P450-Mediated Coupling of Indole Fragments To Forge Communesin and Unnatural Isomers

Abstract

<p class="first" id="P1">Dimeric indole alkaloids are structurally diverse natural products that have attracted significant attention from the synthetic and biosynthetic communities. Here we describe the characterization of a P450 monooxygenase CnsC from <i>Penicillium</i> that catalyzes the heterodimeric coupling between two different indole moieties, tryptamine and aurantioclavine, to construct vicinal quaternary stereocenters and yield the heptacyclic communesin scaffold. We show, using biochemical characterization, substrate analogs, and computational methods, that CnsC not only catalyzes the C3-C3 carbon-carbon bond formation, but also controls the regioselectivities of the pair of subsequent aminal bond formations to yield the communesin core. The use of ω- <i>N</i>-methyltryptamine and tryptophol in place to tryptamine led to the enzymatic synthesis of isocommunesin compounds, which have not been isolated to date. </p><p id="P2"> <div class="figure-container so-text-align-c"> <img alt="" class="figure" src="/document_file/ee207329-e3ad-4735-9bfe-fcf764570134/PubMedCentral/image/nihms793048u1.jpg"/> </div> </p>