Zheng Yin, Yang Tilong, Chan Ka Fai, Lin Zhenyang, Huang Zhongxing
State Key Laboratory of Synthetic Chemistry, Department of Chemistry, The University of Hong Kong, Hong Kong, China.
Department of Chemistry, The Hong Kong University of Science and Technology, Hong Kong, China.
Nat Chem. 2024 Nov;16(11):1845-1854. doi: 10.1038/s41557-024-01592-z. Epub 2024 Oct 4.
The high nitrogen content and diverse reactivity of malononitrile are widely harnessed to access nitrogen-rich fine chemicals. Although the facile substitutions of malononitrile can give structurally diverse quaternary carbons, their access to enantioenriched molecules, particularly chiral amines that are prevalent in bioactive compounds, remains rare. Here we report a cobalt-catalysed desymmetric reduction of disubstituted malononitriles to give highly functionalized β-quaternary amines. The pair of cobalt salt and sodium borohydride is proposed to generate a cobalt-hydride intermediate and initiate the reduction. Meanwhile, the enantiocontrol of the dinitrile is achieved through a tailored bisoxazoline ligand with two large flanks that create a narrow gap to host the bystanding nitrile and thus restrict the C(ipso)-C(α) bond rotation of the complexed one. Combined with the extensive derivatization possibilities of all substituents on the quaternary carbon, this asymmetric reduction unlocks pathways from malononitrile as a bulk chemical feedstock to intricate, chiral nitrogen-containing molecules.
丙二腈的高氮含量和多样的反应活性被广泛用于合成富氮精细化学品。尽管丙二腈的取代反应可轻松生成结构多样的季碳，但获得对映体富集的分子，尤其是生物活性化合物中普遍存在的手性胺，仍然很少见。在此，我们报道了一种钴催化的二取代丙二腈的去对称还原反应，以生成高度官能化的β-季胺。钴盐和硼氢化钠组合被认为可生成钴氢中间体并引发还原反应。同时，通过一种定制的双恶唑啉配体实现了二腈的对映体控制，该配体具有两个大的侧翼，形成一个狭窄的间隙以容纳旁立的腈，从而限制了络合腈的C（本位）-C（α）键旋转。结合季碳上所有取代基广泛的衍生化可能性，这种不对称还原反应为从作为大宗化学原料的丙二腈到复杂的手性含氮分子开辟了途径。
