Nature Chemistry ( IF 21.8 ) Pub Date : 2020-12-30 , DOI: 10.1038/s41557-020-00576-z Srikrishna Bera 1 , Runze Mao 1 , Xile Hu 1
Cross-coupling of two alkyl fragments is an efficient method to produce organic molecules rich in sp3-hybridized carbon centres, which are attractive candidate compounds in drug discovery. Enantioselective C(sp3)–C(sp3) coupling is challenging, especially of alkyl electrophiles without an activating group (aryl, vinyl, carbonyl). Here, we report a strategy based on nickel hydride addition to internal olefins followed by nickel-catalysed alkyl–alkyl coupling. This strategy enables the enantioselective cross-coupling of non-activated alkyl halides with alkenyl boronates to produce chiral alkyl boronates. Employing readily available and stable olefins as pro-chiral nucleophiles, the coupling proceeds under mild conditions and exhibits broad scope and high functional-group tolerance. Applications for the functionalization of natural products and drug molecules, as well as the synthesis of chiral building blocks and a key intermediate to (S)-(+)-pregabalin, are demonstrated.
中文翻译:
氢化镍催化非活化烷基亲电体的对映选择性C(sp 3)–C(sp 3)交叉偶联
两个烷基片段的交叉偶联是生产富含sp 3-杂化碳中心的有机分子的有效方法,这是药物发现中有吸引力的候选化合物。对映选择性C(sp 3)–C(sp 3)偶合是有挑战性的,特别是对于没有活化基团(芳基,乙烯基,羰基)的烷基亲电体。在这里,我们报告了一种基于将氢化镍添加到内部烯烃中,然后再进行镍催化的烷基-烷基偶联的策略。该策略使得未活化的烷基卤化物与烯基硼酸酯的对映选择性交叉偶联以产生手性烷基硼酸酯。利用容易获得且稳定的烯烃作为手性亲核试剂,该偶联在温和条件下进行,并显示出广泛的范围和较高的官能团耐受性。证明了在天然产物和药物分子的功能化以及手性结构单元和(S)-(+)-普瑞巴林的关键中间体的合成中的应用。