Zhu Minghui, Sun Jianwei
Department of Chemistry and the Hong Kong Branch of Chinese National Engineering Research Centre for Tissue Restoration & Reconstruction, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong SAR 999077, China.
J Am Chem Soc. 2025 Jul 9;147(27):24085-24094. doi: 10.1021/jacs.5c07821. Epub 2025 Jun 24.
Disclosed here is a highly enantioselective difunctionalization of azetines for convenient access to chiral 2,3-disubstituted azetidines, a family of important scaffolds previously lacking general access. With Cu/bisphosphine as a catalyst, two versatile functionalities (boryl and allyl) were installed on azetine with concomitant construction of two new stereogenic centers. This represents a rare demonstration of Cu-catalyzed asymmetric boryl alkylation of electron-rich olefins and C═C bonds in strained heterocycles. The use of allyl phosphates proved critical not only to overcome the low reactivity of the borylated alkylcuprate intermediate toward alkylation but also to avoid competing side reactions. Remarkably, in almost all cases, single isomers were obtained with complete regio-, enantio-, and diastereoselectivies on the azetidine motif as well as excellent control on the double bond configuration. The mild conditions exhibited outstanding functional group compatibility and chemoselectivity. The versatile boryl and allyl functionalities allowed for easy transformations of the products to other useful chiral azetidines previously lacking straightforward access. Control experiments and kinetic studies indicated that the reaction proceeds by a fast boryl cupration of azetine followed by rate-determining allylation via an intrinsically controlled S2' pathway.
本文公开了一种氮杂环丁烷的高度对映选择性双官能化反应，可方便地获得手性2,3-二取代氮杂环丁烷，这是一类重要的骨架，此前缺乏通用的合成方法。以铜/双膦为催化剂，在氮杂环丁烷上引入了两种通用的官能团（硼基和烯丙基），同时构建了两个新的立体中心。这是富电子烯烃和张力杂环中碳-碳双键的铜催化不对称硼基烷基化的罕见实例。事实证明，使用烯丙基磷酸酯不仅对于克服硼化烷基铜酸盐中间体对烷基化的低反应活性至关重要，而且对于避免竞争性副反应也很关键。值得注意的是，在几乎所有情况下，在氮杂环丁烷骨架上都以完全的区域选择性、对映选择性和非对映选择性获得了单一异构体，并且对双键构型有出色的控制。温和的反应条件表现出优异的官能团兼容性和化学选择性。通用的硼基和烯丙基官能团使得产物能够轻松转化为其他有用的手性氮杂环丁烷，而这些氮杂环丁烷此前缺乏直接的合成方法。对照实验和动力学研究表明，反应通过氮杂环丁烷的快速硼基铜化反应进行，随后通过内在控制的S2'途径进行速率决定步骤的烯丙基化反应。
