Cyclohepta[b]indoles: A Privileged Structure Motif in Natural Products

Article pubs.acs.org/accounts

Cyclohepta[b]indoles: A Privileged Structure Motif in Natural Products and Drug Design Erik Stempel† and Tanja Gaich*,‡ †

Institut für Organische Chemie, Leibniz Universität Hannover, 30167 Hannover, Germany Lehrstuhl für Organische Chemie, Universität Konstanz, 78457 Konstanz, Germany

‡

CONSPECTUS: Seven-membered rings fused with an indole are termed cyclohepta[b]indoles. Compounds exhibiting this structure motif display a broad spectrum of biological activities, ranging from inhibition of adipocyte fatty-acidbinding protein (A-FABP), deacetylation of histones, inhibition of leukotriene production p53, antituberculosis activities, and anti-HIV activities. These biological profiles are found in natural products containing the cyclohepta[b]indole motif, as well as in pharmaceuticals that contain this structure motif. Therefore, the biology of molecules derived from the skeleton of cyclohepta[b]indoles, as well as cyclopenta- and cyclohexa[b]indoles, has attracted considerable interest from the pharmaceutical industry as potential therapeutics in recent years. This is reflected by more than two dozen patents that have been issued in the past decade, solely based on the cyclohepta[b]indole structure motif. The efficient preparation of highly functionalized and unsymmetrically substituted cyclohepta[b]indoles has therefore become of central interest for synthetic organic chemists. Historically, this structure motif most often has been prepared by means of a Fischer indole synthesis. Although very robust and useful, this reaction poses certain limitations. Especially unsymmetrically functionalized cyclohepta[b]indoles are not suitable for a Fischer indole type synthesis, since product mixtures are inevitable. Therefore, novel methodologies to overcome these synthetic obstacles have been developed in recent years. This Account introduces all natural products and pharmaceutical compounds exhibiting the cyclohepta[b]indole motif. The structural variability within cyclohepta[b]indole alkaloids in combination with the broad range of organisms where these alkaloids have been isolated from, strongly suggests that the cyclohepta[b]indole is somehow a “privileged” structure motif. The organisms producing these compounds range from evergreen trees (actinophyllic acid) to cyanobacteria (ambiguinines). The synthetic methodologies to construct these molecular scaffolds (natural and unnatural in origin) are in turn highlighted and discussed with regard to their potential to access highly functionalized and unsymmetrical cyclohepta[b]indoles, for which they specifically have been designed. The methods are classified with respect to reaction type and whether or not they are enantioselective. Finally, the syntheses of cyclohepta[b]indole natural products are presented, thereby in each case, focusing on the construction of this structure motif in the course of the respective total synthesis. As a conclusion, we end by contrasting the methodological progress in the field with the actual successful application of the newly developed methods to the synthesis of complex structures to pinpoint the urgent requirement for further synthetic development for efficient synthetic design of this “privileged” structure motif.

1. INTRODUCTION The cyclohepta[b]indole structure motif occurs in a variety of natural products as well as in non-natural pharmaceutical compounds. It is associated with a broad spectrum of biological profiles ranging from anti-inflammation and antiaging, to antituberculosis activities (Figure 1). Among the pharmaceutically active compounds based on this structure motif, around two dozen patents have been issued within the past decade. This interest has sparked numerous synthetic efforts to efficiently and elegantly access this structure motif. The methodology development together with the description of both © 2016 American Chemical Society

natural product containing and non-natural compound containing cyclohepta[b]indoles comprises the main part of this Account. In the final section, these methodologies are contrasted with the total syntheses of natural products exhibiting the cyclohepta[b]indole motif, to analyze whether and how far the development of methods for the syntheses of this structure motif has impacted complex molecule synthesis. Received: May 30, 2016 Published: October 6, 2016 2390

DOI: 10.1021/acs.accounts.6b00265 Acc. Chem. Res. 2016, 49, 2390−2402

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Accounts of Chemical Research

Figure 1. Natural products containing the cyclohepta[b]indole motif.

Figure 2. Ambiguines, a large group containing alkaloids with a cyclohepta[b]indole skeleton.

2. NATURAL PRODUCTS The cyclohepta[b]indole is a common core structure motif in indole alkaloids. Probably the most complex natural product is actinophyllic acid (1) which was isolated in 2005 by Carroll and co-workers1 from the leaves of Alstonia actinophylla. It possesses a unique carboskeleton which drew the attention of several synthetic groups, and culminated in two total syntheses by Overman and Martin.2,3 Arcyriacyanin A (2) is a pigment from Arcyria nutans. It is a cytotoxic compound and inhibits protein kinase C and protein tyrosine kinase.4,5 The green-blue bisindolylmaleimide comprises a cyclohepta[b]indole and a cyclohepta[cd]indole at the same time, and has been synthesized by two groups in the late 1990s.6,7 The cis-dihydro modification dihydroarcyriacyanin A (3) has been found in the yellow sporangia of Arcyria nutans8 and recently in the fruiting bodies of Arcyria denudate and Arcyria obvelata.9 The bisindole caulersine (4) was isolated from the alga Caulerpa serrulata which is endemic to marine habitats around Paracel Islands.10 It inhibits the multixenobiotic resistance (MXR) pump in algae and acts as plant growth regulator; several syntheses have been published.11−13 Most recently exotines A (5) and B (6), two heterodimers of isopentenyl-substituted indoles and coumarin derivatives were

isolated from Murraya exotica. For these structures, inhibitory effects on lipopolysaccharide induced nitric oxide production in BV-2 microglial cells has been reported.14 Aristolasol (7) and aristolasene (8), two minor alkaloids from the aerial parts of Aristotelia australasica (Elaeocarpaceae),15 have drawn very little attention from the synthetic community, with only one total synthesis for aristolasene (8).16 The cyclohepta[b]indole skeleton is most common to ambiguines and structurally related hapalindoles.17−22 Of 17 known congeners (ambiguines A−Q), 13 contain the cyclohepta[b]indole motif (ambiguines D−G and ambiguines I−Q; see Figure 2). These scaffolds display a variety of different biological activities.18,21 Although many derivatives of ambiguines with a cyclohepta[b]indole motif have been isolated, no total synthesis of ambiguines has been reported so far. The ervitsine−ervatamine alkaloids comprise another large group of alkaloids with a cyclohepta[b]indole core (Figure 3). Ervatamine (22), a sodium channel blocker,4 is the main alkaloid of the ervatamia alkaloids, which are corynanthean-type 2-acylindole alkaloids, lacking the characteristic tryptamine moiety.23 Compounds 22, 23, and 31 were isolated from Ervatamia orientalis and Ervatamia lif uana (Apocynaceae),24,25 19,20-didehydro-N1-methoxyervatamine (32) from Ervatamia malaccensis (Apocynaceae),26 19,20-didehydro-5-oxoervatamine 2391


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Figure 3. Ervitsine−ervatamine alkaloids.

Figure 4. Non-natural products with a cyclohepta[b]indole.

(33) originates from leaves of Tabernaemontana corymbosa (Apocynaceae),27 and 19,20-didehydro-6α-hydroxyervatamine (34) and dehydroxyervataminol (41) are alkaloids from Ervatamia divaricate.28 Decarboxylation of the ester at C-16 leads to the methuenine−silicine alkaloids. Methuenine (35) is an anticholinergic agent.26,29−32 and has closely related siblings such as its 16-epimer (36),26,31,33,34 its N-oxide (37),31 its 16-epimer-N-oxide (38),33 the 6-oxo derivative (39),26,29,31 and the N1-methoxy derivative (40).26 Silicine (24) possesses an ethyl group at C-20 instead of an ethylidene function.30,35−38 Seven further derivatives of 24 have been isolated: 16-episilicine (25),39 20-episilicine (26),29,32 16,20-diepisilicine (27),32 6-oxosilicine (28),29,30,38 6-oxo-16-episilicine (29),30 6-oxo16,20-diepisilicine (30),32 and 6,16-didehydro-20-episilicine (42).32 Ervitsine (43) is a minor alkaloid from the root bark of Pandaca boiteaui (Apocynaceae).40,41 It is the only member

of this alkaloid family which has an additional link between C-5 and the C-7. Total syntheses of several members of the ervitsine−ervatamine alkaloids have been published.42−44 2.1. Non-Natural Products with Biological Activities

Besides their widespread occurrence in natural products, cyclohepta[b]indoles exhibit a broad spectrum of biological activities and have attracted considerable interest from the pharmaceutical industry as potential therapeutics (Figure 4). Several different inhibitors based on the cyclohepta[b]indole motif are known. Indole 44a selectively inhibits (IC50 = 100 nM) leukotriene B4 (LTB4) production which is involved in numerous inflammatory and allergic diseases.45 Compound 44b selectively inhibits adipocyte fatty-acid binding protein (A-FABP, IC50 = 100 μM),46 thus lowering the risk for hypertriglyceridemia, type 2 diabetes, and coronary heart disease. 2392


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Accounts of Chemical Research Scheme 1. Synthesis of Cyclohepta[b]indoles via Ga(III) Mediated [4 + 3] Cycloaddition by Wu and Co-Workersa

a

R = H, Me, Bn. R1 = OMe, CO2Me, halide. R2 = H, alkyl. R3 = alkyl, aryl. R4 = alkyl, (CH2)n.53

Scheme 2. Synthesis of Cyclohepta[b]indoles via One Pot Hydroamination/[4 + 3] Cycloaddition by Li and Co-Workersa

a

R = alkyl, aryl. R1 = H, Me.73

Scheme 3. Synthesis of Cyclohepta[B]indoles via [4 + 3] Cycloaddition−Cyclization−Elimination Sequence by Hsung and CoWorkersa

a

R = CO2Me, halide.74

Scheme 4. Syntheses of Cyclohepta[B]indoles via a formal [4 + 3] Cycloaddition Reaction of Vinyl Fischer Carbenes and Silyloxydienesa

a

(a) Protocol by Tang and co-workers (R = alkyl, aryl).75 (b) Protocol by Iwasawa and co-workers (R = alkyl, aryl).76

HT29 cell lines.50 Indole 47 is a novel opioid ligand with a C-homomorphinan skeleton and shows strong binding affinities for the δ receptor.51

SIRT1-inhibitor IV (44c), a compound heavily investigated, shows outstanding biological activity. It belongs to a new class of histone deacetylase (HDAC) inhibitors and is involved in gene silencing via a new mode of action. Data shows that inhibition of SIRT1 enhances acetylation of p53. Compound 44c is one of the most potent compounds described (IC50 = 63 nM) representing a 500-fold improvement over previously reported inhibitors.47 Enantioselective gram-scale synthesis of (S)-44c has been reported.48 Indole 45 shows excellent activity against Gram positive bacteria and high antituberculosis activity with a minimum inhibitory concentration of 3.12 μg/mL. Similar compounds bearing a pyrazole or pyrimidine instead of the isoxazole display similar activities, with the chlorine at the C-5 position of the indole being crucial for the activity.49 Furthermore, it has been shown that N-substituted 5,6dihydrobenzo-[5,6]cyclohepta[b]indol-6-one derivatives like compound 46 are an interesting class of cytotoxic compounds and show activities against L1210 murine leukemia and

3. METHODOLOGIES FOR CONSTRUCTION OF CYCLOHEPTA[b]INDOLES The use of the Fischer indole synthesis for constructing cyclohepta[b]indoles is very common. Despite being a well established transformation, this reaction possesses certain limitations.52,53 This has triggered the invention of novel methodologies, which mostly involve pericyclic reactions. This section exclusively deals with the construction of this structure motif. Formation of benzocyclohepta[b]indoles,50,54−57 and carbocycle-fused indoles, also suitable for the generation of cyclohepta[b]indoles, are not covered here.58−72 3.1. Via Cycloaddition Reactions

3.1.1. [4 + 3] Cycloaddition. Cyclohepta[b]indole synthesis via [4 + 3] cycloaddition was first published by Wu et al.53 2393


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Accounts of Chemical Research Scheme 5a

a

(a) Formation of vinyl Fischer carbene 72. (b) Proposed mechanisms for the formal [4 + 3] cycloaddition by Tang and co-workers.75

Scheme 6. Proposed Mechanisms for the Formal [4 + 3] Cycloaddition by Iwasawa and Co-Workers76

Scheme 7. Synthesis of Cyclohepta[B]indoles via Dearomative Indole [5 + 2] Cycloaddition Reaction by Li and Co-Workersa

a

R = H, Me, Ts, Bn, allyl. R1 = H, OMe, halide.80

and later in 2014 by Li and co-workers.73 Wu et al. reacted indole 48 with an aldehyde or ketone to form indolyl alcohol 51, which generates corresponding indolyl cation 52 in the presence of a Lewis acid (Scheme 1). It was observed that especially gallium(III) bromide and gallium(III) triflate were

effectively promoting this desired reaction. Once indolyl cation 52 is formed, it reacts with diene 50 in a [4 + 3] cycloaddition furnishing cyclohepta[b]indole 53. The scope of this gallium(III) mediated regio- and diastereoselective three-component [4 + 3] cycloaddition is quite broad and allows the access to 2394


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Scheme 8. Synthesis of Cyclohepta[b]indoles via in Situ Generated Divinylcyclopropyl Fischer Base Derivatives by Sinha and Co-Workersa

a

R = H, halide, CF3. R1 = alkyl, aryl. R2 = alkyl.85

Scheme 9. Pd-Catalyzed Intramolecular Cyclization via Alkyl Migration Process in Indolylboratesa

a

R = H, Me. R1 = H, alkyl.86

Scheme 10. Pd-Catalyzed Synthesis of Cycloalkyl[b]indoles by Widenhoefer and Co-Workers87

cycloadduct 62 in hands, indoline formation is accomplished via intramolecular Grignard reaction using iPrMgCl·LiCl, yielding alcohol 63. Transformation of the alcohol into the corresponding xanthate anion followed by elimination furnishes tetracyclic cyclohepta[b]indoles 64 in good yields. 3.1.2. Formal [4 + 3] Cycloaddition. In 2013, the groups of Tang and Iwasawa independently published an almost identical protocol for the synthesis of cyclohepta[b]indoles using metal-catalyzed intermolecular formal [4 + 3] cycloaddition reaction of vinyl Fischer carbenes with silyloxydienes.75,76 The protocol of Tang uses catalytic amounts of platinum(II) chloride enhancing its reactivity by addition of electrondeficient tris(pentafluorophenyl)phosphine ligand in the presence of sodium carbonate in absolute 1,4-dioxane at 80 °C. Typical reaction times with 5 equiv of silyloxydiene 66 are 12 h (Scheme 4a). In some cases, the metal catalyst has been substituted with [{Rh(CO)2Cl}2] in combination with P[OCH(CF3)2]3 as a ligand. The protocol of Iwasawa is quite similar, but differs in the amount of diene 68 (1.2−2.0 equiv). Furthermore, a slightly different platinum(II) catalyst is used ([PtCl2(C2H4)]2) and addition of 4 Å molecular sieves reduces the reaction time and temperature drastically compared to the

several cyclohepta[b]indoles with different substitution patterns in one step albeit as racemic mixtures. Li et al. synthesized cyclohepta[b]indoles by means of Fischer base derivative 55 and various dienes instead of using an indole (Scheme 2). Fischer base 55 derives from silver(I) catalyzed intramolecular hydroamination reaction of N-Tosyl protected hydroxypropynylaniline 54. The 5-exo-dig ring closure was exclusively promoted by silver(I) triflate. Thereafter cation 56 was formed by ZnCl2 in high yields. The N-Tosyl protection was crucial, since the use of Boc or Bn protecting groups lead to complete recovery of starting material. By adding 5 equiv of a diene (57), cation 56 undergoes [4 + 3] cycloaddition to furnish cyclohepta[b]indole 59. In general, electronrich dienes show better reactivity, and many substituents at the indole are tolerated. In conclusion, racemic cyclohepta[b]indoles are furnished via one pot tandem reaction containing hydroamination/[4 + 3]. Hsung and co-workers developed a different [4 + 3] cycloaddition strategy,74 by starting with N-arylallenamides 60 which are subjected to Murray’s reagent, zinc chloride, and furan. This results in the formation of oxyallyl cation 61, which undergoes [4 + 3] cycloaddition with furan to afford cycloadduct 62 as a single diastereomer (Scheme 3). With 2395


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a

(a) Synthesis of cyclohepta[b]indoles via organo- and gold-based catalysis by Enders and co-workers. (b) Mechanistic explanation for the stereochemical outcome (R = H, Me, OMe. R1 = Ph, 3-tolyl. R2 = H, F).89

Scheme 12. Enantioselective Synthesis of Cyclohepta[b]indoles by Gaich and Co-Workersa

a

R = H, Cl. R1 = alkyl, EWG. R2 = alkyl, EWG. R3 = alkyl, EWG.48

Scheme 13. Organocatalytic Synthesis of Chiral Cyclohepta[b]indoles by Hong and Co-Workersa

a

R = H, OMe, Br. R1 = alkyl. R2 = H, Me, OMe, CN, halide.90

methodology of Tang (1 vs 12 h, room temperature vs 100 °C; see Scheme 4b). Albeit it is a formal [4 + 3] cycloaddition reaction, different reaction mechanisms are proposed by both groups. The Tang group suggests a metal catalyzed 5-endo-dig cyclization followed by elimination of methanol (Scheme 5a)77 for the formation of vinyl Fischer carbene 72 and several potential pathways for the cycloaddition with silyloxydiene 66. Thereby, cyclopropanation can afford Fischer base derivative 73 which undergoes divinylcyclopropane rearrangement to directly furnish cyclohepta[b]indole 67. There is no plausible justification for the divinylcyclopropane intermediate since different regioselectivity for the cyclopropanation had been reported before.78,79 Furthermore, the vinyl Fischer carbene can be attacked by silyl enol ether 74 in a 1,4-manner followed by formation of metallacycle 75. This metallacycle can also be furnished via

concerted [4 + 4] cycloaddition reaction between 72 and silyl enol ether 66. Reductive elimination gives cyclohepta[b]indole 67. It can also be formed via concerted [4 + 3] cycloaddition reaction between 76 and silyloxydiene 66 and concomitant elimination of the metal (Scheme 5b). Iwasawa et al. proposed a different mechanistic pathway due to the observation of the formation of a minor product (Scheme 6). Here too, vinyl Fischer carbene 72 is attacked by silyl enol ether 68 in a 1,4-manner, but ring closure occurs at the β-position of the metal to yield six-membered spiro-cyclic carbene intermediate 79. Formation of 79 is also conceivable via [4 + 2] cycloaddition reaction between carbene 72 and silyloxydiene 68. With electron donation from the nitrogen in mind 1,2-alkyl shift occurs at the carbene moiety forming N-acyliminium ion 81. Regeneration of the metal catalyst furnishes cyclohepta[b]indole 69. When using less electron-deficient 2396


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Widenhoefer and co-workers published a protocol for a palladium(II)-catalyzed tandem cyclization/carboalkoxylation of alkenyl indoles.87 Alkenyl indole 99 forms complex 100 with palladium(II) which undergoes carbopalladation (Scheme 10). This leads to the formation of halo acylpalladium species 102 which is transferred into methyl ester 103 with methanol. Regeneration of the catalyst is effected by copper(II) chloride. The use of palladium(II) catalysts is beneficial due to the reactivity of palladium(II) alkyl complexes toward carbon monoxide. Furthermore, Stoltz and Ferreira had already demonstrated the oxidative cyclization of alkenyl indoles catalyzed by palladium(II).88 This protocol allows an efficient palladium(II)-catalyzed formation of functionalized polycyclic indole derivatives.

phosphine ligands, tetracyclic compound 80 has been observed as byproduct, which is formed via insertion of the carbene intermediate 79 into the C−H bond. In conclusion, a unique method for an indole annulation/ [4 + 3] cycloaddition sequence has been developed independently by the groups of Tang and Iwasawa. In both cases, a highly regioselective formation of achiral cyclohepta[b]indoles via metal-catalyzed reaction of propargylic aniline derivatives and electron-rich dienes is described. 3.1.3. [5 + 2] Cycloaddition. Li and co-workers developed a highly functionalized oxacyclohepta[b]indole synthesis via [5 + 2] cycloaddition reaction.80 Inspired by the work of Wender and Mascarenas,81 γ-pyrone 82 is treated with methyltriflate to form the methoxy pyrylium salt of kojic acid derivative 83 (Scheme 7). When this salt is exposed to anhydrous cesium fluoride, generation of oxidopyrylium ylide 84 occurs and [5 + 2] cycloaddition proceeds smoothly at ambient temperature to give cycloadduct 85. Exclusive production of the endo-cycloaddition product is observed in accordance with DFT calculations. The protocol allows the formation of a variety of indole systems with electronwithdrawing or electron-donating substituents at the indoleN1 or the indole-C5 positions. Electronically mismatched oxidopyrylium ylides are also suitable. In summary, racemic oxacyclohepta[b]indoles are furnished via intramolecular indole [5 + 2] cycloaddition using an oxidopyrylium ylide with exclusive endo selectivity.

3.4. Enantioselective Approaches

The methodologies presented so far furnish inherently racemic products or have not yet been developed in enantioselective manner. A combination of organo- and gold-based catalysis was the first enantioselective method published in 2011 by Enders and co-workers.89 Indoles 104 react with ortho-alkyne substituted nitrostyrenes 105 in an organocatalytic Friedel− Crafts-type reaction catalyzed by thioamide-based organocatalyst 107 to form chiral C-3 substituted indoles. These undergo concomitant gold-catalyzed cyclization yielding cyclohepta[b]indoles 106 (Scheme 11a) with of up to 99% ee. This protocol is limited to the formation of benzocyclohepta[b]indoles, and requires a nitromethyl group at C-12 of the cyclohepta[b]indoles for enantioselectivity. The stereochemical outcome is explained in Scheme 11b. Bifunctional organocatalyst 107 forms hydrogen-bonding interactions with indole 104 and nitroolefin 105. As a result, both reactions partners are preoriented favoring Si-attack of indole 104 to give C-3 substituted indole 108. Concomitant addition of π-acidic [Au(PPh3)]NTf2 activates the alkyne moiety, favoring a second Friedel−Crafts-type 6-endo-dig cyclization to form spirocycle 109. Indolenine−indole rearrangement furnishes cyclohepta[b]indole 106. Gaich and co-workers used the divinylcyclopropane rearrangement for the synthesis of cyclohepta[b]indoles with the indole C2−C3 bond as 2π unit (Scheme 12). Chiral cyclopropyl alcohols 110 are easy accessible via asymmetric Charette cyclopropanation (R1 = H) or via enantioselective carbenoid cyclopropanation using bis(oxazoline) ligands (R1 ≠ H). Oxidation of the alcohol followed by diverse olefination protocols gives divinylcyclopropane 111. The rearrangement proceeds smoothly under with loss of the aromaticity, forming 3alkylideneindoline 112. Rearomatization to the corresponding cyclohepta[b]indole 113 is accomplished under acidic conditions. This domino olefination/divinylcyclopropane rearrangement sequence has been applied in the first enantioselective gram-scale synthesis of (S)-SIRT1-inhibitor IV.48

3.2. Via Sigmatropic Rearrangements

The divinylcyclopropane rearrangement has extensively been used in a number of natural product syntheses.82−84 Therefore, it is not surprising that this variation of the Cope rearrangement has also been applied to syntheses of cyclohepta[b]indoles. The group of Sinha and co-workers developed a protocol using in situ generated Fischer base derivatives as a substrate for this rearrangement.85 Alkynylaniline 86 is transformed into 2,3-disubsituted indole 88 with 4 equiv of 3,4-dichloro-1-butene (87) in the presence of 5 mol % bis(acetonitrile)palladium(II) chloride and propylene oxide (Scheme 8). Treatment with sodium hydroxide leads to decarboxylation followed by intramolecular allylic alkylation in SN2′ manner to give 90. Depending on the rest at the indole C-2 position different pathways are conceivable. If R2 = aryl, then vinylcyclopropane rearrangement takes place and spiroindole 91 is formed. In the case of R2 = alkyl, isomerization occurs forming divinylcyclopropane 92 which undergoes divinylcyclopropane rearrangement to furnish cyclohepta[b]indole 93 directly. This methodology allows simple formation of racemic cyclohepta[b]indoles bearing an alkyl rest at C-6 position. 3.3. Via Palladium-Catalyzed Cyclization

Ishikura and Kato developed a methodology for the synthesis of different cycloalkyl[b]indoles using several known concepts: the indole C-3 nucleophilicity, the 1,2-alkyl migration from boron to carbon, and the Tsuji−Trost allylic alkylation.86 C-2 lithiated indole 94 is added to boron species 95 forming indolylborate 96 which is treated with a palladium(0) species. This leads to π-allyl cation 97 which is attacked by the indole core forming cycloalkyl[b]indoles 98 after reductive elimination and oxidative workup whereupon rearomatization takes place (Scheme 9). In summary, this protocol describes the one-pot intramolecular cyclization for cycloalkyl[b]indoles via an intramolecular alkyl migration reaction using indolylborates.

Scheme 14. Synthesis of (+)-Aristolasene16

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a

(a) En route to caulersine.11 (b) Synthesis of caulersine.13

Scheme 16. Synthesis of N-Methylarcyriacyanin A6

Scheme 17a

a (a) Key step in the synthesis of actinophyllic acid.2 (b) Key step in the synthesis of actinophyllic acid.3 (c) Key step in the synthesis of actinophyllic acid.91

4. SYNTHESES OF NATURAL PRODUCTS

Hong et al. developed an organocatalytic synthesis of cyclohepta[b]indoles.90 α,β-unsaturated aldehyde 115 is activated by conversion into the corresponding Schiff base with L-proline derivative 119 and is attacked in an 1,4-manner by indolylalkyl malononitrile 114 from the Re-face (Scheme 13). The Si-face is shielded efficiently by the catalyst, yielding 116 with 90% ee. Subsequent reaction of 117 with Brønstedt-acid (20 mol % (+)-CSA) gave an iminium-ion which underwent Pictet−Spengler type cyclization to afford cyclohepta[b]indoles 118 in moderate yields (ca. 60%) and diastereoselectivity (ca. 70:30 syn/anti). In summary, this one-pot strategy affords enantioenriched cyclohepta[b]indoles via tandem organocatalytic Michael addition/Pictet−Spengler reation.

Total syntheses of actinophyllic acid (1), arcyriacyanin A (2) caulersine (4), aristolasene (8), and ervitsine−ervatamine alkaloids 22 and 43 have been published up to date. Notably, none of them applies the synthetic methodologies for cyclohepta[b]indole construction discussed above. By contrast, the cyclohepta[b]indole construction involves well established methodology such as Friedel−Crafts-type reaction for aristolasene (8, Scheme 14),16 addition/elimination or simple condensation for caulersine (4, Scheme 15),11,13 and a domino Heck strategy for N-methylarcyriacyanin A (126, Scheme 16).6 This is also true for actinophyllic acid (1), ervitsine (43), and ervatamine (22), of which the key steps are all tandem 2398


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a

(a) Key step in the synthesis of (±)-ervitsine.44 (b) Key step in the synthesis of (±)-ervatamine.44.

Author Contributions

cyclizations and depicted in Schemes 17a,b and 18. For the synthesis of (±)-1, the Overman group used the tandem azaClaisen/aldol strategy,2 whereas Martin and co-workers applied Mukaiyama type chemistry to construct the cyclohepta[b]indole core.3 In the most recent synthesis the Kwon group constructed the cyclohepta[b]indole core of (−)-1 via SmI2mediated intramolecular pinacol coupling between ketone and lactone subunits (Scheme 17c).91 Bosch et al. synthesized both ervatamine (22) and ervitsine (43). Their tandem cyclization involves 1,4-addition of 139 to pyridinium salt 140 to give 141 followed by aza-Mannich reaction with Eschenmoser’s reagent and final Pictet-Spengler reaction to yield 142. The synthesis of ervatamine contains an aza-Mannich reaction followed by quaternarization of the amine and alkylation of the indole as cyclization step (Scheme 18).44

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. Funding

Funding was granted by the Alexander von Humboldt Foundation by a Sofja Kovalevskaja prize. Notes

The authors declare no competing financial interest. Biographies Tanja Gaich studied Chemistry at the University of Vienna (Austria). She received her Ph.D. in Chemistry from the University of Vienna under the supervision of Prof. Dr. J. Mulzer in 2009, and afterward went to Prof. Dr. P. S. Baran as a postdoctoral fellow. In 2010, she moved to the Leibniz University Hannover to start her independent career under the mentorship of Prof. Dr. M. Kalesse. Since July 2015 she is a full professor of Organic Chemistry at the University of Konstanz.

5. CONCLUSION By far the biggest progress in methodology development has been made within the past decade. This coincides with the enhanced attention of pharmaceutical industry toward compounds exhibiting the cyclohepta[b]indole motif. However, up to date methods for enantioselective construction of cyclohepta[b]indoles are very scarce. Among the completed six total syntheses containing this structure motif, three (ervatamine, ervitsine, and N-methylarcyriacyanin A; Schemes 16 and 18) date back to 1997. The total syntheses of actinophyllic acid (Scheme 17) have been accomplished very recently. Analysis especially of the most recent syntheses reveals that the methodology development of the past decade has so far not found its way into application in complex molecule synthesis. This is a very promising perspective, since further advancement can therefore be expected with regard to an efficient access to these compounds. Evermore, this shows the urgent demand for the development of synthetic methodologies involving the construction of cyclohepta[b]indoles, explicitly when it comes to the development of methods for enantioselective construction of this privileged structure motif.

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Erik Stempel studied chemistry at University of Hannover and Cambridge, UK and received his Master’s degree from the University of Hannover. He is currently a Ph.D. student under the supervision of Prof. Tanja Gaich at University of Hannover (2013 to present), where his research focuses on total syntheses of indole alkaloids.

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*Mailing address: Department of Chemistry, University of Konstanz, Universitaetsstrasse 10, 78464 Konstanz, Germany. Phone: (049) 7531 88-3334. E-mail: [email protected]. 2399


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Cyclohepta[b]indoles: A Privileged Structure Motif in Natural Products

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