole-based platform molecules for Nazarov-type cyclizations and develop organocatalytic Nazarov-type cyclizations for synthesizing indole derivatives. To fulfill this task, in this work, by changing the alkynyl terminal substituent from t-Bu to an aryl group, the reactivity of 3-alkynyl-2-indolylmethanols is modulated and the new platform molecules serve as competent substrates for Brønsted acid-catalyzed Nazarov-type cyclization. Based on this new reactivity, the first organocatalytic Nazarov-type cyclization of aryl-substituted 3-alkynyl-2-indolylmethanols with 2-naphthols is accomplished, leading to the efficient construction of a new class of axially chiral 3, 4-dihydrocyclopenta[b]indole scaffolds. This preliminary investigation of organocatalytic asymmetric Nazarov-type cyclization provides an optional strategy for the atroposelective construction of this new class of axially chiral cyclopenta[b]indole scaffolds. In addition, the first preparation of axially chiral 3, 4-dihydrocyclopenta[b]indole with optical purity is established through chiral resolution, which could serve as a complementary method to catalytic asymmetric approaches.

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“…Of these cyclopentindole skeletons, 2-indolylmethanols belong to a class of particularly important indole-based platform molecules for synthesizing indole derivatives. [26][27][28][29][30][31] Note that various chemically selective products were formed in the reaction of 3-alkenyl-2-indolylmethanol with tryptophol under the catalysis of TsOH (Fig. 1).…”

Section: Introductionmentioning

confidence: 99%

Insights into the regioselectivity and diastereoselectivity of the Nazarov cyclization of 3-alkenyl-2-indolylmethanol with tryptophol

et al. 2023

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A breakthrough in 2-indolylmethanol-involved organocatalytic asymmetric reactions

Abstract: no

Cited by 17 publications

References 7 publications

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

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

Organocatalytic Nazarov-type cyclization of 3-alkynyl-2-indolylmethanols: construction of axially chiral cyclopenta[b]indole scaffolds

Insights into the regioselectivity and diastereoselectivity of the Nazarov cyclization of 3-alkenyl-2-indolylmethanol with tryptophol

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