Atroposelective Synthesis of Axially Chiral Diaryl Ethers by Copper-Catalyzed Enantioselective Alkyne–Azide Cycloaddition

Diaryl ethers are important structural
motifs widely found in bioactive
natural products, ligands, and catalysts. While there are a variety
of methods available to generate diaryl ethers, progress on the construction
of axially chiral diaryl ethers has been slow. We report herein an
atroposelective copper-catalyzed cycloaddition between bisalkynes
and azides. With an indane-fused BOX ligand used, a diverse array
of C–O atropisomers are obtained with up to 97% yield and 99%
ee. Control experiments showed that a sequential enantioselective
desymmetrization–kinetic resolution process is involved, and
the former plays a major role. In addition, an asymmetric depletion
is observed for this catalytic synthesis by nonlinear effect studies.
By thermal racemization experiments, the rotational barrier of the
C–O axis of 3aa is calculated to be 35.9 kcal/mol,
which lays the foundation for its isolation, as well as further applications.