Remote C–H Hydroxylation by an α-Ketoglutarate-Dependent Dioxygenase Enables Efficient Chemoenzymatic Synthesis of Manzacidin C and Proline Analogs

Selective C-H functionalization at distal positions remains a highly challenging problem in organic synthesis. Though Nature has evolved a myriad of enzymes capable of such feat, their synthetic utility has largely been overlooked. Here, we functionally characterize an α-ketoglutarate-dependent dioxygenase (Fe/αKG) that selectively hydroxylates the δ position of various aliphatic amino acids. Kinetic analysis and substrate profiling of the enzyme show superior catalytic efficiency and substrate promiscuity relative to other Fe/αKGs that catalyze similar reactions. We demonstrate the practical utility of this transformation in the concise syntheses of a rare alkaloid, manzacidin C, and densely substituted amino acid derivatives with remarkable step efficiency. This work provides a blueprint for future applications of Fe/αKG hydroxylation in complex molecule synthesis and the development of powerful synthetic paradigms centered on enzymatic C-H functionalization logic.