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.