Abstract
A 5-8-5 carbocyclic ring system forms the core of over 30 distinct natural products. Several members of this family have gained attention for their diverse activity in cell culture. In these cases, biological function is mediated by the arrangement of substituents around a conserved 5-8-5 nucleus. Despite the potential applications of this privileged substructure in medicinal chemistry, modular strategies for its assembly are underdeveloped. Herein, we describe a cycloisomerization reaction that forms the 5-8-5 framework directly. This strategy uniquely allows access to gram quantities of this valuable scaffold in four steps.
Highlights
The dicyclopenta[a,d]cyclooctene (5–8–5) ring system is central to over 30 di- and sesterterpene natural products.[1]. This molecular framework is produced by an array of plants and microorganisms,[2] and several members of this terpene family possess activity in human cell culture (Scheme 1)
We considered ring system 3 and the possibility of preparing this motif in one step from more readily accessible isomer 4
This study describes a modular strategy for the synthesis of 5–8–5 scaffolds
Summary
The dicyclopenta[a,d]cyclooctene (5–8–5) ring system is central to over 30 di- and sesterterpene natural products.[1]. Fusicoccin A (1) functions as an orthosteric stabilizer of 14–3–3 protein–protein interactions (PPIs).[3,4] ophiobolin A is a potent cytotoxin that modulates calmodulin activity,[5] and cyclooctatin inhibits lysophospholipases.[6,7] Intriguingly, the avidity of these natural products for their disparate biological targets is tightly linked to both the identity and arrangement of peripheral groups surrounding a common 5–8–5 core (i.e. 2) Taken together, these observations indicate that substructure 2 is a privileged scaffold capable of serving as a ligand for a diverse group of receptors.[8]. With an eye toward exploiting the potential pharmacology of substructure 2, we set out to develop a route to this molecular architecture that would facilitate straightforward diversi cation of functional groups surrounding the 5–8–5 nucleus Along these lines, we considered ring system 3 and the possibility of preparing this motif in one step from more readily accessible isomer 4. We report the development of this photoinduced cycloisomerization strategy and demonstrate its application as a versatile entry point to scaffold 2
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