Huang Jianhong, Li Jiahang, Liu Shenli, Zhao Wanyao, Xia Yan, Liu Xiaoyan, Shao Kuizhan, Li Wenliang, Yuan Haiyan, Zhao Jinbo
Faculty of Chemistry and Life Sciences, Changchun University of Technology, 2055 Yan'An Street, Changchun, Jilin, 130012, P. R. China.
Faculty of Chemistry, Northeast Normal University, 5268 Renmin Street, Changchun, Jilin, 130024, P. R. China.
Nat Commun. 2025 Apr 29;16(1):4019. doi: 10.1038/s41467-025-59048-y.
Since its advent 120 years ago, the [2+n] coupling cyclization of ketene has been prevalently used for the synthesis of N- and O-heterocycles. In contrast, its vinylogous version, i.e., use of alkenyl ketene as 4 C synthon, remain elusive. We report herein that in the rare S1-type ring-opening of electron-deficient cyclopropene, the initially formed sp-carbocation-containing zwitterionic intermediate undergoes facile 1,4-alkoxy migration to generate a functionalized alkenyl ketene. This electrophilic intermediate not only allows for challenging N-nucleophiles to be engaged in the conventional ketene [2+n] reactions (n = 1 ~ 3), also unveiled the vinylogous [4+n] cyclization mode, as exemplified by the [4 + 1] and formal [4 + 4] cyclization to construct pyrrolidinone and azocine frameworks. The protocol offers a unified entry to a distinct class of lactam scaffolds that exhibit anti-cancer potential, constituent key natural product scaffold and display interesting 1e- and 2e- reactivities. This work reveals a broader synthetic potential of the facile S1 type ring-opening of cyclopropene as "dehydro"-donor-acceptor cyclopropane (DDAC) substrate, and could have ramifications in ketene chemistry, N-heterocyclic chemistry and related medicinal research, as well as the donor-acceptor system chemistry.
自120年前问世以来，乙烯酮的[2 + n]偶联环化反应已广泛应用于N-和O-杂环的合成。相比之下，其插烯型反应，即使用烯基乙烯酮作为4C合成子的反应，仍然难以实现。我们在此报告，在缺电子环丙烷罕见的S1型开环反应中，最初形成的含sp-碳正离子的两性离子中间体经历了容易的1,4-烷氧基迁移，生成了功能化的烯基乙烯酮。这种亲电中间体不仅能使具有挑战性的N-亲核试剂参与传统的乙烯酮[2 + n]反应（n = 1 ~ 3），还揭示了插烯型[4 + n]环化模式，例如通过[4 + 1]和形式上的[4 + 4]环化反应构建吡咯烷酮和氮杂环辛烷骨架。该方法为一类具有抗癌潜力、构成关键天然产物骨架且展现出有趣的1e-和2e-反应性的内酰胺支架提供了统一的合成途径。这项工作揭示了环丙烷的简便S1型开环反应作为“脱氢”-供体-受体环丙烷（DDAC）底物具有更广泛的合成潜力，并且可能对乙烯酮化学、N-杂环化学及相关药物研究以及供体-受体体系化学产生影响。
