A Chiral-Pool-Based Strategy to Access trans-syn-Fused Drimane Meroterpenoids: Chemoenzymatic Total Syntheses of Polysin, N-Acetyl-polyveoline and the Chrodrimanins

trans-syn-Fused drimane meroterpenoids are unique natural products that arise from contra-thermodynamic polycyclizations of their polyene precursors. Herein we report the first total syntheses of four trans-syn-fused drimane meroterpenoids, namely polysin, N-acetyl-polyveoline, chrodrimanin C, and verruculide A, in 7-18 steps from sclareolide. The trans-syn-fused drimane unit is accessed through an efficient acid-mediated C9 epimerization of sclareolide. Subsequent applications of enzymatic C-H oxidation and contemporary annulation methodologies install the requisite C3 hydroxyl group and enable rapid generation of structural complexity to provide concise access to these natural products.

Automated summary

In this study, the first total syntheses of four trans-syn-fused drimane meroterpenoids were reported, achieved in 7-18 steps from sclareolide. The trans-syn-fused drimane unit was accessed through efficient acid-mediated epimerization of sclareolide, and subsequent enzymatic C-H oxidation and contemporary annulation methodologies were applied to rapidly generate structural complexity for concise access to these natural products.