Department of Chemistry, North Carolina State University, Raleigh, North Carolina 27695, United States.
Department of Chemistry, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213, United States.
J Am Chem Soc. 2022 May 11;144(18):8257-8266. doi: 10.1021/jacs.2c01924. Epub 2022 Apr 28.
Utilization of mononuclear iron- and 2-oxoglutarate-dependent (Fe/2OG) enzymes to enable C-H bond functionalization is a widely used strategy to diversify the structural complexity of natural products. Besides those well-studied reactions including hydroxylation, epoxidation, and halogenation, in the biosynthetic pathway of dehydrofosmidomycin, an Fe/2OG enzyme is reported to catalyze desaturation, alkyl chain elongation, along with demethylation in which trimethyl-2-aminoethylphosphonate is converted into methyldehydrofosmidomycin. How this transformation takes place is largely unknown. Herein, we characterized the reactive species, revealed the structure of the reaction intermediate, and used mechanistic probes to investigate the reaction pathway and mechanism. These results led to the elucidation of a two-step process in which the first reaction employs a long-lived Fe(IV)-oxo species to trigger C═C bond installation. During the second reaction, the olefin installed in situ enables C-C bond formation that is accompanied with a C-N bond cleavage and hydroxylation to furnish the alkyl chain elongation and demethylation. This work expands the reaction repertoire of Fe/2OG enzymes by introducing a new pathway to the known C-C bond formation mechanisms utilized by metalloenzymes.
利用单核铁和 2-氧戊二酸依赖性（Fe/2OG）酶实现 C-H 键功能化是一种广泛用于多样化天然产物结构复杂性的策略。除了那些研究充分的反应，包括羟化、环氧化和卤化反应外，在去氢福米霉素的生物合成途径中，据报道 Fe/2OG 酶催化去饱和、烷基链延长以及甲基去氢福米霉素的脱甲基反应，其中三甲基-2-氨基乙基膦酸酯转化为甲基去氢福米霉素。这种转化是如何发生的在很大程度上是未知的。在此，我们对反应活性物质进行了表征，揭示了反应中间体的结构，并使用机制探针研究了反应途径和机制。这些结果导致阐明了一个两步过程，其中第一个反应采用长寿命的 Fe(IV)-氧物种引发 C═C 键安装。在第二个反应中，原位安装的烯烃可实现 C-C 键形成，同时伴随着 C-N 键断裂和羟化，从而提供烷基链延长和脱甲基。这项工作通过引入一种新途径来扩展 Fe/2OG 酶的反应范围，该途径是金属酶所利用的已知 C-C 键形成机制的补充。
