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Organocatalytic asymmetric synthesis of bioactive hexahydropyrrolo[2,3-b]indole-containing tetrasubstituted allenes bearing multiple chiral elements

Open AccessPublished:February 03, 2022DOI:https://doi.org/10.1016/j.tchem.2022.100007

      Abstract

      An organocatalytic asymmetric construction of hexahydropyrrolo[2,3-b]indole-containing tetrasubstituted allene scaffolds bearing both axial chirality and central chirality has been established via a cascade 1,8-addition/dearomatization-cyclization reaction of para-aminophenyl propargylic alcohols with tryptamines in the presence of chiral phosphoric acid (CPA), thus affording a wide range of such tetrasubstituted allenes bearing multiple chiral elements in generally good yields (up to 94%) with high diastereo- and enantioselectivities (up to 95:5 dr, 95% ee). In addition, the evaluation on the cytotoxicity of some selected products indicated that this class of chiral tetrasubstituted allenes could inhibit the growth of the pancreatic cancer cells to some extent. This work not only solved the challenging issues in enantioselective construction of tetrasubstituted allenes via alkynyl (aza)-para-quinone methides, but also represents the first example of using alkyne derivatives as electrophiles in organocatalytic asymmetric dearomatizations of tryptamines.

      Graphical abstract

      Keywords

      1. Introduction

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      Fig. 1
      Fig. 1Representative axially chiral allene derivatives.
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      One-step synthesis of substituted dihydro- and tetrahydroisoquinolines by FeCl3·6H2O catalyzed intramolecular Friedel-Crafts reaction of benzylamino-substituted propargylic alcohols.
      ,
      • Xia Y.
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      Contrasteric coupling of allenes and tetrahydroisoquinolines by iron-catalysed allenic C(sp2)–H functionalization.
      ] and imidazole[7i] substituted allenes. However, most of the transformations are non-enantioselective and only racemic heterocycle-substituted allenes were prepared. So, it is in a great demand to develop catalytic asymmetric strategies for enantioselective synthesis of axially chiral heterocycle-containing tetrasubstituted allenes. To this end, considering asymmetric organocatalysis has demonstrated its great power in enantioselective construction of important chiral scaffolds in the last two decades [
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      Asymmetric organocatalysis.
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      The advent and development of organocatalysis.
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      Amino acid-derived bifunctional phosphines for enantioselective transformations.
      • Zong L.
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      Phase-transfer and ion-pairing catalysis of pentanidiums and bisguanidiniums.
      • Wang Y.-B.
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      Construction of axially chiral compounds via asymmetric organocatalysis.
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      Peptide-based catalysts eeach the outer sphere through remote desymmetrization and atroposelectivity.
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      Advances in organocatalytic asymmetric reactions of vinylindoles: powerful access to enantioenriched indole derivatives.
      ,
      • Houk K.N.
      • List B.
      Asymmetric organocatalysis.
      ,
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      The advent and development of organocatalysis.
      ,
      • Wang T.
      • Han X.
      • Zhong F.
      • Yao W.
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      Amino acid-derived bifunctional phosphines for enantioselective transformations.
      ,
      • Zong L.
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      Phase-transfer and ion-pairing catalysis of pentanidiums and bisguanidiniums.
      ,
      • Wang Y.-B.
      • Tan B.
      Construction of axially chiral compounds via asymmetric organocatalysis.
      ,
      • Metrano A.J.
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      Peptide-based catalysts eeach the outer sphere through remote desymmetrization and atroposelectivity.
      ,
      • Tu M.
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      Advances in organocatalytic asymmetric reactions of vinylindoles: powerful access to enantioenriched indole derivatives.
      ], it is highly appealing to develop organocatalytic asymmetric approaches for synthesizing axially chiral heterocycle-containing tetrasubstituted allenes.
      Recently, racemic para-hydroxyl and para-aminophenyl propargylic alcohols have been recognized as competent reactants for synthesizing axially chiral tetrasubstituted allenes under asymmetric organocatalysis (Scheme 1a) because they can easily generate alkynyl para-quinone methides (p-QMs)[
      • Pan X.
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      Cross-dehydrogenative coupling enables enantioselective access to CF3-substituted allcarbon quaternary stereocenters.
      ,
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      Dearomatization of 2,3-disubstituted indoles via 1,8-addition of propargylic (aza)-para-quinone methides.
      ,
      • Wang J.-R.
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      Catalytic asymmetric conjugate addition of indoles to para-quinone methide derivatives.
      • Wang Z.
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      Synthesis of chiral triarylmethanes bearing all-carbon quaternary stereocenters: catalytic asymmetric oxidative cross-coupling of 2,2-diarylacetonitriles and (hetero)arenes.
      • Pan X.
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      • Kan L.
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      Cross-dehydrogenative coupling enables enantioselective access to CF3-substituted allcarbon quaternary stereocenters.
      • Pan H.-P.
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      • Liu H.-F.
      • Ma J.-D.
      • Li B.Q.
      • Feng N.
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      • Peng J.-B.
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      Dearomatization of 2,3-disubstituted indoles via 1,8-addition of propargylic (aza)-para-quinone methides.
      ,
      • Wang J.-R.
      • Jiang X.-L.
      • Hang Q.-Q.
      • Zhang S.
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      Catalytic asymmetric conjugate addition of indoles to para-quinone methide derivatives.
      ,
      • Wang Z.
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      Synthesis of chiral triarylmethanes bearing all-carbon quaternary stereocenters: catalytic asymmetric oxidative cross-coupling of 2,2-diarylacetonitriles and (hetero)arenes.
      ] and alkynyl aza-para-quinone methides (aza-p-QMs) in the presence of chiral Brønsted acid (B∗-H). Such alkynyl (aza)-p-QMs can serve as highly reactive intermediates to undergo enantioselective 1,8-conjugate addition with suitable nucleophiles (Nu), thus constructing axially chiral allene scaffolds[
      • Zhang L.
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      Organocatalytic remote stereocontrolled 1,8-additions of thiazolones to oropargylic aza-p-quinone methides.
      ,
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      • Li R.
      • Li P.
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      Remote stereocontrolled construction of vicinal axially chiral tetrasubstituted allenes and heteroatom-functionalized quaternary carbon stereocenters.
      ,
      • Qian D.
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      Organocatalytic synthesis of chiral tetrasubstituted allenes from racemic propargylic alcohols.
      • Chen M.
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      Organocatalytic enantioconvergent synthesis of tetrasubstituted allenes via asymmetric 1,8-addition to aza-para-quinone methides.
      • Zhang L.
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      • Huang A.
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      • Li P.
      • Li W.
      Organocatalytic remote stereocontrolled 1,8-additions of thiazolones to oropargylic aza-p-quinone methides.
      • Zhang P.
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      • Cheng Y.
      • Li R.
      • Li P.
      • Li W.
      Remote stereocontrolled construction of vicinal axially chiral tetrasubstituted allenes and heteroatom-functionalized quaternary carbon stereocenters.
      ,
      • Qian D.
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      • Lin Z.
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      Organocatalytic synthesis of chiral tetrasubstituted allenes from racemic propargylic alcohols.
      ,
      • Chen M.
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      Organocatalytic enantioconvergent synthesis of tetrasubstituted allenes via asymmetric 1,8-addition to aza-para-quinone methides.
      ]. This synthetic strategy was pioneered by Sun's group, who devised a chiral phosphoric acid (CPA)-catalyzed 1,8-addition reaction of racemic propargylic alcohols with 1,3-diketones or thioacetic acid to construct axially chiral tetrasubstituted allene scaffolds.[5a] In addition, the same group innovated the application of para-aminophenyl propargylic alcohols in the enantioselective synthesis of axially chiral tetrasubstituted allenes.[5b] Moreover, Li's group successfully utilized thiazolones as suitable nucleophiles in CPA-catalyzed 1,8-addition reactions with alkynyl p-QMs or alkynyl aza-p-QMs for the synthesis of axially chiral tetrasubstituted allenes [
      • Zhang L.
      • Han Y.
      • Huang A.
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      Organocatalytic remote stereocontrolled 1,8-additions of thiazolones to oropargylic aza-p-quinone methides.
      ,
      • Zhang P.
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      • Li R.
      • Li P.
      • Li W.
      Remote stereocontrolled construction of vicinal axially chiral tetrasubstituted allenes and heteroatom-functionalized quaternary carbon stereocenters.
      ]. In spite of these elegant works, there are still some challenging issues in this research field such as discovering other compatible nucleophiles under Brønsted acid catalysis and constructing axially chiral allene-based frameworks bearing multiple chiral elements, which has become an important issue in asymmetric catalysis and synthesis because multiple chiral elements are helpful for developing chiral catalysts and finding bioactive molecules [
      • Kwon Y.
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      Divergent control of point and axial stereogenicity: catalytic enantioselective C−N bond-forming cross-coupling and catalyst-controlled atroposelective cyclodehydration.
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      Design and catalytic asymmetric construction of axially chiral 3,3’-bisindole skeletons.
      • Jiang F.
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      A strategy for synthesizing axially chiral naphthyl-indoles: catalytic asymmetric addition reactions of racemic substrates.
      • Ma C.
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      • Wang H.-Q.
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      • Zhang Y.-C.
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      • Tan W.
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      Atroposelective access to oxindole-based axially chiral styrenes via the strategy of catalytic kinetic resolution.
      • Sheng F.-T.
      • Li Z.-M.
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      • Sun L.-X.
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      • Tan W.
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      Atroposelective synthesis of 3,3’-bisindoles bearing axial and central chirality: using isatin-derived imines as electrophiles.
      • Huang S.
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      Organocatalytic enantioselective construction of chiral azepine skeleton bearing multiple-stereogenic elements.
      • Liu S.-J.
      • Chen Z.-H.
      • Chen J.-Y.
      • Ni S.-F.
      • Zhang Y.-C.
      • Shi F.
      Rational design of axially chiral styrene-based organocatalysts and their application in catalytic asymmetric (2+4) cyclizations.
      ,
      • Kwon Y.
      • Chinn A.J.
      • Kim B.
      • Miller S.J.
      Divergent control of point and axial stereogenicity: catalytic enantioselective C−N bond-forming cross-coupling and catalyst-controlled atroposelective cyclodehydration.
      ,
      • Ma C.
      • Jiang F.
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      • Jiao Y.
      • Mei G.-J.
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      Design and catalytic asymmetric construction of axially chiral 3,3’-bisindole skeletons.
      ,
      • Jiang F.
      • Chen K.-W.
      • Wu P.
      • Zhang Y.-C.
      • Jiao Y.
      • Shi F.
      A strategy for synthesizing axially chiral naphthyl-indoles: catalytic asymmetric addition reactions of racemic substrates.
      ,
      • Ma C.
      • Sheng F.-T.
      • Wang H.-Q.
      • Deng S.
      • Zhang Y.-C.
      • Jiao Y.-C.
      • Tan W.
      • Shi F.
      Atroposelective access to oxindole-based axially chiral styrenes via the strategy of catalytic kinetic resolution.
      ,
      • Sheng F.-T.
      • Li Z.-M.
      • Zhang Y.-Z.
      • Sun L.-X.
      • Zhang Y.-C.
      • Tan W.
      • Shi F.
      Atroposelective synthesis of 3,3’-bisindoles bearing axial and central chirality: using isatin-derived imines as electrophiles.
      ,
      • Huang S.
      • Wen H.
      • Tian Y.
      • Wang P.
      • Qin W.
      • Yan H.
      Organocatalytic enantioselective construction of chiral azepine skeleton bearing multiple-stereogenic elements.
      ,
      • Liu S.-J.
      • Chen Z.-H.
      • Chen J.-Y.
      • Ni S.-F.
      • Zhang Y.-C.
      • Shi F.
      Rational design of axially chiral styrene-based organocatalysts and their application in catalytic asymmetric (2+4) cyclizations.
      ].
      Scheme 1
      Scheme 1Research background and our design in this work.
      To solve these challenging issues, based on our experience in developing indole-based platform molecules for organocatalytic asymmetric reactions [
      • Zhang Y.-C.
      • Jiang F.
      • Shi F.
      Organocatalytic asymmetric synthesis of indole-based chiral heterocycles: strategies, reactions, and outreach.
      ,
      • Wang C.-S.
      • Li T.-Z.
      • Liu S.-J.
      • Zhang Y.-C.
      • Deng S.
      • Jiao Y.
      • Shi F.
      Axially chiral aryl-alkene-indole framework: a nascent member of the atropisomeric family and its catalytic asymmetric construction.
      ,
      • Li T.-Z.
      • Liu S.-J.
      • Sun Y.-W.
      • Deng S.
      • Tan W.
      • Jiao Y.
      • Zhang Y.-C.
      • Shi F.
      Regio- and enantioselective (3+3) cycloaddition of nitrones with 2-indolylmethanols enabled by cooperative organocatalysis.
      ,
      • Wang J.-Y.
      • Sun M.
      • Yu X.-Y.
      • Zhang Y.-C.
      • Tan W.
      • Shi F.
      Atroposelective construction of axially chiral alkene-indole scaffolds via catalytic enantioselective addition reaction of 3-alkynyl-2-indolylmethanols.
      ,
      • Zhang Y.-C.
      • Jiang F.
      • Shi F.
      Organocatalytic asymmetric synthesis of indole-based chiral heterocycles: strategies, reactions, and outreach.
      • Wang C.-S.
      • Li T.-Z.
      • Liu S.-J.
      • Zhang Y.-C.
      • Deng S.
      • Jiao Y.
      • Shi F.
      Axially chiral aryl-alkene-indole framework: a nascent member of the atropisomeric family and its catalytic asymmetric construction.
      • Li T.-Z.
      • Liu S.-J.
      • Sun Y.-W.
      • Deng S.
      • Tan W.
      • Jiao Y.
      • Zhang Y.-C.
      • Shi F.
      Regio- and enantioselective (3+3) cycloaddition of nitrones with 2-indolylmethanols enabled by cooperative organocatalysis.
      • Wang J.-Y.
      • Sun M.
      • Yu X.-Y.
      • Zhang Y.-C.
      • Tan W.
      • Shi F.
      Atroposelective construction of axially chiral alkene-indole scaffolds via catalytic enantioselective addition reaction of 3-alkynyl-2-indolylmethanols.
      ], we consider that tryptamines might be a class of compatible nucleophiles under Brønsted acid catalysis for constructing hexahydropyrrolo[2,3-b]indole-containing tetrasubstituted allenes bearing multiple chiral elements. As summarized in Scheme 1b, tryptamines have proven to be competent nucleophiles in organo-catalytic asymmetric dearomatization (organo-CADA) reactions[
      • You S.-L.
      Asymmetric dearomatization reactions.
      • Zheng C.
      • You S.-L.
      Catalytic asymmetric dearomatization (CADA) reaction-enabled total synthesis of indole-based natural products.
      • Xia Z.-L.
      • Xu-Xu Q.-F.
      • Zheng C.
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      Chiral phosphoric acid-catalyzed asymmetric dearomatization reactions.
      • An J.
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      Recent advances in the catalytic dearomatization of naphthols.
      • Sheng F.-T.
      • Wang J.-Y.
      • Tan W.
      • Zhang Y.-C.
      • Shi F.
      Progresses in organocatalytic asymmetric dearomatization reactions of indole derivatives.
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      Advances in catalytic asymmetric dearomatization.
      ,
      • Wang H.
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      Phosphine-catalyzed enantioselective dearomative [3 + 2]-cycloaddition of 3-nitroindoles and 2-nitrobenzofurans.
      • Li K.
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      • Huang K.-W.
      • Lu Y.
      Dearomatization of 3-nitroindoles via a phosphine-catalyzed enantioselective [3 + 2] annulation reaction.
      • Mei G.-J.
      • Tang X.
      • Tasdan Y.
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      Enantioselective dearomatization of indoles via an azoalkene enabled [3 + 2] reaction: facile access to pyrroloindolines.
      • Wang Y.
      • Zhang W.-Y.
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      • Yu Z.-L.
      • Tian J.-H.
      • Zheng C.
      • Hou X.-L.
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      Enantioselective desymmetrization of bisphenol derivatives via Ir-catalyzed allylic dearomatization.
      • Zhang Y.-Q.
      • Chen Y.-B.
      • Liu J.-R.
      • Wu S.-Q.
      • Fan X.-Y.
      • Zhang Z.-X.
      • Hong X.
      • Ye L.-W.
      Asymmetric dearomatization catalysed by chiral Brønsted acids via activation of ynamides.
      ]. Due to the C3-nucleophilicity of the indole ring, tryptamines can readily attack electrophiles (E) in the presence of chiral organocatalysts and initiate a cascade cyclization, thus accomplishing the organo-CADA reactions and constructing indoline-fused rings with multiple stereogenic centers [
      • Austin J.F.
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      Enantioselective organocatalytic construction of pyrroloindolines by a cascade addition–cyclization strategy: synthesis of (–)-flustramine B.
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      • Cai Q.
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      Enantioselective construction of pyrroloindolines via chiral phosphoric acid catalyzed cascade michael addition–cyclization of tryptamines.
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      Chiral phosphoric acid-catalyzed asymmetric cascade reaction of C(3) substituted indoles and methyl vinyl ketone.
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      Enantioselective construction of pyrroloindolines via chiral phosphoric acid catalyzed cascade michael addition–cyclization of tryptamines.
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      • Duan D.-H.
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      Chiral phosphoric acid-catalyzed asymmetric cascade reaction of C(3) substituted indoles and methyl vinyl ketone.
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      • Zhang H.
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      Highly enantioselective bromocyclization of tryptamines and its application in the synthesis of (−)-Chimonanthine.
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      Chiral-amine-catalyzed asymmetric bromocyclization of tryptamine derivatives.
      • Liang X.-W.
      • Liu C.
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      Asymmetric fluorinative dearomatization of tryptamine derivatives.
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      Asymmetric dearomatizing fluoroamidation of indole derivatives with dianionic phase-transfer catalyst.
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      • Xie W.
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      Highly enantioselective bromocyclization of tryptamines and its application in the synthesis of (−)-Chimonanthine.
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      • Cai Q.
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      Chiral-amine-catalyzed asymmetric bromocyclization of tryptamine derivatives.
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      • Liang X.-W.
      • Liu C.
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      Asymmetric fluorinative dearomatization of tryptamine derivatives.
      ,
      • Egami H.
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      • Niwa T.
      • Yamashita K.
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      Asymmetric dearomatizing fluoroamidation of indole derivatives with dianionic phase-transfer catalyst.
      ,
      • Li Q.
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      Enantioselective and diastereoselective azo-coupling/iminium-cyclizations: a unified strategy for the total syntheses of (−)-psychotriasine and (+)-pestalazine B.
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      Enantioselective synthesis of pyrroloindolines via noncovalent stabilization of indole radical cations and applications to the synthesis of alkaloid natural products.
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      Enantioselective radical cyclization of tryptamines by visible light-excited nitroxides.
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      • Cheng Y.-Z.
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      Asymmetric dearomatization of indole derivatives with N-hydroxycarbamates enabled by photoredox catalysis.
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      • Zhang Z.
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      Enantioselective construction of pyrroloindolines catalyzed by chiral phosphoric acids: total synthesis of (−)-DebromoflustramineB.
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      Organocatalytic asymmetric selenofunctionalization of tryptamine for the synthesis of hexahydropyrrolo[2,3-b]indole derivatives.
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      Chiral anion phase transfer of aryldiazonium cations: an enantioselective synthesis of C3-diazenated pyrroloindolines.
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      Enantioselective and diastereoselective azo-coupling/iminium-cyclizations: a unified strategy for the total syntheses of (−)-psychotriasine and (+)-pestalazine B.
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      Enantioselective synthesis of pyrroloindolines via noncovalent stabilization of indole radical cations and applications to the synthesis of alkaloid natural products.
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      • Shi B.
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      • Yan P.
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      Enantioselective radical cyclization of tryptamines by visible light-excited nitroxides.
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      Asymmetric dearomatization of indole derivatives with N-hydroxycarbamates enabled by photoredox catalysis.
      ,
      • Zhang Z.
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      Enantioselective construction of pyrroloindolines catalyzed by chiral phosphoric acids: total synthesis of (−)-DebromoflustramineB.
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      • Wei Q.
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      Organocatalytic asymmetric selenofunctionalization of tryptamine for the synthesis of hexahydropyrrolo[2,3-b]indole derivatives.
      ,
      • Nelson H.M.
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      Chiral anion phase transfer of aryldiazonium cations: an enantioselective synthesis of C3-diazenated pyrroloindolines.
      ]. However, in the literature, the electrophiles utilized in the organo-CADA reactions of tryptamines mainly involve electronically poor alkenes such as α,β-unsaturated aldehydes [
      • Austin J.F.
      • Kim S.-G.
      • Sinz C.J.
      • Xiao W.-J.
      • MacMillan D.W.C.
      Enantioselective organocatalytic construction of pyrroloindolines by a cascade addition–cyclization strategy: synthesis of (–)-flustramine B.
      ] and vinyl ketones [
      • Duan D.-H.
      • Yin Q.
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      • Gu Q.
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      Chiral phosphoric acid-catalyzed asymmetric cascade reaction of C(3) substituted indoles and methyl vinyl ketone.
      ,
      • Cai Q.
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      • Liang X.-W.
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      Enantioselective construction of pyrroloindolines via chiral phosphoric acid catalyzed cascade michael addition–cyclization of tryptamines.
      • Duan D.-H.
      • Yin Q.
      • Wang S.-G.
      • Gu Q.
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      Chiral phosphoric acid-catalyzed asymmetric cascade reaction of C(3) substituted indoles and methyl vinyl ketone.
      ,
      • Cai Q.
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      • Liang X.-W.
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      Enantioselective construction of pyrroloindolines via chiral phosphoric acid catalyzed cascade michael addition–cyclization of tryptamines.
      ],halogen precursors [
      • Xie W.
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      • Zhang H.
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      • Lai Y.
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      Highly enantioselective bromocyclization of tryptamines and its application in the synthesis of (−)-Chimonanthine.
      ,
      • Cai Q.
      • Yin Q.
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      Chiral-amine-catalyzed asymmetric bromocyclization of tryptamine derivatives.
      ,
      • Liang X.-W.
      • Liu C.
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      ]. In contrast, alkyne derivatives, particularly alkynes bearing an electron-withdrawing group (EWG), have scarcely been utilized as electrophiles in organo-CADA reactions of tryptamines (eq. 2) in spite of the fact that this class of reactions could afford an alkene or allene functionality with simultaneous generation of multiple stereogenic centers. In this context, we consider propargylic alcohols can serve as alkyne-type electrophiles to react with tryptamines, therefore synthesizing hexahydropyrrolo[2,3-b]indole-containing tetrasubstituted allenes bearing multiple chiral elements.
      So, we designed a chiral phosphoric acid (CPA) [
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      Stronger brønsted acids.
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      ] catalyzed cascade reaction of propargylic alcohols with tryptamines (Scheme 1c). In this design, under the catalysis of CPA, propargylic alcohols would undergo dehydration to give intermediates of alkynyl (aza)-p-QMs, and tryptamines would serve as suitable nucleophiles to attack alkynyl (aza)-p-QMs via a 1,8-addition/CADA-cyclization cascade sequence, therefore generating hexahydropyrrolo[2,3-b]indole-containing tetrasubstituted allenes bearing multiple chiral elements. Nevertheless, there are still some challenges in this design, mainly include: (1) controlling the regioselectivity in 1,8-addition rather than 1,6-addition to generate tetrasubstituted allenes, (2) controlling the diastero- and enantioselectivity in CADA-cyclization reaction to construct hexahydropyrrolo[2,3-b]indole moiety bearing adjacent stereogenic centers, (3) controlling both axial chirality and central chirality of this class of unique scaffolds to generate multiple chiral elements. Herein, we report our efforts in solving these challenges.

      2. Results and discussion

      At the outset, the reaction of propargyl alcohol 1a with tryptamine 2a was employed as a model reaction to testify the feasibility of our design (Table 1). Gratifyingly, under the catalysis of CPA 4a in toluene with 3 ​Å molecular sieves (MS) as additives at 25 ​°C (entry 1), the designed reaction indeed occurred to afford hexahydropyrrolo[2,3-b]indole-containing tetrasubstituted allene 3aa bearing multiple chiral elements in an excellent yield of 95% albeit with a poor diastereoselectivity (67:33 dr) and a low enantioselectivity (48% ee), which indicated the challenges in controlling the stereoselectivity during the generation of both axial chirality and central chirality. To solve these challenges, a series of BINOL-derived CPAs 4b-4f were screened (entries 2–6), which found that CPA 4c bearing 3,3′-di(9-phenanthrenyl) groups could catalyze the reaction to afford product 3aa in the highest enantioselectivity of 78% ee and the best diastereoselectivity of 82:18 dr (entry 3). In order to further improve the enantioselectivity and diastereoselectivity, the backbone of CPA 4c was changed from BINOL to H8-BINOL and SPINOL (entries 7–8). To our delight, H8-BINOL-derived CPA 5 was better than CPA 4c to catalyze the reaction in a higher enantioselectivity of 85% ee and diastereoselectivity of 89:11 dr (entry 7 vs entry 3). Thus, CPA 5 was selected as the optimal catalyst for this reaction. Subsequently, under the catalysis of CPA 5, other types of solvents were evaluated (entries 9–12), which revealed that only dichloromethane could facilitate this reaction (entry 9), and other solvents including ethyl acetate, acetonitrile and tetrahydrofuran could hardly promote the reaction (entries 10–12). Considering dichloromethane was inferior to toluene in terms of controlling the enantioselectivity and the diastereoselectivity (entry 9 vs entry 7), a series of benzene-type solvents were further evaluated (see Table S1 of Supporting Information). Nevertheless, none of them was better than toluene in controlling the enantioselectivity of product 3aa. So, toluene was chosen as the most suitable solvent for this reaction. Afterwards, other reaction conditions including additives such as molecular sieves (MS), reaction concentration, catalyst loading and reagent ratio were further optimized (see Table S2 of Supporting Information), which resulted in the optimal reaction conditions (entry 13) and delivered product 3aa in a high yield of 87% with a good stereoselectivity of 92:8 dr and 86% ee.
      Table 1Condition optimization and effects of N-protective groups in propargyl alcohols 1
      Unless indicated otherwise, the reaction was carried out in 0.05 ​mmol scale and catalyzed by 20 ​mol% Cat. in a solvent (0.5 ​mL) with 3 ​Å ​MS (50 ​mg) at 25 ​°C for 16 ​h, and the molar ratio of 1a:2a was 1:1.5.
      .
      Table thumbnail fx1
      a Unless indicated otherwise, the reaction was carried out in 0.05 ​mmol scale and catalyzed by 20 ​mol% Cat. in a solvent (0.5 ​mL) with 3 ​Å ​MS (50 ​mg) at 25 ​°C for 16 ​h, and the molar ratio of 1a:2a was 1:1.5.
      b Isolated yield.
      c The dr value was determined by HPLC and 1H NMR.
      d The ee value referred to that of the major diastereomer and was determined by HPLC.
      e The reaction was carried out in 0.1 ​mmol scale and catalyzed by 10 ​mol% (R)-5 in toluene (4.0 ​mL) with 3 ​Å ​MS (100 ​mg) at 25 ​°C for 24 ​h, and the molar ratio of 1:2a was 1:2. N.R. ​= ​No reaction.
      After establishing the optimal reaction conditions, we investigated the effect of the N-protective groups (PG) of propargyl alcohols 1 on the reaction (Table 1, entries 14–17) since the N-protective groups are closely related to the formation of alkynyl aza-p-QM intermediates. Firstly, the N-protective group was changed from pivaloyl group (1a) to t-butoxycarbonyl group (1b), and product 3ba was generated in a much lower yield with a sharply decreased stereoselectivity (entry 14 vs entry 13), which indicated that the acyl group was superior to its corresponding ester group as a N-protective group for substrates 1. Secondly, iso-butyryl group (1c) with smaller steric hindrance than pivaloyl group (1a) was used as a N-protective group, which gave product 3ca in a reduced yield with a greatly decreased stereoselectivity (entry 15 vs entry 13). However, when using very bulky adamantanecarbonyl group (1d) as a N-protective group, the stereoselectivity of product 3da was also decreased to some extent (entry 16), which implied that the steric hindrance of the N-protective group had a delicate effect on controlling the stereoselectivity of the reaction. Moreover, when substrate 1’ bearing a N-tosyl group was employed to the reaction under the optimal conditions, no reaction occurred (entry 17). So, these results demonstrated that pivaloyl group was the most suitable N-protective group for substrates 1.
      Then, we investigated the substrate scope of para-aminophenyl propargylic alcohols 1 by the reactions with tryptamine 2a or 2m. As shown in Table 2, this protocol could be applicable to a variety of substrates 1 bearing different R groups, which smoothly underwent the catalytic asymmetric cascade reaction to afford chiral hexahydropyrrolo[2,3-b]indole-containing tetrasubstituted allenes 3 in overall good yields, satisfactory diastereoselectivities and high enantioselectivities. Specifically, the R groups of substrates 1 could be phenyl groups bearing electronically distinct substituents at different positions (entries 2–7). Among them, substrates 1e-1f bearing electronically rich para-substituted phenyl groups such as p-MeOC6H4 and p-MeSC6H4 groups are superior reactants (entries 2–3), which participated in the reaction to afford products 3ea-3fa in high yields (90% and 94%) with excellent diastereo- and enantioselectivities (95:5 dr, 94% and 93% ee). Moreover, piperonyl group could also serve as a suitable R group for substrate 1k, which smoothly took part in the reaction to generate product 3ka in a high yield with a good stereoselectivity (entry 8).
      Table 2Substrate scope of para-aminophenyl propargylic alcohols 1
      Unless indicated otherwise, the reaction was carried out in 0.1 ​mmol scale and catalyzed by 10 ​mol% (R)-5 in toluene (4.0 ​mL) with 3 ​Å ​MS (100 ​mg) at 25 ​°C for 24 ​h, and the molar ratio of 1:2a was 1:2.
      .
      Table thumbnail fx7
      a Unless indicated otherwise, the reaction was carried out in 0.1 ​mmol scale and catalyzed by 10 ​mol% (R)-5 in toluene (4.0 ​mL) with 3 ​Å ​MS (100 ​mg) at 25 ​°C for 24 ​h, and the molar ratio of 1:2a was 1:2.
      b Isolated yield.
      c The dr value was determined by 1H NMR.
      d The ee value referred to that of the major diastereomer and was determined by HPLC.
      e Catalyzed by 20 ​mol% (R)-5.
      f Catalyzed by 20 ​mol% (R)-4c.
      To further investigate the substrate scope of this catalytic asymmetric cascade reaction, we utilized other propargylic alcohols 1l-1n as substrates in the reaction with tryptamine 2m (entries 9–11). At first, propargylic alcohol 1l bearing a terminal 3-thienyl group, a heteroaromatic group, was utilized as a substrate (entry 9), which smoothly participated in the reaction under the standard conditions to give tetrasubstituted allene 3lm in a moderate yield of 61%, excellent stereoselectivity of 92:8 dr and considerable enantioselectivity of 70% ee. Furthermore, propargylic alcohol 1m bearing a terminal cyclopropyl group, an aliphatic group, was employed as a substrate in the reaction (entry 10). However, under the standard conditions, product 3mm was generated in a low stereoselectivity. Fortunately, by changing the catalyst from (R)-5 to (R)-4c, product 3mm bearing a cyclopropyl moiety could be synthesized in a high yield of 87% with good stereoselectivity of 88:12 dr and 81% ee. Moreover, propargylic alcohol 1n bearing a terminal n-pentanyl group, a sp3-hybridized alkyl group, could smoothly participated in the reaction under the catalysis of (R)-4c (entry 11), affording product 3nm in a good yield of 71% with a moderate diastereo- and enantioselectivity (85:15 dr, 69% ee).
      Next, we studied the substrate scope of tryptamines 2 by the reactions with para-aminophenyl propargylic alcohol 1e under the standard conditions. As listed in Table 3, this cascade reaction was amenable to a wide range of tryptamines 2 bearing different R substituents at C4 to C7 positions of the indole ring, affording hexahydropyrrolo[2,3-b]indole-containing tetrasubstituted allenes 3 with multiple chiral elements in moderate to high yields (50%–87%), good diastereoselectivities (84:16 to 95:5 dr) and excellent enantioselectivities (84%–95% ee). It should be noted that C4-substituted tryptamines seldom served as competent substrates in CADA reactions because the steric congestion of C4-substituents would decrease the reactivity of tryptamines [
      • Pan H.-P.
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      Dearomatization of 2,3-disubstituted indoles via 1,8-addition of propargylic (aza)-para-quinone methides.
      ]. Nevertheless, in our case, C4-fluoro-substituted tryptamine 2b could serve as a competent substrate for this cascade CADA reaction, which generated the corresponding product 3eb in a high yield with a good stereoselectivity (entry 1). As for C5-substituted tryptamines 2c-2g (entries 2–6), it seemed that the electronic nature of the substituents had no remarkable effect on the enantioselectivity of the reaction because all of the products 3ec-3eg were generated in uniformly excellent enantioselectivities (90%–94% ee). However, electron-donating substituents such as methyl and methoxyl groups seemed helpful to improve the diastereoselectivity of the reaction, and the two substrates 2f-2g participated in the reaction to give products 3ef-3eg in an excellent diastereoselectivity of 95:5 dr (entries 5–6). Moreover, C6 and C7-substituted tryptamines 2h-2m bearing either electron-withdrawing groups or electron-donating groups could smoothly engage in the reaction to offer hexahydropyrrolo[2,3-b]indole-containing tetrasubstituted allene products 3eh-3em in overall good yields with excellent diastereo- and enantioselectivities (entries 7–12).
      Table 3Substrate scope of tryptamines 2
      Unless indicated otherwise, the reaction was carried out in 0.1 ​mmol scale and catalyzed by 10 ​mol% (R)-5 in toluene (4.0 ​mL) with 3 ​Å ​MS (100 ​mg) at 25 ​°C for 24 ​h, and the molar ratio of 1e:2 was 1:2.
      .
      Table thumbnail fx12
      a Unless indicated otherwise, the reaction was carried out in 0.1 ​mmol scale and catalyzed by 10 ​mol% (R)-5 in toluene (4.0 ​mL) with 3 ​Å ​MS (100 ​mg) at 25 ​°C for 24 ​h, and the molar ratio of 1e:2 was 1:2.
      b Isolated yield.
      c The dr value was determined by 1H NMR.
      d The ee value referred to that of the major diastereomer and was determined by HPLC.
      e Catalyzed by 20 ​mol% (R)-5.
      Notably, in all cases of products 3, the two stereocenters in indole C2 and C3 positions are well-controlled because of the formation of two fused five-membered rings, which confined the relative configuration of the indole C2 and C3 positions. So, the diastereomeric ratio (dr) between two numbers indicates the ratio between allene stereocenter versus the indole stereocenters.
      This class of hexahydropyrrolo[2,3-b]indole-containing tetrasubstituted allene products 3 has both axial chirality and central chirality, which represents a class of unique structures with multiple chiral elements. As show in Scheme 3 below, the absolute configuration of hexahydropyrrolo[2,3-b]indole-containing tetrasubstituted allene product 3ea was unambiguously determined to be (Sa,S,R) based on the X-ray diffraction analysis of its single crystal (CCDC 2130810). So, the absolute configurations of other products 3 were assigned by analogy with 3ea.
      In order to gain some insights into the activation mode of catalyst (R)-5 to the substrates, we performed some control experiments (Scheme 2). Firstly, p-hydroxylphenyl propargylic alcohol 7, a precursor of alkynyl para-quinone methide (p-QM) intermediate, was engaged in the reaction under the standard conditions (Scheme 2a), which could generate allene product 8 bearing multiple chiral elements in a high yield of 87% albeit with low diastereo- and enantioselectivity. This result indicated that p-QM intermediate was inferior to aza-p-QM intermediate in this cascade reaction in terms of controlling the stereoselectivity. Secondly, when N-methyl-substituted tryptamine 2n was utilized as a substrate for this reaction under the standard conditions, the desired product 3en was not detected (Scheme 2b). So, this result indicated that the N–H group of tryptamines 2 played a crucial role in controlling the reactivity of the designed cascade reaction possible via forming hydrogen bond with catalyst (R)-5.
      Scheme 3
      Scheme 3Suggested reaction pathway and activation mode.
      Based on the experimental results, we suggested a possible reaction pathway and activation mode of this catalytic asymmetric cascade reaction (Scheme 3). As exemplified by the formation of product 3ea, under the catalysis of CPA (R)-5, the dehydration of para-aminophenyl propargylic alcohol 1e led to the formation of alkynyl aza-para-QM intermediate A. Then, (R)-5 activated both the intermediate A and tryptamine 2 via forming two hydrogen bonds, thus facilitating an enantioselective 1,8-addition/CADA reaction between them to generate tetrasubstituted allene intermediate B. Subsequently, still facilitated by (R)-5, the intermediate B underwent a stereoselective intramolecular cyclization process to afford hexahydropyrrolo[2,3-b]indole-containing tetrasubstituted allene 3ea bearing both axial and central chirality with the observed (Sa,S,R)-configuration.
      To demonstrate the utility of this catalytic asymmetric cascade reaction for the synthesis of hexahydropyrrolo[2,3-b]indole-containing tetrasubstituted allenes bearing multiple chiral elements, a one-mmol-scale reaction of propargylic alcohol 1e with tryptamine 2a was carried out under the standard conditions (Scheme 4a). Compared with the small-scale reaction (Table 2, entry 2), this one-mmol-scale reaction afforded tetrasubstituted allene product 3ea in a maintained high yield of 92% with a retained excellent stereoselectivity of 95:5 dr and 94% ee, which indicated that this reaction could be scaled up. In addition, a preliminary derivation of product 3ec was performed via a Suzuki coupling with 4-methoxyphenylboronic acid (Scheme 4b), which generated product 9 in a high yield of 87% with retained diastereo- and enantioselectivity (87:13 dr, 91% ee).
      Scheme 4
      Scheme 4One-mmol-scale reaction and derivation of product 3ec.
      Finally, to discover the possible bioactivity of this class of chiral hexahydropyrrolo[2,3-b]indole-containing tetrasubstituted allenes, some selected products 3 were subjected to the evaluation on their cytotoxicity toward human pancreatic cancer cell line (QGP-1) in vitro. As summarized in Table 4, the cytotoxicity of these chiral allenes 3 was tested in five concentrations ranging from 7.82 ​μg/mL to 250 ​μg/mL. On the basis of the viability rate of QGP-1 cancel cells at the five concentrations, the IC50 values of these products 3 were calculated. This preliminary evaluation indicated that these compounds 3 could inhibit the growth of the QGP-1 ​cells to some extent, which might find their potential applications in medicinal chemistry.
      Table 4Cytotoxicity of selected products 3 on QGP-1 cancer cell line.
      Table thumbnail fx13
      a The IC50 value corresponded to the compound concentration causing 50% mortality in cancer cells.

      3. Conclusion

      In summary, we have established the organocatalytic asymmetric synthesis of bioactive hexahydropyrrolo[2,3-b]indole-containing tetrasubstituted allenes bearing multiple chiral elements via a cascade 1,8-addition/CADA-cyclization reaction of para-aminophenyl propargylic alcohols with tryptamines in the presence of chiral phosphoric acid. By this approach, a wide range of such tetrasubstituted allenes bearing both axial chirality and central chirality were synthesized in generally good yields (up to 94%) with high diastereo- and enantioselectivities (up to 95:5 dr, 95% ee). In addition, the evaluation on the cytotoxicity of some selected products indicated that this class of chiral tetrasubstituted allenes could inhibit the growth of pancreatic cancer cells to some extent, which might find their potential applications in medicinal chemistry. This work not only solved the challenging issues in enantioselective construction of tetrasubstituted allenes via alkynyl (aza)-p-QMs, but also represents the first example of using alkyne derivatives as electrophiles in organo-CADA reactions of tryptamines.

      Declaration of competing interest

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

      Acknowledgements

      We are grateful for financial support from the National Natural Science Foundation of China (22125104 and 21831007), Natural Science Foundation of Jiangsu Province (BK20210916), High Education Natural Science Foundation of Jiangsu Province (No. 21KJB150009), and Natural Science Foundation of JSNU (No. 19XSRX013).

      Appendix A. Supplementary data

      The following is the Supplementary data to this article:

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        Nat. Prod. Rep. 2019; 36: 1589-1605https://doi.org/10.1039/C8NP00098K
      76. c)
        • Xia Z.-L.
        • Xu-Xu Q.-F.
        • Zheng C.
        • You S.-L.
        Chiral phosphoric acid-catalyzed asymmetric dearomatization reactions.
        Chem. Soc. Rev. 2020; 49: 286-300https://doi.org/10.1039/C8CS00436F
      77. d)
        • An J.
        • Bandini M.
        Recent advances in the catalytic dearomatization of naphthols.
        Eur. J. Org Chem. 2020; 2020: 4087-4097https://doi.org/10.1002/ejoc.202000107
      78. e)
        • Sheng F.-T.
        • Wang J.-Y.
        • Tan W.
        • Zhang Y.-C.
        • Shi F.
        Progresses in organocatalytic asymmetric dearomatization reactions of indole derivatives.
        Org. Chem. Front. 2020; 7: 3967-3998https://doi.org/10.1039/D0QO01124J
      79. f)
        • Zheng C.
        • You S.-L.
        Advances in catalytic asymmetric dearomatization.
        ACS Cent. Sci. 2021; 7: 432-444https://doi.org/10.1021/acscentsci.0c01651
      80. (For some recent examples:)

      81. a)
        • Wang H.
        • Zhang J.
        • Tu Y.
        • Zhang J.
        Phosphine-catalyzed enantioselective dearomative [3 + 2]-cycloaddition of 3-nitroindoles and 2-nitrobenzofurans.
        Angew. Chem. Int. Ed. 2019; 58: 5422-5426https://doi.org/10.1002/anie.201900036
      82. b)
        • Li K.
        • Gonçalves T.P.
        • Huang K.-W.
        • Lu Y.
        Dearomatization of 3-nitroindoles via a phosphine-catalyzed enantioselective [3 + 2] annulation reaction.
        Angew. Chem. Int. Ed. 2019; 58: 5427-5431https://doi.org/10.1002/anie.201900248
      83. c)
        • Mei G.-J.
        • Tang X.
        • Tasdan Y.
        • Lu Y.
        Enantioselective dearomatization of indoles via an azoalkene enabled [3 + 2] reaction: facile access to pyrroloindolines.
        Angew. Chem. Int. Ed. 2020; 59: 648-652https://doi.org/10.1002/anie.201911686
      84. d)
        • Wang Y.
        • Zhang W.-Y.
        • Xie J.-H.
        • Yu Z.-L.
        • Tian J.-H.
        • Zheng C.
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        • You S.-L.
        Enantioselective desymmetrization of bisphenol derivatives via Ir-catalyzed allylic dearomatization.
        J. Am. Chem. Soc. 2020; 142: 19354-19359https://doi.org/10.1021/jacs.0c09638
      85. e)
        • Zhang Y.-Q.
        • Chen Y.-B.
        • Liu J.-R.
        • Wu S.-Q.
        • Fan X.-Y.
        • Zhang Z.-X.
        • Hong X.
        • Ye L.-W.
        Asymmetric dearomatization catalysed by chiral Brønsted acids via activation of ynamides.
        Nat. Chem. 2021; 13: 1093-1100https://doi.org/10.1038/s41557-021-00778-z
        • Austin J.F.
        • Kim S.-G.
        • Sinz C.J.
        • Xiao W.-J.
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        Enantioselective organocatalytic construction of pyrroloindolines by a cascade addition–cyclization strategy: synthesis of (–)-flustramine B.
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      86. (For examples using vinyl ketones as electrophiles):

      87. (a)
        • Cai Q.
        • Liu C.
        • Liang X.-W.
        • You S.-L.
        Enantioselective construction of pyrroloindolines via chiral phosphoric acid catalyzed cascade michael addition–cyclization of tryptamines.
        Org. Lett. 2012; 14: 4588-4590https://doi.org/10.1021/ol302043s
      88. b)
        • Duan D.-H.
        • Yin Q.
        • Wang S.-G.
        • Gu Q.
        • You S.-L.
        Chiral phosphoric acid-catalyzed asymmetric cascade reaction of C(3) substituted indoles and methyl vinyl ketone.
        Acta Chim. Sin. 2014; 72: 1001-1004https://doi.org/10.6023/A14060497
      89. (For examples using halogen precursors as electrophiles):

      90. a)
        • Xie W.
        • Jiang G.
        • Liu H.
        • Hu J.
        • Pan X.
        • Zhang H.
        • Wan X.
        • Lai Y.
        • Ma D.
        Highly enantioselective bromocyclization of tryptamines and its application in the synthesis of (−)-Chimonanthine.
        Angew. Chem. Int. Ed. 2013; 52: 12924-12927https://doi.org/10.1002/anie.201306774
      91. b)
        • Cai Q.
        • Yin Q.
        • You S.-L.
        Chiral-amine-catalyzed asymmetric bromocyclization of tryptamine derivatives.
        Asian J. Org. Chem. 2014; 3: 408-411https://doi.org/10.1002/ajoc.201300146
      92. c)
        • Liang X.-W.
        • Liu C.
        • Zhang W.
        • You S.-L.
        Asymmetric fluorinative dearomatization of tryptamine derivatives.
        Chem. Commun. 2017; 53: 5531-5534https://doi.org/10.1039/C7CC02419C
      93. d)
        • Egami H.
        • Hotta R.
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        • Rouno T.
        • Niwa T.
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        Asymmetric dearomatizing fluoroamidation of indole derivatives with dianionic phase-transfer catalyst.
        Org. Lett. 2020; 22: 5656-5660https://doi.org/10.1021/acs.orglett.0c02026
      94. (For examples using other electrophiles)

      95. a)
        • Zhang Z.
        • Antilla J.C.
        Enantioselective construction of pyrroloindolines catalyzed by chiral phosphoric acids: total synthesis of (−)-DebromoflustramineB.
        Angew. Chem. Int. Ed. 2012; 51 (https ://doi.org/10.1002/anie.201203553): 11778-11782
      96. b)
        • Wei Q.
        • Wang Y.-Y.
        • Du Y.-L.
        • Gong L.-Z.
        Organocatalytic asymmetric selenofunctionalization of tryptamine for the synthesis of hexahydropyrrolo[2,3-b]indole derivatives.
        Beilstein J. Org. Chem. 2013; 9: 1559-1564https://doi.org/10.3762/bjoc.9.177
      97. c)
        • Nelson H.M.
        • Reisberg S.H.
        • Shunatona H.P.
        • Patel J.S.
        • Toste F.D.
        Chiral anion phase transfer of aryldiazonium cations: an enantioselective synthesis of C3-diazenated pyrroloindolines.
        Angew. Chem. Int. Ed. 2014; 53: 5600-5603https://doi.org/10.1002/anie.201310905
      98. d)
        • Li Q.
        • Xia T.
        • Yao L.
        • Deng H.
        • Liao X.
        Enantioselective and diastereoselective azo-coupling/iminium-cyclizations: a unified strategy for the total syntheses of (−)-psychotriasine and (+)-pestalazine B.
        Chem. Sci. 2015; 6: 3599-3605https://doi.org/10.1039/C5SC00338E
      99. e)
        • Gentry E.C.
        • Rono L.J.
        • Hale M.E.
        • Matsuura R.
        • Knowles R.R.
        Enantioselective synthesis of pyrroloindolines via noncovalent stabilization of indole radical cations and applications to the synthesis of alkaloid natural products.
        J. Am. Chem. Soc. 2018; 140: 3394-3402https://doi.org/10.1021/jacs.7b13616
      100. f)
        • Liang K.
        • Tong X.
        • Li T.
        • Shi B.
        • Wang H.
        • Yan P.
        • Xia C.
        Enantioselective radical cyclization of tryptamines by visible light-excited nitroxides.
        J. Org. Chem. 2018; 83: 10948-10958https://doi.org/10.1021/acs.joc.8b01597
      101. g)
        • Cheng Y.-Z.
        • Zhao Q.-R.
        • Zhang X.
        • You S.-L.
        Asymmetric dearomatization of indole derivatives with N-hydroxycarbamates enabled by photoredox catalysis.
        Angew. Chem. Int. Ed. 2019; 58: 18069-18074https://doi.org/10.1002/anie.201911144
      102. (For early examples)

      103. a)
        • Akiyama T.
        • Itoh J.
        • Yokota K.
        • Fuchibe K.
        Enantioselective mannich-type reaction catalyzed by a chiral Brønsted acid.
        Angew. Chem. Int. Ed. 2004; 43: 1566-1568https://doi.org/10.1002/anie.200353240
      104. b)
        • Uraguchi D.
        • Terada M.
        Chiral Brønsted acid-catalyzed direct Mannich reactions via electrophilic activation.
        J. Am. Chem. Soc. 2004; 126: 5356-5357https://doi.org/10.1021/ja0491533
      105. (For some reviews):

      106. a)
        • Akiyama T.
        Stronger brønsted acids.
        Chem. Rev. 2007; 107: 5744-5758https://doi.org/10.1021/cr068374j
      107. b)
        • Terada M.
        Binaphthol-derived phosphoric acid as a versatile catalyst for enantioselective carbon–carbon bond forming reactions.
        Chem. Commun. 2008; 35: 4097-4112https://doi.org/10.1039/B807577H
      108. c)
        • Terada M.
        Chiral phosphoric acids as versatile catalysts for enantioselective transformations.
        Synthesis. 2010; 2010 (https://doi.org/10.1055/s-0029-1218801): 1929-1982
      109. d)
        • Yu J.
        • Shi F.
        • Gong L.-Z.
        Brønsted-acid-catalyzed asymmetric multicomponent reactions for the facile synthesis of highly enantioenriched structurally diverse nitrogenous heterocycles.
        Acc. Chem. Res. 2011; 44: 1156-1171https://doi.org/10.1021/ar2000343
      110. e)
        • Parmar D.
        • Sugiono E.
        • Raja S.
        • Rueping M.
        Complete field guide to asymmetric BINOL-phosphate derived Brønsted acid and metal catalysis: history and classification by mode of activation; Brønsted acidity, hydrogen bonding, ion pairing, and metal phosphates.
        Chem. Rev. 2014; 114: 9047-9153https://doi.org/10.1021/cr5001496
      111. f)
        • Wu H.
        • He Y.-P.
        • Shi F.
        Recent advances in chiral phosphoric acid catalyzed asymmetric reactions for the synthesis of enantiopure indole derivatives.
        Synthesis. 2015; 47: 1990-2016https://doi.org/10.1055/s-0034-1378837
      112. g)
        • Li S.
        • Xiang S.-H.
        • Tan B.
        Chiral phosphoric acid creates promising opportunities for enantioselective photoredox catalysis.
        Chin. J. Chem. 2020; 38: 213-214https://doi.org/10.1002/cjoc.201900472
      113. h)
        • Lin X.
        • Wang L.
        • Han Z.
        • Chen Z.
        Chiral spirocyclic phosphoric acids and their growing applications.
        Chin. J. Chem. 2021; 39: 802-824https://doi.org/10.1002/cjoc.202000446
      114. i)
        • Da B.-C.
        • Xiang S.-H.
        • Li S.
        • Tan B.
        Chiral phosphoric acid catalyzed asymmetric synthesis of axially chiral compounds.
        Chin. J. Chem. 2021; 39: 1787-1796https://doi.org/10.1002/cjoc.202000751
      115. (For highlights:)

      116. (a)
        • Liu L.
        • Zhang J.
        Catalytic asymmetric [4 + 3] cyclizations of 2-indolylmethanols with ortho-quinone methides.
        Chin. J. Org. Chem. 2019; 39 (https://doi.org/10.6023/cjoc201900004): 3308-3309
      117. (b)
        • Tan B.
        Design and catalytic asymmetric construction of axially chiral aryl-alkene-indole frameworks.
        Chin. J. Org. Chem. 2020; 40 (https://doi.org/10.6023/cjoc202000027): 1404-1405
      118. (c)
        • Jiang M.
        • Zhou T.
        • Shi B.
        Construction of a new class of oxindole-based axially chiral styrenes via kinetic resolution.
        Chin. J. Org. Chem. 2020; 40 (https://doi.org/10.6023/cjoc202000083): 4364-4366
      119. (For some recent examples)

      120. a)
        • Ma D.
        • Miao C.-B.
        • Sun J.
        Catalytic enantioselective house–meinwald rearrangement: efficient construction of all-carbon quaternary stereocenters.
        J. Am. Chem. Soc. 2019; 141: 13783-13787
      121. b)
        • Mei G.-J.
        • Zheng W.
        • Gonçalves T.P.
        • Tang X.
        • Huang K.-W.
        • Lu Y.
        Catalytic asymmetric formal [3 + 2] cycloaddition of azoalkenes with 3-vinylindoles: synthesis of 2,3-dihydropyrroles.
        iScience. 2020; 23: 100873-110088https://doi.org/10.1016/j.isci.2020.100873
      122. c)
        • Zhang R.
        • Ge S.
        • Sun J.
        SPHENOL, a new chiral framework for asymmetric synthesis.
        J. Am. Chem. Soc. 2021; 143: 12445-12449https://doi.org/10.1021/jacs.1c05709
      123. d)
        • An Q.-J.
        • Xia W.
        • Ding W.-Y.
        • Liu H.-H.
        • Xiang S.-H.
        • Wang Y.-B.
        • Zhong G.
        • Tan B.
        Nitrosobenzene-enabled chiral phosphoric acid catalyzed enantioselective construction of atropisomeric N-arylbenzimidazoles.
        Angew. Chem. Int. Ed. 2021; 60: 24888-24893https://doi.org/10.1002/anie.202111251
      124. e)
        • Yang J.
        • Zhang J.-W.
        • Bao W.
        • Qiu S.-Q.
        • Li S.
        • Xiang S.-H.
        • Song J.
        • Zhang J.
        • Tan B.
        Chiral phosphoric acid-catalyzed remote control of axial chirality at boron–carbon bond.
        J. Am. Chem. Soc. 2021; 143: 12924-12929https://doi.org/10.1021/jacs.1c05079
      125. f)
        • Mao J.-H.
        • Wang Y.-B.
        • Yang L.
        • Xiang S.-H.
        • Wu Q.-H.
        • Cui Y.
        • Lu Q.
        • Lv J.
        • Li S.
        • Tan B.
        Organocatalyst-controlled site-selective arene C–H functionalization.
        Nat. Chem. 2021; 13: 982-991https://doi.org/10.1038/s41557-021-00750-x