Four-Step Access to the Sesquiterpene Natural Product Presilphiperfolan-1β-ol and Unnatural Derivatives via Supramolecular Catalysis

Abstract

Terpenes constitute one of the most structurally varied classes of natural products. A wide range of these structures are produced in nature by type I terpene cyclase enzymes, but such reactivity has proven difficult to reproduce in solution with man-made systems. Herein we report the shortest synthesis of the tricyclic sesquiterpene presilphiperfolan-1β-ol to date, utilizing the supramolecular resorcinarene capsule as catalyst for the key step. This synthetic approach also allows access to unnatural derivatives of the natural product, which would not be accessible through the biosynthetic machinery. Additionally, this study provides useful insight into the biosynthesis of the presilphiperfolanol natural products, including the first direct experimental evidence for the proposed biosynthetic connection between caryophyllene and the presilphiperfolanols.

Supramolecular Catalysis with Self‐Assembled Capsules and Cages: What Happens in Confined Spaces

“…Tiefenbacher and coworkers showed that the capsule C R , in the presence of 2.5 mol % of HCl (Scheme 11), is able to perform such cyclase mimicking, catalysing the cyclization cascade from caryophyllenyl alcohol 33 to (−)‐presilphiperfolan‐1β‐ol 34 . In this way, the postulated biosynthetic connection between caryophyllene and presilphiperfolanols was proved [37] …”

“…The authors highlighted that C R and the acid work in a synergistic fashion, and that the capsule works as an apoenzyme while the protonated capsule C R ‐ H + acts as holoenzyme . Exploiting the cyclase‐mimicking ability of C R , Tiefenbacher and coworkers investigated the biosynthetic connection between caryophyllene and the presilphiperfolanols [37] . This connection was only postulated before and no experimental evidences were previously reported.…”

Molecular Capsule Catalysis: Ready to Address Current Challenges in Synthetic Organic Chemistry?

“…The recent report of the biomimetic synthesis of presilphiperfolan-1β-ol (31, Scheme 3b) represents the first such example. [35] Presilphiperfolan-1β-ol ( 31) is a tricyclic sesquiter-pene that displays antimycobacterial properties; [36] other members of the family act as insect antifeedants. [37] Its complex structure makes it a challenging target for total synthesis: the only previous total synthesis consisted of 13 steps.…”

Frustrated behavior of Lewis/Brønsted pairs inside molecular cages

“…7 Such complex structures have been obtained either by self-assembly or covalent strategies. 8,9 When used as supramolecular catalysts, the nano-confinement of the reactants and/or the catalytic site can lead (i) to an increase in the reaction rate, for instance, by changing the conformation of the substrate or by stabilizing transition states, 10–12 (ii) to an improvement or change in the selectivity by substrate size selectivity, 13 by controlling the second coordination sphere or the folding of the substrate, 14,15 or by masking with a supramolecular shadow some specific reactive sites, 16 and (iii) to protection of the catalytic site, allowing for example the improvement of the stability of the catalyst or sequential catalysis with incompatible systems. 17…”