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.