Asymmetric total syntheses of (+)- and (−)-versicolamide B and biosynthetic implications

Abstract

The Diels-Alder reaction is one of the most well-studied, synthetically useful organic transformations. While a significant number of naturally occurring substances are postulated to arise by biosynthetic Diels-Alder reactions, rigorous confirmation of a mechanistically distinct natural Diels-Alderase enzyme remains elusive. Within this context, several related fungi within the Aspergillus genus produce a number of metabolites of opposite absolute configuration including (+)- or (−)-versicolamide B. These alkaloids are hypothesized to arise via biosynthetic Diels-Alder reactions implying that each Aspergillus species possesses enantiomerically distinct Diels-Alderases. Herein, experimental validation of these biosynthetic proposals via deployment of the IMDA reaction as a key step in the asymmetric total syntheses of (+)- and (−)-versicolamide B is described. Laboratory validation of the proposed biosynthetic Diels-Alder construction, coupled with the secondary metabolite profile of the producing fungi, reveals that each Aspergillus species has evolved enantiomerically distinct indole oxidases, as well as enantiomerically distinct Diels-Alderases.

Structural and stereochemical diversity in prenylated indole alkaloids containing the bicyclo[2.2.2]diazaoctane ring system from marine and terrestrial fungi

“…101,102 Similar to the previous discussion, pinacol rearrangement of reverse prenylated indole 68 allows for formation of a set of spiro -oxindole diastereomers. Upon separation, they can consequently be converted into both enantiomers of versicolamide B via IMDA cycloaddition.…”

“…It should be noted that many laboratories in the synthetic community have published elegant, yet non-biomimetic total syntheses of numerous natural products in this family of alkaloids. 41,46,47,57,58,66,67,85,86,88,90,95,97,99,102,108,115,131–146 These efforts have been reviewed by Miller and Williams in 2009 (ref. 40) and additional total syntheses have appeared in the literature since 2009.…”

Oxidative radical cyclizations of diketopiperazines bearing an amidomalonate unit. Heterointermediate reaction sequences toward the asperparalines and stephacidins

“…A provocative biosynthetic hypothesis involving an oxidative hetero-Diels-Alder cycloaddition, that generates the central diazabicyclo[2.2.2]octane core, was proposed by Porter and Sammes [7]. Based on that, biomimetic synthetic strategies were pursued independently by Williams [8], Liebscher [9], and more recently by Scheerer [10][11][12][13] and others [14,15].…”

Study on the NBS-Induced Rearrangement of 2-tert-Prenyltryptamines

“…A related rearrangement affording 2-oxoindoles with a free 3-tert-prenyl group has been reported by Williams and co-workers, who used oxaziridines for oxidation and achieved the total synthesis of notoamide C 4 and versicolamide B. 5 Williams also showed that the biosynthesis of 3-tert-prenylated tryptophan derivatives can proceed via 2-tert-prenylated precursors, as in the case of the paraherquamides. 6 Since regioselective introduction of tert-prenyl moieties at the indole nucleus is important for the synthesis of many tryptophan-derived natural products, 7 we investigated the scope of the facile NBS-induced oxidative cyclization/rearrangement.…”