Zhang Li-Zhi, Zhang Pei-Chao, Wang Qian, Zhou Min, Zhang Junliang
School of Ethnic Medicine, Yunnan Minzu University, Kunming, Yunnan, China.
The Center for Basic Research and Innovation of Medicine and Pharmacy (MOE), School of Pharmacy, Second Military Medical University (Naval Medical University), Shanghai, P. R. China.
Nat Commun. 2025 Jan 22;16(1):930. doi: 10.1038/s41467-025-56142-z.
The enantioselective domino Heck/cross-coupling has emerged as a powerful tool in modern chemical synthesis for decades. Despite significant progress in relative rigid skeleton substrates, the implementation of asymmetric Heck/cross-coupling cascades of highly flexible haloalkene substrates remains a challenging and and long-standing goal. Here we report an efficient asymmetric domino Heck/Tsuji-Trost reaction of highly flexible vinylic halides with 1,3-dienes enabled by palladium catalysis. Specifically, the Heck insertion as stereodetermining step to form ƞ allyl palladium complex and in situ trapping with nucleophiles enable efficient Heck/etherification in a formal (4 + 2) cycloaddition manner. Engineering the Sadphos bearing androgynous non-C-symmetric chiral sulfinamide phosphine ligands are vital component in achieving excellent catalytic reactivity and enantioselectivity. This strategy offers a general, modular and divergent platform for rapidly upgrading feedstock flexible vinylic halides and dienes to various value-added molecules and is expected to inspire the development of other challenging enantioselective domino Heck/cross-couplings.
几十年来，对映选择性多米诺 Heck/交叉偶联反应已成为现代化学合成中的一种强大工具。尽管在相对刚性骨架底物方面取得了重大进展，但实现高度灵活的卤代烯烃底物的不对称 Heck/交叉偶联级联反应仍然是一个具有挑战性的长期目标。在此，我们报道了一种由钯催化的高度灵活的卤代乙烯与 1,3 - 二烯的高效不对称多米诺 Heck/Tsuji - Trost 反应。具体而言，作为立体决定性步骤的 Heck 插入反应形成 η - 烯丙基钯络合物，并通过亲核试剂进行原位捕获，从而以形式上的（4 + 2）环加成方式实现高效的 Heck/醚化反应。设计带有雌雄同体非 C - 对称手性亚磺酰胺膦配体的 Sadphos 是实现优异催化活性和对映选择性的关键成分。该策略为将原料灵活的卤代乙烯和二烯快速升级为各种增值分子提供了一个通用、模块化且多样化的平台，并有望推动其他具有挑战性的对映选择性多米诺 Heck/交叉偶联反应的发展。
