Styrene-Based Axial Chiral Catalyst-Catalyzed Asymmetric Synthesis of Spirobarbiturates through Chiral Proton Shuttle

Chiral spirobarbiturates have become recognized as crucial
structural
motifs in biologically active compounds owing to their rigid frameworks.
However, current approaches for constructing chiral spirobarbiturates
that utilize barbiturates as Michael donors remain underdeveloped.
Herein, we present a synthetic strategy for the construction of chiral
spirobarbiturates through a chiral proton shuttle approach designed
to suppress background and side reactions. Barbituric isothiocyanates
are employed as effective Michael donors, enabling asymmetric cyclization
with enynamides to proceed in good yields and with high enantioselectivity
under mild reaction conditions. Mechanistic investigations, encompassing
control experiments, kinetic analyses, and density functional theory
(DFT) calculations, are conducted to clarify the reaction pathway
and to elucidate the roles of the chiral proton shuttle and the styrene-based
axial chiral catalyst in achieving asymmetric induction.