Asymmetric Csp³–Csp³ bond formation has been a grand pursuit in synthetic chemistry. The regioselective and enantioselective hydroalkylation of 1,3-diene has emerged as an appealing approach for constructing chiral allylic Csp³–Csp³ bonds. However, this method is presently confined to the use of stabilized Csp³ nucleophilic substrates. Herein, we present a nickel-catalyzed asymmetric hydroalkylation of 1,3-dienes with simple unstabilized alkyl carbanion enabled by naturally abundant carbonyls’ umpolung under mild reaction conditions. A range of simple alkylated chiral allylic compounds were generated in good to high yields (up to 96%), with an enantiomeric ratio (er) of up to 98:2 to form the Csp³–Csp³ bond. The protocol is applicable to heterocycles, polyenes, and unsaturated hydrazones as well as late-stage functionalization of various complex pharmaceuticals. Density functional theory calculations elucidated the mechanism and enantioselectivity of the reaction. An enantiocontrol model is also proposed, emphasizing the crucial role of a chiral NHC ligand in facilitating this asymmetric reaction, as revealed by the two-layer two-dimensional (2D) contour maps.

中文翻译：

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通过羰基 Umpolung 对线性 1,3-二烯的区域和对映选择性氢烷基化形成不对称的 Csp3-Csp3 键


不对称的 Csp^{3-Csp 3} 键形成一直是合成化学中的一个宏伟追求。1,3-二烯的区域选择性和对映选择性氢烷基化已成为构建手性烯丙基 Csp^{3-Csp 3} 键的一种有吸引力的方法。然而，这种方法目前仅限于使用稳定的 Csp³ 亲核底物。在此，我们提出了一种镍催化的 1,3-二烯不对称氢烷基化反应，该反应在温和的反应条件下由天然丰富的羰基化合物实现的简单不稳定的烷基碳阴离子。以高产率（高达 96%）生成了一系列简单的烷基化手性烯丙基化合物，对映体比 （er） 高达 98：2，以形成 Csp³–Csp³ 键。该方案适用于杂环、多烯和不饱和腙以及各种复杂药物的后期功能化。密度泛函理论计算阐明了反应的机制和对映选择性。还提出了一种对映体控制模型，强调了手性 NHC 配体在促进这种不对称反应中的关键作用，如两层二维 （2D） 等值线图所示。