Total Syntheses of (+)-Waixenicin A, (+)-9-Deacetoxy-14,15-deepoxyxeniculin, and (-)-Xeniafaraunol A

The first asymmetrictotal synthesis of the Xenia diterpenoid waixenicinA, a potent and highly selective TRPM7 inhibitor,is reported. The characteristic trans-fused oxabicyclo[7.4.0]-tridecanering system was constructed via a diastereoselective conjugate addition/trappingsequence, followed by an intramolecular alkylation to forge the 9-memberedring. While a beta-keto sulfone motif enabled efficient ring-closure,the subsequent radical desulfonylation suffered from (E)/(Z)-isomerization of the C7/C8-alkene. Conductingthe sequence with a trimethylsilylethyl ester allowed for a fluoride-mediateddecarboxylation that proceeded without detectable isomerization. Theacid-labile enol acetal of the delicate dihydropyran core was introducedat an early stage and temporarily deactivated by a triflate function.The latter was critical for the introduction of the side chain. Divertingfrom a common late-stage intermediate provided access to waixenicinA and 9-deacetoxy-14,15-deepoxyxeniculin. A high-yielding base-mediateddihydropyran-cyclohexene rearrangement of 9-deacetoxy-14,15-deepoxyxeniculinled to xeniafaraunol A in one step.

Automated summary

The first asymmetric total synthesis of waixenicinA, a potent TRPM7 inhibitor, was achieved. The synthesis involved the construction of a characteristic trans-fused oxabicyclo[7.4.0]-tridecane ring system through a diastereoselective conjugate addition/trapping sequence, followed by an intramolecular alkylation to form a 9-membered ring. The synthesis also employed a beta-keto sulfone motif for efficient ring-closure and a fluoride-mediated decarboxylation to prevent isomerization. Additionally, a base-mediated rearrangement reaction led to the synthesis of xeniafaraunol A.