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.

中文翻译：

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α-酮戊二酸依赖性双加氧酶的远程 C-H 羟基化使 Manzacidin C 和脯氨酸类似物的高效化学酶法合成成为可能

远端位置的选择性 CH 官能化仍然是有机合成中极具挑战性的问题。尽管大自然已经进化出无数能够实现这一壮举的酶，但它们的合成效用在很大程度上被忽视了。在这里，我们在功能上表征了一种α-酮戊二酸依赖性双加氧酶（Fe/αKG），它选择性地羟基化各种脂肪族氨基酸的 δ 位置。与催化类似反应的其他 Fe/αKG 相比，该酶的动力学分析和底物分析显示出优异的催化效率和底物混杂性。我们证明了这种转化在稀有生物碱、manzacin C 和密集取代的氨基酸衍生物的简洁合成中的实际效用，具有显着的步骤效率。