Practical Synthesis and Antifungal Investigation of Drimane Meroterpenoids Enabled by Nickel-Catalyzed Decarboxylative Coupling

Drimane meroterpenoids have drawn increasing attentionin the discoveryof novel pharmaceutical leads owing to their structural diversityand bioactivity variation, but further development is significantlyimpeded by the lack of an efficient modular route of preparation.A nickel-catalyzed decarboxylative cross-coupling paradigm has beenestablished to expeditiously access a constellation of drimane meroterpenoids.The redox-active drimane precursor is a bench-stable coupling partnerand is easily available from the inexpensive feedstock sclareol. Thistransformation features the tolerance of challenging functional groups(phenol, aldehyde, ester, etc.) and mild conditions with a low-costnickel catalytic system. The synthetic utility is further highlightedby the direct scalable synthesis of challenging drimane meroterpenoidsas diversifiable advanced intermediates for late-stage functionalizations.This method facilitated antifungal investigations and culminated inthe discovery of compounds C8 and C3 asnew antifungal leads against Rhizoctonia solani,with EC50 values of 4.9 and 7.2 mu M, respectively.

Automated summary

Drimane meroterpenoids have attracted attention for their structural diversity and bioactivity, but the lack of an efficient synthetic route has hindered further development. A nickel-catalyzed decarboxylative cross-coupling method has been established to access a variety of drimane meroterpenoids, featuring mild conditions and tolerance for challenging functional groups. This method enables the scalable synthesis of advanced intermediates for late-stage functionalizations, which has led to the discovery of new antifungal leads against Rhizoctonia solani.