Concise Total Synthesis of (±)-<i>cis</i>-Trikentrin A and (±)-Herbindole A via Intermolecular Indole Aryne Cycloaddition

Buszek, Keith R.; Brown, Nicholas J. L.; Luo, Diheng

doi:10.1021/ol802425m

Cited by 94 publications

(32 citation statements)

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“…The use of the somewhat more exotic Fu catalyst/ligand combination13 was found to be the best conditions in this case to achieve the optimal yield of the 4-ethylindole. This intermediate is identical in all respects to that synthesized by our first-generation method beginning with 4-ethylaniline,7 and thus constitutes a formal total synthesis of (±)- cis -trikentrin A, as well as the shortest route to this target reported to date.…”

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confidence: 79%

“…We subsequently examined the regioselectivity of indolynes in Diels–Alder reactions with 2-substituted furans 6a. These studies quickly led to the first application of indolynes in the construction of natural products and culminated in a concise synthesis of (±)- cis -trikentrin A 7 and (±)-herbindole A, 9 7. This work clearly validated the utility of indolynes to gain quick access to architecturally challenging structures 8…”

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confidence: 80%

“…Whereas our first-generation synthesis of cis -trikentrin A relied on 4-ethylaniline,7 a potentially far more flexible approach required the preparation of the versatile silyl protected 4,6,7-tribromoindole 18 (Scheme 2). Thus inexpensive o -nitroaniline 14 was brominated [Br 2 (4 equiv), CH 2 Cl 2 /MeOH (2:1), rt, 1 h] in nearly quantitative yield to give 4,6-dibromo-2-nitroaniline 15 .…”

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confidence: 99%

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New synthesis of (±)-cis-trikentrin A via tandem indole aryne cycloaddition/Negishi reaction. Applications to library development

Brown

Luo

Decapo

et al. 2009

Tetrahedron Letters

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We describe herein an efficient new route to the trikentrins and their related structures using a tandem 6,7-indolyne cycloaddition/Negishi cross-coupling reaction starting from a 4,6,7-tribromoindole (obtained in good yield via the Bartoli indole synthesis). The key step of this second generation route to the trikentrins is based on our observation that the 7-bromo substituent appears to undergo selective metal-halogen exchange and elimination to give the 6,7-indolyne, which is trapped in the presence of excess cyclopentadiene. Subsequent Negishi cross-coupling at the 4-bromoindole position with Et 2 Zn gave directly the same intermediate obtained from our previous work. Application of this chemistry to the construction of trikentrin-related libraries using this general cycloaddition/crosscoupling tactic will also be described.Arynes derived from all three benzenoid positions of the ubiquitous indole nucleus (indolynes 1-3, Fig. 1) represent potentially attractive and powerful new tools for the total synthesis of complex alkaloid natural products such as the trikentrins, 1 herbindoles, 1a,c teleocidins, 2 cytoblastin, 3 and lyngbyatoxin 4 (Fig. 2). Our group recently discovered the first successful and general route to these intermediates via metal-halogen exchange of o-dihalides 5 and later, via fluoride-induced decomposition of o-silyltriflates.6 We subsequently examined the regioselectivity of indolynes in Diels-Alder reactions with 2-substituted furans. 6a These studies quickly led to the first application of indolynes in the construction of natural products and culminated in a concise synthesis of (±)-cis-trikentrin A 7 and (±)-herbindole A, 9. 7 This work clearly validated the utility of indolynes to gain quick access to architecturally challenging structures. 8 We now describe an efficient and flexible new route to the trikentrins using a novel tandem intermolecular 6,7-indolyne cycloaddition/Negishi cross-coupling reaction starting from a versatile 4,6,7-tribromoindole, which itself was obtained via the Bartoli indole synthesis. 9 Application of this general cycloaddition/cross-coupling tactic to the construction of novel small-molecule libraries will also be introduced. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptWe were intrigued by the idea of using a potentially new scaffold, namely, a 4,6,7-tribromoindole 11 for the synthesis of the antibacterial cis-trikentrin A as well as libraries derived from it (Scheme 1).Based on our earlier work with the various reaction manifolds of 6,7-indolynes, 6a it occurred to us that it might be possible to generate selectively the 6,7-indolyne as described previously 5,6a without simultaneously inducing metal-halogen exchange at the 4-bromo position. In this manner indolyne cycloaddition would be followed by further elaboration of the scaffold at the 4-bromo position of 12 by any of the several metal-mediated coupling strategies (e.g., Buchwald-Hartwig, Heck, Negishi, Sonogashira, Stille, and Suzuki). We are now pleased to rep...

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confidence: 80%

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confidence: 99%

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New synthesis of (±)-cis-trikentrin A via tandem indole aryne cycloaddition/Negishi reaction. Applications to library development

Brown

Luo

Decapo

et al. 2009

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“…101 The two reactions have similar yields (21% overall from 31 to 36 with respect to 23% overall from 35 to 36).…”

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confidence: 90%

Applications of Bartoli indole synthesis

2014

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In 1989, the reaction of vinyl magnesium halides with ortho-substituted nitroarenes leading to indoles was discovered. This reaction is now frequently reported as the "Bartoli reaction" or the "Bartoli indole synthesis" (BIS). It has rapidly become the shortest and most flexible route to 7-substituted indoles, because the classical indole syntheses generally fail in their preparation. The flexibility of the Bartoli reaction is great as it can be extended to heteroaromatic nitro derivatives and can be run on solid support. This review will focus on the use of the Bartoli indole synthesis as the key step in preparations of complex indoles, which appeared in the literature in the last few years.

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“…5a These studies quickly led to the first application of indolynes in the construction of natural products and culminated in a concise and efficient total synthesis of (±)- cis -trikentrin A and the (±)-herbindoles A and B. 6 This work and recently that of Garg clearly validated the utility of indolynes to gain quick access to architecturally challenging structures. 7 …”

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Experimental and Theoretical Investigations into the Unusual Regioselectivity of 4,5-, 5,6-, and 6,7-Indole Aryne Cycloadditions

et al. 2009

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The 6,7-indolyne shows remarkable regioselectivity in its cycloaddition with 2-substituted furans. Electron-donating groups give predominantly the more sterically crowded product, while electron-withdrawing groups display the opposite regioselectivity. By contrast, 4,5- and 5,6-indolynes show no regioselectivity. Optimized electronic structure calculations using the M06-2X density functional and 6-311+G(2df,p) basis set revealed that the 6,7-indolynes are highly polar structures and that their cycloadditions have substantial electrophilic substitution character that leads to the observed preference for contrasteric products.

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Concise Total Synthesis of (±)-cis-Trikentrin A and (±)-Herbindole A via Intermolecular Indole Aryne Cycloaddition

Cited by 94 publications

References 30 publications

New synthesis of (±)-cis-trikentrin A via tandem indole aryne cycloaddition/Negishi reaction. Applications to library development

New synthesis of (±)-cis-trikentrin A via tandem indole aryne cycloaddition/Negishi reaction. Applications to library development

Applications of Bartoli indole synthesis

Experimental and Theoretical Investigations into the Unusual Regioselectivity of 4,5-, 5,6-, and 6,7-Indole Aryne Cycloadditions

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