Chemoenzymatic Synthesis of Arisugacins and Terreulactones via Directed Evolution of a Privileged Sclareolide Dioxygenase

Site- and chemoselective oxidation of polycyclic terpenes remains a central challenge in synthesis. We report a chemoenzymatic platform that operates directly on sclareolide to program C1, C3, and C5 C-H hydroxylation. Directed evolution of the nonheme Fe(II)/α-ketoglutarate oxygenase AndA furnishes STAC variants with complementary C1α/C3α/C5α selectivity and up to 82-fold activity improvements, delivering five privileged oxidized labdane scaffolds on gram to decagram scale. A C5-hydroxylation module streamlines access to (+)-phorbadione via a concise formal synthesis from sclareolide. Orthogonal C1/C3/C5 oxidation, combined with Suárez oxidative cleavage and an amine-catalyzed formal [3 + 3] annulation, converges on a common diol that undergoes late-stage diversification. These sequences enable the first syntheses of arisugacin J, arisugacin D, arisugacin M, terreulactone C, and terreulactone B. This work establishes AndA as an Fe/αKG analogue of P450_BM3 for tunable, multisite terpene oxidation and illustrates a general strategy for platform synthesis of densely oxidized meroterpenoids from chiral-pool feedstocks.