Gong Yi, Zhang Zheng, Liu Huijuan, Wang Tao, Jiang Mengmeng, Feng Nan, Peng Peiying, Wang Huimin, Zhou Feng, Wang Xin, Zhou Jian
State Key Laboratory of Petroleum Molecular & Process Engineering, Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, Shanghai Key Laboratory of Green Chemistry and Chemical Processes, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, 200062, China.
College of Chemistry, Sichuan University, Chengdu, 610064, China.
Nat Commun. 2025 May 16;16(1):4571. doi: 10.1038/s41467-025-59845-5.
We report the highly enantioselective Cu-catalyzed asymmetric propargylic substitution (APS) of α-tertiary propargylic electrophiles using hydrazines and hydroxylamines as a fruitful strategy to access multifunctional α-tertiary hydrazines or hydroxylamines. Using trifluoroethanol (TFE) as the solvent play a key role to decrease the nucleophilicity of hydrazines to suppress side reactions such as elimination, thus improve the yield and the enantioselectivity. NMR analysis and theoretical calculations suggest the formation of an H-bond adduct of TFE with hydrazide, stabilized by multiple H-bonding interactions, including C-F···H-N interaction. The sterically confined pyridinebisoxzolines (PYBOX), featuring a bulky benzylthio shielding group also contribute to the excellent enantioselectivity. Aryl- and aliphatic-ketone-derived α-ethynylalcohol carbonates, α-tertiary α-ethynyl epoxides, cyclic carbonates and and α-hydroxycarboxylates all are competent substrates to afford α-tertiary α-ethynylhydrazines with high structural diversity. The obtained products can be readily converted into various α-tertiary hydrazines and azacycles featuring an aza-quaternary stereocenter.
我们报道了使用肼和羟胺对α-叔炔丙基亲电试剂进行高度对映选择性的铜催化不对称炔丙基取代反应（APS），这是一种获得多功能α-叔肼或羟胺的有效策略。使用三氟乙醇（TFE）作为溶剂对于降低肼的亲核性以抑制消除等副反应起着关键作用，从而提高产率和对映选择性。核磁共振分析和理论计算表明，TFE与酰肼形成了氢键加合物，通过包括C-F···H-N相互作用在内的多种氢键相互作用得以稳定。具有庞大苄硫基屏蔽基团的空间受限吡啶双恶唑啉（PYBOX）也有助于实现优异的对映选择性。芳基和脂肪族酮衍生的α-乙炔基碳酸酯、α-叔α-乙炔基环氧化物、环状碳酸酯和α-羟基羧酸盐都是能够提供具有高度结构多样性的α-叔α-乙炔基肼的合适底物。所得到的产物可以很容易地转化为各种具有氮杂季立体中心的α-叔肼和氮杂环。
