浙江科技学院朱世发研究团队揭示了Rh₂（II）催化1,6-烯环异构化对映选择性合成1-二氢苯卓类药物。相关论文发表在2025年3月13日出版的《美国化学会杂志》上。

在此，该课题组研究人员报道了第一个分子间的不对称环异构化，并通过双氢催化合成手性1-二氢苯氮卓类化合物。该方法具有高效率（产率高达98%）、高对映选择性（高达99%ee）和广泛的亲核试剂范围，包括氧亲核试剂（醇、酚和羧酸）和碳亲核试剂（硅烯醇醚）。理论和实验机理研究表明，该反应途径包括一个不对称环异构化过程，该过程产生含有供体-受体（D-A）环丙烷的羰基二钠，然后是开环过程和外部亲核试剂对环丙基环的立体选择性亲核攻击。对照实验表明，底物上的炔基端基在获得良好效率方面起着关键作用。

据介绍，1-二氢苯氮卓骨架已成为生物活性分子中的一个特殊结构基序。然而，由于缺乏不对称方法，获得手性1-二氢苯氮卓类药物的途径仍然有限。

附：英文原文

Title: Enantioselective Synthesis of 1-Dihydrobenzazepines through Rh2(II)-Catalyzed Cycloisomerization of 1,6-Enyne

Author: Chuntao Wang, Zi-Hao Liao, Rui Wu, Kai Chen, Shifa Zhu

Issue&Volume: March 13, 2025

Abstract: The 1-dihydrobenzazepine skeleton has emerged as a privileged structural motif in bioactive molecules. However, due to a lack of asymmetric methodology, access to chiral 1-dihydrobenzazepines has remained limited. Herein, we report the first intermolecular asymmetric cycloisomerization of benzo-fused enynes for the synthesis of chiral 1-dihydrobenzazepines via dirhodium catalysis. This methodology features high efficiency (up to 98% yield), high enantioselectivity (up to 99% ee), and broad scope of nucleophiles, including oxygen nucleophiles (alcohols, phenols, and carboxylic acids) and carbon nucleophiles (silyl enol ethers). Theoretical and experimental mechanistic studies reveal that the reaction pathway encompasses an asymmetric cycloisomerization, which gives rise to a dirhodium carbene containing a donor–acceptor (D-A) cyclopropane moiety, followed by a ring-opening process and stereoselective nucleophilic attack by external nucleophiles on the cyclopropyl ring. Control experiments demonstrate the pivotal role of the terminal group capped on the alkynyl group of substrates in achieving good efficiency.

DOI: 10.1021/jacs.5c00053

Source: https://pubs.acs.org/doi/abs/10.1021/jacs.5c00053