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.