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...