Synthetic Studies Towards Pallamolide A

Abstract

Pallamolides A–E (20–24) are 7,8-seco-labdanes isolated from the Chinese liverwort Pallavicinia ambigua. The tautomeric pair 23 and 24 exhibits anti-fungal activity, by inhibition of mycelium hyphae formation in a dose dependent manner, with an MIC of 32 μg/mL. Additionally, 23 and 24 were found to significantly destroy the biofilm structure of DSY654 cells at 16 μg/mL. The unique structural complexity of 20–24, and the promise held by 23 and 24 as antifungal therapeutics, make them desirable targets for total synthesis. Herein, the evolution of an asymmetric synthetic strategy towards pallamolide A (20) is described. The initial aim targeted the construction of the caged bicyclo[2.2.2]octane core (177) of pallamolide A (20). Access to keto-aldehyde 252 was secured first by synthesis of ketone 182, followed by a 7-step sequence hinging on a modified Shapiro reaction to effect ring opening. Unfortunately, NHC-catalysed acyloin condensation of 252 to 253 could not be effected, however, the intramolecular aldol reaction of its homologue, aldehyde 268, to 269 was successful. Despite access to the caged core of pallamolide A (20), an alternative strategy towards the total synthesis of 20 was employed, hinging on an intramolecular vinylogous Mukaiyama aldol (VMA) reaction of 274, accessed by the hydration of bicyclic dihydropyran 276. A model study demonstrated that a robust synthesis of lactol 299 could be achieved, but investigation of the key VMA reaction was hindered by failure to capture any analogues of the ring-opened tautomers of 311 or lactone 316. The revised strategy employed the autoxidation of 333 to 378, from which a VMA reaction with 414 provided intermediate 413. Upon purification, 413 serendipitously underwent an intramolecular vinylogous aldol reaction to provide 411, possessing the central core and spiro butenolide moiety of pallamolide A (20). Introduction of the hydroxymethyl group of pallamolide A (20) at C8 was demonstrated via a palladium-catalysed CH activation sequence on intermediate 435, providing alcohol 438. The synthetic approaches investigated herein have provided a sound foundation for the total synthesis of pallamolide A (20). The current synthetic strategy provided a highly decorated intermediate possessing the central scaffold of 20, and elaboration of this approach towards the synthesis of pallamolide A (20) remains an ongoing pursuit within this research group.