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

Abstract

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 Penicillium 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-N-methyltryptamine and tryptophol in place to tryptamine led to the enzymatic synthesis of isocommunesin compounds, which have not been isolated to date.

Convergent and Biomimetic Enantioselective Total Synthesis of (−)-Communesin F

“…23 Significantly, only the desired heptacycle 52 was formed in preference to other constitutional isomers. 15b Methanol was found to be an excellent solvent 38 for this transformation, likely due to its ability to stabilize reactive intermediates as the corresponding O -alkyl-hemiaminals. Although intermediate 52 could be observed by in situ 1 H NMR spectroscopy, 23 this compound did not show sufficient stability for isolation.…”

“…A highly convergent enantioselective total synthesis of (−)-communesin F ( 1 ) with late-stage chemistry that parallels the latest insights 15 and hypotheses concerning the biogenesis of these alkaloids is described. Our expedient synthesis involves the union of fragments (+)- 24 and (+)- 27 to provide complex sulfamide (+)- 50 on gram-scale.…”

“…12,14, While our biosynthetic considerations were purely hypothetical at the outset of this synthesis campaign, Houk, Garg, and Tang have recently disclosed 15 incisive biosynthetic and computational studies that echo the key transformations developed in our synthesis. Herein, we present the shortest enantioselective total chemical synthesis of (−)-communesin F ( 1 ) with late-stage chemistry that fortuitously parallels the latest insights 15b and hypotheses concerning the biogenesis of these alkaloids.…”

“…Consistent with this hypothesis, an enzyme capable of the oxidative coupling of tryptamines and Penicillium fungal alkaloid (−)-aurantioclavine ( 12 ) 17,18 has been identified that leads to the formation of the communesin core or an isomeric heptacycle depending on the tryptamine. 15b We began our studies with the recognition that successful implementation of a biomimetic strategy for the efficient synthesis of these alkaloids requires the directed and stereocontrolled union of two dissimilar fragments followed by selective reorganization of a C3a–C3a′ linked heterodimer to a single constitutional isomer consistent with the communesin skeleton 18 .…”

Oxidative Cyclization in Natural Product Biosynthesis

“…While numerous total syntheses of communesin have been reported, 77–87 the biosynthetic pathway was only recently uncovered from P. expansum and was shown to be highly efficient (Scheme 15). 88,89 The two indole-containing building blocks are tryptamine ( 50 ) derived from decarboxylation of L-tryptophan, and (−)-aurantioclavine ( 53 ) derived from the decarboxylative cyclization of 4-dimethylallyltryptophan. A P450 enzyme (CnsC) was found to be solely responsible in combining the two fragments to generate the core structure 63 , which is one N- methylation step away from the stable communesin K ( 65 ).…”