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Stereoselective Functionalization of Racemic Cyclopropylzinc Reagents via Enantiodivergent Relay Coupling
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2020-06-12 , DOI: 10.1021/jacs.0c04462
Lun An 1 , Fei-Fei Tong 1 , Shu Zhang 2 , Xingang Zhang 1
Affiliation  

Efficient construction of optically pure molecules from readily available starting materials in a simple manner is an on-going goal in asymmetric synthesis. As a straightforward route, transition-metal catalyzed enantioconvergent coupling between widely available secondary alkyl electrophiles and organometallic nucleophiles has emerged as a powerful strategy to construct chiral center(s). However, the scope of racemic secondary alkylmetallic nucleophiles for this coupling remains limited in specific substrates due to the difficulties in stereoselective formation of the key alkylmetal in-termediates. Here, we report an enantiodivergent strategy to efficiently achieve an array of synthetically useful chiral cyclopropanes, including chiral fluoroalkylated cyclopropanes and enantiomerically enriched cyclopropanes with chiral side chains, from racemic cyclopropylzinc reagents. This strategy relies on a one-pot, two-step enantiodivergent relay coupling (EDRC) process of the racemic cis-cyclopropylzinc reagents with two different electrophiles, which involves kinetic resolution of racemic cis-cyclopropylzinc reagents through a nickel-catalyzed enantioselective coupling with alkyl electrophiles, followed by a stereospecific relay coupling of the remaining enantiomeric cyclopropylzinc reagent with various electrophiles, to produce two types of functionalized chiral cyclopropanes with opposite configuration on the cyclopropane ring. These chiral cyclopropanes are versatile synthons for diverse transformations, rendering this strategy effective to structurally diversified molecules of medicinal interests.

中文翻译:

通过对映发散中继偶联对外消旋环丙基锌试剂进行立体选择性官能化

以简单的方式从容易获得的起始材料有效构建光学纯分子是不对称合成中的一个持续目标。作为一种直接的途径,广泛可用的仲烷基亲电试剂和有机金属亲核试剂之间的过渡金属催化对映会聚偶联已成为构建手性中心的有力策略。然而,由于关键烷基金属中间体的立体选择性形成困难,用于这种偶联的外消旋仲烷基金属亲核试剂的范围在特定底物中仍然受到限制。在这里,我们报告了一种对映发散策略,以有效地实现一系列合成有用的手性环丙烷,包括手性氟烷基化环丙烷和具有手性侧链的对映体富集的环丙烷,来自外消旋环丙基锌试剂。该策略依赖于外消旋顺式环丙基锌试剂与两种不同亲电试剂的一锅两步对映发散中继耦合 (EDRC) 过程,该过程涉及通过镍催化对映选择性偶联与烷基对外消旋顺式环丙基锌试剂进行动力学拆分。亲电试剂,然后将剩余的对映体环丙基锌试剂与各种亲电试剂进行立体定向中继偶联,以产生两种类型的在环丙烷环上具有相反构型的官能化手性环丙烷。这些手性环丙烷是用于多种转化的多功能合成子,使这种策略对结构多样化的药用分子有效。外消旋顺式环丙基锌试剂与两种不同亲电试剂的两步对映发散中继偶联 (EDRC) 过程,包括通过镍催化的对映选择性偶联与烷基亲电试剂进行外消旋顺式环丙基锌试剂的动力学拆分,然后是立体定向中继偶联剩余的对映体环丙基锌试剂与各种亲电子试剂,以产生两种类型的环丙烷环上具有相反构型的官能化手性环丙烷。这些手性环丙烷是用于多种转化的多功能合成子,使这种策略对结构多样化的药用分子有效。外消旋顺式环丙基锌试剂与两种不同亲电试剂的两步对映发散中继耦合 (EDRC) 过程,包括通过镍催化对映选择性偶联与烷基亲电试剂进行外消旋顺式环丙基锌试剂的动力学拆分,然后是立体定向中继耦合剩余的对映体环丙基锌试剂与各种亲电子试剂,以产生两种类型的环丙烷环上具有相反构型的官能化手性环丙烷。这些手性环丙烷是用于多种转化的多功能合成子,使这种策略对结构多样化的药用分子有效。这涉及通过镍催化的对映选择性偶联与烷基亲电试剂对外消旋顺式环丙基锌试剂进行动力学拆分,然后将剩余的对映体环丙基锌试剂与各种亲电试剂进行立体定向中继偶联,以产生两种类型的具有相反构型的功能化手性环丙烷环丙烷环。这些手性环丙烷是用于多种转化的多功能合成子,使这种策略对结构多样化的药用分子有效。这涉及通过镍催化的对映选择性偶联与烷基亲电试剂对外消旋顺式环丙基锌试剂进行动力学拆分,然后将剩余的对映体环丙基锌试剂与各种亲电试剂进行立体定向中继偶联,以产生两种类型的具有相反构型的功能化手性环丙烷环丙烷环。这些手性环丙烷是用于多种转化的多功能合成子,使这种策略对结构多样化的药用分子有效。制备两种在环丙烷环上具有相反构型的官能化手性环丙烷。这些手性环丙烷是用于多种转化的多功能合成子,使这种策略对结构多样化的药用分子有效。制备两种在环丙烷环上具有相反构型的官能化手性环丙烷。这些手性环丙烷是用于多种转化的多功能合成子,使这种策略对结构多样化的药用分子有效。
更新日期:2020-06-12
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