Terpenoid-derived β-ketoesters: acid-induced rearrangements in homocamphor series

Abstract

An acid-induced skeletal rearrangement of homocamphor-derived β-ketoesters has been developed, providing efficient access to previously inaccessible bicyclo[2.2.2]octane-fused lactones. The method utilizes the inherent stereochemical features of the previously obtained [3.2.1] bicyclic framework to trigger cascade rearrangements involving alkyl shifts and lactonization, controlled by the participation of neighboring carboxylate or cyano groups. The starting homocamphor-based β-ketoester was functionalized via diastereoselective reduction and α-alkylation. Upon treatment with sulfuric or triflic acid, these substrates undergo Wagner-Meerwein-type rearrangements followed by intramolecular nucleophilic trapping, yielding polycyclic γ-and δ-lactones with complete stereocontrol. The obtained lactones represent structural scaffolds of interest for anticancer drug discovery, and as potential GABA analogues for CNS disorder modulation. The developed methodology enables the construction of complex molecular architectures that are difficult to access by conventional synthetic routes..