近日，美国伊利诺伊大学White, M. Christina团队研究了α，β-不饱和羰基天然产物的选择性亚甲基氧化。相关论文发表在2025年10月20日出版的《自然》杂志上。

α，β-不饱和羰基官能团-具有连接的碳-碳和碳-氧双键-通常存在于生物活性化合物中。这些化合物的后期功能化可能涉及氧化亚甲基（2°）C-H键，而保留对生物活性重要的C-C双键完整。在芳烃和氮杂环存在的情况下，人们已经开发了选择性氧化亚甲基的催化体系，但烯烃仍然是一个未解决的问题。

研究组表明，在位阻锰PDP催化剂中，用氢键给体溶剂取代羧酸将活性氧化剂转变为加速富电子亚甲基氧化的活性氧化剂，并显著减缓缺电子烯烃的环氧化反应（k_C-H[O]/k_epox = 38.5）。研究组展示了在四十五种含有α,β-不饱和羰基结构的分子中实现的化学选择性亚甲基氧化反应，而以往所有方法仅能实现烯丙位氧化或环氧化。

机理研究证实，新型氧化剂通过电荷化程度更高的反应路径进行反应，该路径不利于电子缺失键的参与，表明高活性金属氧化剂可通过调控实现化学选择性。这些突破性发现首次实现了对含有这些药效团亚结构的复杂天然产物及其衍生物进行后期氧化，从而成功制备出新型类似物与已知代谢产物。

附：英文原文

Title: Selective Methylene Oxidation in α,β-Unsaturated Carbonyl Natural Products

Author: Ahn, Chiyoung, Gomez, Alexander, Hartmann, Marc A., White, M. Christina

Issue&Volume: 2025-10-20

Abstract: α,β-Unsaturated carbonyl functionality- those with connected carbon-carbon and carbon-oxygen double bonds- are commonly found in bioactive compounds. Late-stage functionalization of these compounds could involve oxidation of methylene (2°) C—H bonds while leaving the C—C double bonds that are important for biological activity intact1–3. Catalytic systems have been developed for selective oxidation of methylenes in the presence aromatics4 and N-heterocycles5, however olefins remain an unsolved problem. Here we show that replacing the carboxylic acid with a H-bond donor solvent in sterically hindered manganese PDP catalysts changes the active oxidant to one that accelerates electron rich methylene oxidation and significantly slows epoxidation of electron deficient olefins (kC-H[O]/kepox = 38.5). Chemoselective methylene oxidation is demonstrated in forty-five molecules housing α,β-unsaturated carbonyl functionality where all previous methods afforded allylic oxidation or epoxidation. Mechanistic studies support that the new oxidant proceeds via a more charged pathway that disfavors electron deficient bonds, demonstrating that highly reactive metal oxidants can be tuned to achieve chemoselectivity. These discoveries enable the first late-stage oxidations in complex natural products and derivatives housing these pharmacophoric substructures to furnish novel analogues and known metabolites.

DOI: 10.1038/s41586-025-09742-0

Source: https://www.nature.com/articles/s41586-025-09742-0