Total Synthesis and Computational Investigations of Sesquiterpene-Tropolones Ameliorate Stereochemical Inconsistencies and Resolve an Ambiguous Biosynthetic Relationship

Abstract

The sesquiterpene-tropolones belong to a distinctive structural class of meroterpene natural products with impressive biological activities, including anticancer, antifungal, antimalarial, and antibacterial. In this article, we describe a concise, modular, and cycloaddition-based approach to a series of sesquiterpene mono-and bistropolones, including (−)-epolone B, (+)-isoepolone B, (±)-dehydroxypycnidione, and (−)-10-epi-pycnidione. Alongside the development of a general strategy to access this unique family of metabolites were computational modeling studies that justified the diastereoselectivity observed during key cycloadditions. Ultimately, these studies prompted stereochemical reassignments of the pycnidione subclass and shed additional light on the biosynthesis of these remarkable natural products.

Convergent biomimetic semisynthesis of disesquiterpenoid rumphellolide J

“…Only few examples to date depict the applicability of β-caryophyllene and β-caryophyllene oxide in gram-scale syntheses of natural products of rare occurrence. 11,12…”

“…Only few examples to date depict the applicability of β-caryophyllene and β-caryophyllene oxide in gramscale syntheses of natural products of rare occurrence. 11,12 Our ongoing research in the field of natural product semisynthesis from β-caryophyllene has resulted in the convergent biomimetic gram-scale synthesis of rumphellolide J (7) 2 by esterification of rumphellaoic acid A (5) 13,14 and 4β,8β-epoxycaryophyllan-5-ol (6) 15,16 (Scheme 1).…”

Understanding and Engineering the Stereoselectivity of Humulene Synthase

“…xenovulene A 1, neosetophomone B 2, pycnidione 3, eupenifeldin 4; Scheme 1 A) possess potent psychoactive, antitumor and antiarthritic properties. [1][2][3][4][5] All TS feature a core 11-membered macrocycle that is derived from the sesquiterpene humulene. [6,7] The biosynthesis of TS proceeds via a core intermolecular hetero Diels-Alder reaction that connects humulene with the polyketidederived tropolone nucleus observed in 1-4 (Electronic Supplementary Information [ESI] Figure S1-S2).…”

Recent Chemical Methodology Advances in the Total Synthesis of Meroterpenoids

“…The Sarlah group's interest in hetero-Diels-Alder reactions and meroterpenoids culminated in biomimetic and modular total syntheses of two naturally occurring tropolones; (-)-epolone B (188) and (±)-dehydroxypycnidione (189) (Scheme 20). 31 Both compounds share a common 11-membered core but differ in the number of attached tropolone moieties. It was envisioned that these two compounds could be prepared through the union of a tropolone-derived ortho-quinone methide and α-humulene (12) (or its 10-hydroxy derivative 193).…”