Bioinspired chemical synthesis of monomeric and dimeric stephacidin A congeners

Abstract

Stephacidin A and its congeners are a collection of secondary metabolites that possess intriguing structural motifs. They stem from unusual biosynthetic sequences that lead to the incorporation of a prenyl or reverse-prenyl group into a bicyclo[2.2.2]diazaoctane framework, a chromene unit or the vestige thereof. To complement biosynthetic studies, which normally play a significant role in unveiling the biosynthetic pathways of natural products, here we demonstrate that chemical synthesis can provide important insights into biosynthesis. We identify a short total synthesis of congeners in the reverse-prenylated indole alkaloid family related to stephacidin A by taking advantage of a direct indole C6 halogenation of the related ketopremalbrancheamide. This novel strategic approach has now made possible the syntheses of several natural products, including malbrancheamides B and C, notoamides F, I and R, aspergamide B, and waikialoid A, which is a heterodimer of avrainvillamide and aspergamide B. Our approach to the preparation of these prenylated and reverse-prenylated indole alkaloids is bioinspired, and may also inform the as-yet undetermined biosynthesis of several congeners.

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

“…To date, the only monooxopiperazine-producing fungi that construct the corresponding anti -diastereomeric series are Penicillium purpurogenum G59 (penicimutamides D and E; P. purpurogenum G59 has been mischaracterized and is a Penicillium citrinum ), 15 Penicillium chrysogenum (chrysogenamide A) 29 and Penicillium citrinum F53 (the recently described citrinalin C). 146 In stark contradistinction, the dioxopiperazine families display a broader range of relative and absolute stereochemistry, where a myriad of both syn - and anti -metabolites have been isolated in both enantiomeric forms. Most intriguing from an evolutionary perspective, the enantio-divergence evident in both marine- and terrestrial-producing fungi, provides for a very rich and unique opportunity to study molecular evolution of these organisms.…”

“…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.…”

“…40) and additional total syntheses have appeared in the literature since 2009. 138–146 Complete knowledge of the structural and stereochemical homologies and disparities among these compounds continues to motivate research into the synthesis, chemistry, biochemistry, genetics and biology of natural fungal metabolites. It is anticipated that exciting new chapters of these fascinating natural alkaloids remain to be written.…”

Mimicking of Phase I Metabolism Reactions of Molindone by HLM and Photocatalytic Methods with the Use of UHPLC-MS/MS

“…The synthesis and isolation of metabolites is a distinct issue. Since the conventional approach of obtaining metabolites assumes organic synthesis, some modern techniques such as biosynthesis, enzymatic methods, and electrochemical (EC) synthetic reactions are particularly gaining attention [35][36][37][38][39][40]. In this context, the photocatalytic transformation of drugs in order to further metabolite isolation seems to become a promising tool.…”

Indole anion cycloadditions with methyl coumalate

“…Recent synthetic approaches to polycyclic indoles include the innovative strategies of Stoltz 1 and Sarpong. 2 The Gribble research group and others laid the groundwork for many of these achievements. His innovative studies on nucleophilic and radical additions to indoles and his use of furo [3,4-b]indoles in synthesis have had an impact on the field.…”