Yan Xinlong, Zhang Zichun, Wu Zhenwei, Wu Fule, Feng Xiaoming, Liu Yangbin
State Key Laboratory of Chemical Oncogenomics, Guangdong Provincial Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen 518055, P. R. China.
Institute of Chemical Biology, Shenzhen Bay Laboratory, Shenzhen 518132, P. R. China.
J Am Chem Soc. 2025 Sep 11. doi: 10.1021/jacs.5c11017.
Stereodivergent synthesis of the structural motif bearing vicinal stereocenters is highly important for complete evaluation of their physiological activities. Branched- and enantioselective allylic alkylation using synergistic dual catalysis has emerged as a powerful strategy to access multiple molecular stereoisomers with precise control of the absolute and relative configuration. Despite impressive progress in this field, the stereodivergent allylic alkylation by employing trisubstituted allylic electrophiles to construct allylic quaternary stereocenters remains an unsolved challenge. Herein, we report a combination of iridium and magnesium catalysis for stereodivergent allylic alkylation of α-benzothiazyl acetamide by using challenging trisubstituted allylic carbonates. Such a stereodivergent process gives a range of all four stereoisomers of α-allylated acetamide products containing congested allylic quaternary and vicinal tertiary stereocenters in good yields with excellent diastereo- and enantioselectivities. The synthetic utility of this methodology is demonstrated through the preparation of key intermediates for a number of natural products. Particularly, stereodivergent synthesis of an analgesic drug derivative -tapentadol has been achieved, exhibiting significantly enhanced μ-opioid receptor agonistic activity compared to its parent compound.
对具有邻位立体中心的结构基序进行立体发散合成对于全面评估其生理活性非常重要。利用协同双催化进行支链和对映选择性烯丙基烷基化已成为一种强大的策略，可精确控制绝对和相对构型来获得多种分子立体异构体。尽管该领域取得了令人瞩目的进展，但通过使用三取代烯丙基亲电试剂构建烯丙基季碳立体中心的立体发散烯丙基烷基化仍然是一个未解决的挑战。在此，我们报道了铱和镁催化相结合，用于通过使用具有挑战性的三取代烯丙基碳酸酯对α-苯并噻唑基乙酰胺进行立体发散烯丙基烷基化。这种立体发散过程以良好的产率、优异的非对映选择性和对映选择性得到了一系列含有拥挤烯丙基季碳和邻位叔碳立体中心的α-烯丙基乙酰胺产物的所有四种立体异构体。通过制备多种天然产物的关键中间体证明了该方法的合成实用性。特别地，已实现了一种镇痛药衍生物——他喷他多的立体发散合成，与其母体化合物相比，其μ-阿片受体激动活性显著增强。
