Stereoselective Functionalization of Racemic Cyclopropylzinc Reagents via Enantiodivergent Relay Coupling

Efficient construction
of optically pure molecules from readily
available starting materials in a simple manner is an ongoing 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 because of the difficulties in stereoselective
formation of the key alkylmetal intermediates. 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 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
configurations on the cyclopropane ring. These chiral cyclopropanes
are versatile synthons for diverse transformations, rendering this
strategy effective for obtaining structurally diversified molecules
of medicinal interest.

高效构建光学纯度极高的分子，从易于获取的起始材料出发，以简便的方式实现，这始终是手性合成领域不懈的追求。作为一种直接的方法，过渡金属催化的手性异构耦合反应，在广泛可得的二级烷基亲电试剂与有机金属亲核试剂之间已经显现出构建手性中心（们）的强大策略。然而，由于在形成关键烷基金属中间体时立体选择性的困难，此类耦合反应中，外消旋二级烷基金属亲核试剂的应用范围在特定底物中仍然有限。在本研究中，我们提出了一种手性异构分流的策略，以高效地合成一系列具有合成实用价值的具有手性环丙烷，包括手性氟代烷基环丙烷和具有手性侧链的对映体富集环丙烷，这些均由外消旋环丙基锌试剂制得。该策略依赖于一个一锅两步的手性异构分流传递耦合过程，该过程涉及通过镍催化的手性选择性偶联烷基亲电试剂对外消旋顺式环丙基锌试剂进行动力学分辨，随后通过立体专一性的传递耦合剩余的手性环丙基锌试剂与各种亲电试剂，以产生两种类型的官能化手性环丙烷，它们在环丙烷环上具有相反的构型。这些手性环丙烷作为多用途的合成砌块，适用于多种转化，使得该策略在获取具有结构多样性的具有药用价值的分子方面表现出色。