Enantioselective synthesis of 3-arylindole atropisomers via organocatalytic indolization of iminoquinones

Abstract

The direct enantioselective construction of axially chiral 3-arylindole frameworks via nucleophilic addition of 2-substituted indoles to iminoquinones has been achieved with high efficiencies under mild chiral phosphoric acid (CPA) catalytic conditions. The utility of this method was demonstrated in successful scale-up syntheses without compromising the product yields and enantioselectivities. The oxidation of products yields axially chiral heteroaryl-p-quinone monoimine, which could be subjected to structural diversification via addition of nucleophiles.

Keywords

Organocatalysis / iminoquinones / axial chirality / 3-arylindoles

References

[1] Bandini M.Catalytic functionalization of indoles in a new dimension.Angew Chem Int Ed Engl2009;48:9608-44

[2] Kochanowska-Karamyan AJ.Marine indole alkaloids: potential new drug leads for the control of depression and anxiety.Chem Rev2010;110:4489-97

[3] Wan Y,Yan C,Tang Z.Indole: a privileged scaffold for the design of anti-cancer agents.Eur J Med Chem2019;183:111691-708

[4] Maehr H.Total syntheses of rivularins D₁ and D₃.J Am Chem Soc1985;107:2943-5

[5] Zhang HH.Organocatalytic atroposelective synthesis of indole derivatives bearing axial chirality: strategies and applications.Acc Chem Res2022;55:2562-80

[6] Anilkumar GN,Selyutin O.I. Novel HCV NS5B polymerase inhibitors: discovery of indole 2-carboxylic acids with C3-heterocycles.Bioorg Med Chem Lett2011;21:5336-41

[7] Luz JG,Condon B.Indole glucocorticoid receptor antagonists active in a model of dyslipidemia act via a unique association with an agonist binding site.J Med Chem2015;58:6607-18

[8] Sharma K,Akhtar MS,Kim SH.3-Naphthylindoles as new promising candidate antioxidant, antibacterial, and antibiofilm agents.Res Chem Intermed2017;43:2387-99

[9] Jiang F,Zhu ZQ,Mei GJ.Application of naphthylindole-derived phosphines as organocatalysts in[4 + 1] cyclizations of o-quinone methides with Morita-Baylis-Hillman carbonates.J Org Chem2018;83:10060-9

[10] Li TZ,Tan W.Catalytic asymmetric construction of axially chiral indole-based frameworks: an emerging area.Chem Eur J2020;26:15779-92

[11] Jiang F,Wu P,Jiao Y.A strategy for synthesizing axially chiral naphthyl-indoles: catalytic asymmetric addition reactions of racemic substrates.Angew Chem Int Ed Engl2019;58:15104-10

[12] Sheng FT,Zhang YZ.Atroposelective synthesis of 3,3’-bisindoles bearing axial and central chirality: using isatin-derived imines as electrophiles.Chin J Chem2020;38:583-9

[13] Chen KW,Wu P.Catalytic asymmetric synthesis of 3,3’-bisindoles bearing single axial chirality.J Org Chem2020;85:10152-66

[14] Qi LW,Zhang J.Organocatalytic asymmetric arylation of indoles enabled by azo groups.Nat Chem2018;10:58-64

[15] Zhu S,Wang YB.Organocatalytic atroposelective construction of axially chiral arylquinones.Nat Commun2019;10:4268-77

[16] Lu DL,Xiang SH,Tan B.Atroposelective construction of arylindoles by chiral phosphoric acid-catalyzed cross-coupling of indoles and quinones.Org Lett2019;21:6000-4

[17] Ding WY,An QJ.DFT-guided phosphoric-acid-catalyzed atroposelective arene functionalization of nitrosonaphthalene.Chem2020;6:2046-59

[18] Chen YH,Zhang X,Li S.Organocatalytic enantioselective synthesis of atropisomeric aryl-.p59:11374-8

[19] Zhang HH,Li C,Li Y.Design and enantioselective construction of axially chiral naphthyl-indole skeletons.Angew Chem Int Ed Engl2017;56:116-21

[20] Bisag GD,Mazzanti A.Central-to-axial chirality conversion approach designed on organocatalytic enantioselective povarov cycloadditions: First access to configurationally stable indole-quinoline atropisomers.Chem Eur J2019;25:15694-701

[21] He XL,Song X,Du W.Asymmetric Barton-Zard reaction to access 3-pyrrole-containing axially chiral skeletons.ACS Catal2019;9:4374-81

[22] Lu S,Yang H.Diastereo- and atroposelective synthesis of bridged biaryls bearing an eight-membered lactone through an organocatalytic cascade.J Am Chem Soc2019;141:17062-7

[23] Zhang X,Tan B.Organocatalytic enantioselective transformations involving quinone derivatives as reaction partners.Tetrahedron Lett2018;59:473-86

[24] Chen YH,Fang F.Organocatalytic atroposelective arylation of 2-naphthylamines as a practical approach to axially chiral biaryl amino alcohols.Angew Chem Int Ed Engl2017;56:16308-12

[25] Cheng JK,Tan B.Organocatalytic enantioselective synthesis of axially chiral molecules: development of strategies and skeletons.Acc Chem Res2022;55:2920-37

[26] Kumarasamy E,Sibi MP.Nonbiaryl and heterobiaryl atropisomers: molecular templates with promise for atropselective chemical transformations.Chem Rev2015;115:11239-300

[27] Cheng JK,Li S,Tan B.Recent advances in catalytic asymmetric construction of atropisomers.Chem Rev2021;121:4805-902