Li En, Tang Kai, Ren Zhuhui, Liao Xiaoyun, Liu Qianchen, Huang Yong, Chen Jiean
Pingshan Translational Medicine Center, Shenzhen Bay Laboratory, Shenzhen, 518118, China.
College of Pharmacy, Shenzhen Technology University, Shenzhen, 518118, China.
Adv Sci (Weinh). 2023 Oct;10(29):e2303517. doi: 10.1002/advs.202303517. Epub 2023 Aug 4.
The functionalization of the β-carbon of enals with electrophiles is a signature umpolung reactivity of N-heterocyclic carbene (NHC) derived homoenolates. However, only a limited number of electrophiles are shown to be compatible, with most of them being π-electrophiles. In this study, the successful enantioselective β-alkylation of homoenolates is reported using C electrophiles through an S 2 strategy. The protocol shows a broad scope regarding alkyl electrophiles, delivering good yields, and excellent enantioselectivities (up to 99% ee). It enables the installation of drug-like structural motifs in either enals or alkylating agents, demonstrating its potential as a valuable tool for late-stage modification. Furthermore, a concise synthetic route is presented to chiral pyrroloindoline-type skeletons. Preliminary mechanistic studies support a direct S 2 mechanism.
亲电试剂对烯醛β-碳的官能团化反应是N-杂环卡宾（NHC）衍生的高烯醇盐独特的极性翻转反应活性。然而，只有有限数量的亲电试剂被证明是兼容的，其中大多数是π-亲电试剂。在本研究中，报道了通过S 2策略使用碳亲电试剂成功实现高烯醇盐的对映选择性β-烷基化反应。该方案对烷基亲电试剂具有广泛的适用范围，能提供良好的产率和出色的对映选择性（高达99% ee）。它能够在烯醛或烷基化试剂中引入类药物结构基序，证明了其作为后期修饰有价值工具的潜力。此外，还提出了一条合成手性吡咯并吲哚啉型骨架的简洁路线。初步的机理研究支持直接的S 2机理。
