近日，美国耶鲁大学Seth B. Herzon团队研究了（-）-gukulenin A 的三组分组装及其构效关系。这一研究成果于2025年11月13日发表在《科学》杂志上。

α-托酚酮类化合物由一个不饱和七元环组成，其羟基取代基与极化碳-氧π键相邻。这种极化效应赋予该环系永久分子偶极与芳香稳定化作用，从而产生独特的物理性质，包括对二价金属的亲和性与两亲反应活性。在含有α-托酚酮的次生代谢物中，假二聚体分离物(-)-gukulenin A (7)因其结构复杂性尤为突出，并在治疗小鼠卵巢癌模型方面展现出潜力。

研究组报道了(-)-gukulenin A (7)的对映选择性合成。关键步骤包括：定向C–H芳基化、Grob断裂-烷基化串联反应、创新性甲基托酚酮醚合成法、多组分交叉偶联以及热促羰基-烯反应。结构-功能研究证实二聚托酚酮与醛亚结构是驱动细胞毒性的关键因素。

附：英文原文

Title: Three-component assembly and structure–function relationships of (–)-gukulenin A

Author: Vaani Gupta, Zechun Wang, Joshua B. Combs, Timothy Wright, Lei Chen, Boxu Lin, Ryan Holmes, Bo Qin, Joonseok Oh, Jason M. Crawford, Seth B. Herzon

Issue&Volume: 2025-11-13

Abstract: α-Tropolones comprise an unsaturated seven-membered ring bearing a hydroxyl substituent adjacent to a polarized carbon–oxygen π-bond. This polarization imparts a permanent molecular dipole and aromatic stabilization to the ring, resulting in unique physical properties, including affinity for divalent metals and ambiphilic reactivity. Among secondary metabolites that contain α-tropolones, the pseudodimeric isolate (–)-gukulenin A (7) stands out for its complexity and has shown promise in treating murine models of ovarian cancer. Here we describe an enantioselective synthesis of (–)-gukulenin A (7). Key steps include a directed C–H arylation, a tandem Grob fragmentation–alkylation, an innovative synthesis of methyl tropolone ethers, a multicomponent cross-coupling, and a thermal carbonyl–ene reaction. Structure–function studies establish the dimeric tropolone and aldehyde substructures as drivers of cytotoxicity.

DOI: aea9310

Source: https://www.science.org/doi/10.1126/science.aea9310