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Enantioselective Catalytic Synthesis of N-Alkylated Indoles

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Enantioselective Catalytic Synthesis of N-Alkylated Indoles S S symmetry Review EnantioselectiveReview Catalytic Synthesis ofEnantioselectiveN-alkylated Indoles Catalytic Synthesis of DmitriN-alkylated Trubitsõn and Indoles Tõnis Kanger * DepartmentDmitri Trubitsõn of Chemistry and Tõnis and Biotechnology, Kanger * School of Science, Tallinn University of Technology, Akadeemia tee 15, 12618 Tallinn, Estonia; [email protected] * Correspondence:Department of Chemistry [email protected]; and Biotechnology, Tel.: School+372-620-4371 of Science, Tallinn University of Technology, Akadeemia tee 15, 12618 Tallinn, Estonia; [email protected] Received:* Correspondence: 25 June 2020; [email protected]; Accepted: 14 July 2020; Tel.: Published: +372-620-4371 17 July 2020 Received: 25 June 2020; Accepted: 14 July 2020; Published: date Abstract: During the past two decades, the interest in new methodologies for the synthesis of chiralAbstract:N-functionalized During the past indoles two decades, has grown the interest rapidly. in The new review methodologies illustrates for ethefficient synthesis applications of chiral of organocatalyticN-functionalized and indoles organometallic has grown strategies rapidly. for The the review construction illustrates of chiral efficientα-N -branchedapplications indoles. of Bothorganocatalytic the direct functionalization and organometallic of strate the indolegies for core the construction and indirect of methods chiral α- basedN-branched on asymmetric indoles. N-alkylationBoth the direct of indolines, functionalization isatins and of the 4,7-dihydroindoles indole core and indirect are discussed. methods based on asymmetric N- alkylation of indolines, isatins and 4,7-dihydroindoles are discussed. Keywords: indole; asymmetric synthesis; organocatalysis; transition-metal catalysis; C-N bond formation;Keywords: enantioselective; indole; asymmetric heterocycles synthesis; organocatalysis; transition-metal catalysis; C-N bond formation; enantioselective; heterocycles 1. Introduction 1. Introduction Heterocyclic compounds are of great interest in medicinal chemistry. According to the U.S. Food Heterocyclic compounds are of great interest in medicinal chemistry. According to the U.S. Food and Drug Administration database, approximately 60% of unique small-molecule drugs contain a and Drug Administration database, approximately 60% of unique small-molecule drugs contain a nitrogen heterocyclic motif [1]. The indole core is the most common nitrogen-based heterocyclic nitrogen heterocyclic motif [1]. The indole core is the most common nitrogen-based heterocyclic fragment applied for the synthesis of pharmaceutical compounds and agrochemicals [2]. The indole fragment applied for the synthesis of pharmaceutical compounds and agrochemicals [2]. The indole moietymoiety can can be foundbe found in ain wide a wide range range of natural of natural products products [3]. Therefore,[3]. Therefore, some some biologically biologically active active indoles containindoles a substitutedcontain a substitutedα-chiral carbonα-chiral center carbon on center the N on1-position the N1-position (Figure (Figure1)[4–7]. 1) [4–7]. H H N O N O O NH Cl H N 2 Cl N N N N N N Cl N O O OH OH HO O O O O HO OH O O OH N O O HO Vincamine Staurospporine K-252a α-Neosidomycin β-Ribofuranosyl indole (peripheral vasodilator) (kinase inhibitor) (kinase inhibitor) (antibacterial) (antiviral) MeO HO Me N HO O N N NHMe Me Me OH N N O O N EtO2SN F MeHN CPI-169 (+)-WIN 55,212-2 Human norepinephrine Serotonin (EZH2 inhibitor) (cannabinoid agonist) reuptake inhibitor reuptake inhibitor FigureFigure 1. 1. BiologicallyBiologically active active chiral α--NN-branched-branched indoles. indoles. Symmetry 2020, 12, x; doi: FOR PEER REVIEW www.mdpi.com/journal/symmetry Symmetry 2020, 12, 1184; doi:10.3390/sym12071184 www.mdpi.com/journal/symmetry Symmetry 2020, 12, 1184 2 of 30 SymmetrySymmetry 2020 2020, ,12 12, ,x x FOR FOR PEER PEER REVIEW REVIEW 22 of of 29 29 TheThe synthesis synthesis of ofof enantioenriched enantioenriched indole indole derivatives derivatives isis ofof greatgreat importanceimportance inin organicorganic organic chemistry.chemistry. chemistry. DuringDuring the the past past two two decades, decades, different didifferentfferent strategies strategies ha havehaveve been been proposed proposed for for the the constructionconstruction of of chiral chiral indoleindoleindole derivatives derivativesderivatives [8–11]. [[8–11].8–11]. TheThe most most typical typical synthetic synthetic modifications modificationsmodifications of of indoles indoles take take place placeplace at atat the thethe C3 C3 positionposition (Scheme(Scheme 1 1).1).). TheTheThe enantioselectiveenantioselectiveenantioselective electrophilicelectrophilielectrophilicc substitutionsubstitutionsubstitution atatat C3C3C3 is isis common commoncommon due duedue to toto the thethe high highhigh 13 nucleophilicitynucleophilicity ofof thisthis position,position, whichwhich isis 10101313 timestimestimes more moremore reactive reactivereactive than than benzene benzene [12,13].[[12,13].12,13]. In InIn contrast contrastcontrast to to enantioselectiveenantioselective C3C3 transfortransformations,transformations,mations, thethe stereoselectivestereoselective NN-alkylation-alkylation ofof indole indole is is still stillstill a aa challenge challengechallenge due duedue tototo the the weak weak nucleophilicity nucleophilicity of of the the nitrogen nitrogen atomatom (Scheme(Scheme 1 1).1).). Despite DespiteDespite this, this,this, a aa number numbernumber of ofof publications publicationspublications havehave been been published published recently recently that that demonstr demonstratedemonstrateate new new synthetic synthetic routes routes affordingaaffordingffording chiralchiral NN-substituted-substituted indoleindoleindole derivatives. derivatives.derivatives. In InIn this this review, review, we wewe will willwill introduce introduceintroduce and andand discuss discussdiscuss methodologies methodologiesmethodologies that thatthat provide provideprovide catalytic catalyticcatalytic stereoselectivestereoselective derivatizationderivatization atat thethe NN-atom-atom ofof indole.indole. SchemeScheme 1. 1. Regioselectivity Regioselectivity of of the the asymmetric asymmetric functionalization functionalizationfunctionalization of of indoles. indoles. OnOn a aa structural structural basis, basis,basis, the thethe strategies strategies for forfor the the construction construction of ofof α α---NN-branched-branched-branched indoles indolesindoles can cancan be bebe classified classifiedclassified intointointo two two groups:groups: “direct “direct“direct methods” methods”methods” and andand “indirect “indirect me methods”methods”thods” (Scheme (Scheme 2 2).2).). InInIn thethethe former formerformer case, case,case, indole indoleindole derivativesderivatives are are transformed transformed by by transition-metal transition-metal cata catalysiscatalysislysis or or by byby organocatalysis organocatalysis into intointo chiral chiral compounds compounds (Scheme(Scheme2 2,,2,I ).II).). If IfIf the thethe structure structurestructure of theofof the startingthe startingstarting compound compoucompou doesndnd notdoesdoes contain notnot containcontain an indole anan moiety,indoleindole themoiety,moiety, methods thethe methodsaremethods defined areare as defineddefined indirect asas methods indirectindirect (Scheme methodsmethods2, (SchemeII(Scheme). The indirect2,2, IIII).). TheThe methods indirectindirect are methodsmethods subdivided areare according subdividedsubdivided to accordingtheaccording structure toto thethe of the structurestructure starting ofof compound thethe startingstarting and compcomp theoundound modifications andand thethe modificationsmodifications occurring during occurringoccurring the synthesis duringduring thethe of synthesisαsynthesis-N-branched of of α α--NN indoles-branched-branched (Scheme indoles indoles2, (Scheme (SchemeII). There 2, 2, areIIII).). There severalThere are are ways several several to prepareways ways to to Nprepare prepare-functionalized N N-functionalized-functionalized indoles indolesindirectly.indoles indirectly.indirectly. This review ThisThis covers reviewreview the covers asymmetriccovers thethe asymmetricasymmetricN-alkylation NN of-alkylation-alkylation indolines, isatinsofof indolines,indolines, and 4,7-dihydroindoles, isatinsisatins andand 4,7-4,7- dihydroindoles,followeddihydroindoles, by a redox followed followed reaction, by by a a whichredox redox reaction, providesreaction, which which the corresponding provides provides the the corresponding Ncorresponding-alkylated indoles N N-alkylated-alkylated (Scheme indoles indoles2, III, (SchemeIV(Schemeand V 2,2,respectively). IIIIII,, IVIV andand VV respectively).respectively). SchemeScheme 2. 2. Strategies Strategies for forfor the thethe enantioselective enantioselectiveenantioselective N NN-functionalization-functionalization-functionalization of ofof indoles. indoles.indoles. 2. Direct Organocatalytic Methods 2.2. DirectDirect OrganocatalyticOrganocatalytic MethodsMethods During the past two decades, organocatalysis has become a powerful methodology in DuringDuring thethe pastpast twotwo decades,decades, organocatalyorganocatalysissis hashas becomebecome aa powerfulpowerful methodologymethodology inin enantioselective synthesis [14–17]. In the first part of this review, the direct methods of the stereoselective enantioselectiveenantioselective synthesissynthesis [14–17].[14–17]. InIn thethe firstfirst partpart ofof thisthis
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