Practical, efficient, and economical routes to important and biologically relevant natural products have been recognized as major contemporary objectives of synthetic organic chemists. Since their discovery in 2007 by the Buszek laboratories, indole arynes and their various cycloaddition reactions have demonstrated their value in the total synthesis of many diverse and complex natural products including the benzannulated class of indoles such as the trikentrins and herbindoles, and in library development. Significantly, several members of the trikentrin and herbindole family were recently identified as having potent antibiotic activity, while others were found to possess clinically<br/>significant centrally acting analgesic properties for the treatment of neuropathic pain, including trigeminal neuralgia (TN), aka tic douloureux. The Buszek laboratories reported the first practical, multi-gram synthesis of the cytotoxic agents herbindole A, B, and C from a common intermediate via intermolecular 6,7-indole aryne cycloadditon and Pd(0)-catalyzed cross-coupling reactions. In this presentation, further significant refinements in the indole aryne approach toward these natural products are described along with their medicinal properties. The scalable syntheses make use of the now commercially available polyhaloindoles as key starting materials, and notably, no longer rely on<br/>protecting groups or transition metal-catalyzed cross-coupling reactions. The simplified racemic routes have now been adapted for the synthesis of both antipodes of the trikentrins and herbindoles, as well as for the production of diverse libraries for drug discovery inspired by these natural products.

Total synthesis of the trikentrins and herbindoles via indole aryne cycloaddition and cycloaddition/rearrangement methodologies

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