A Bulky Chiral N‑Heterocyclic Carbene Palladium Catalyst Enables Highly Enantioselective Suzuki–Miyaura Cross-Coupling Reactions for the Synthesis of Biaryl Atropisomers

Axially chiral biaryl
scaffolds are essential structural units
in chemistry. The asymmetric Pd-catalyzed Suzuki–Miyaura cross-coupling
reaction has been widely recognized as one of the most practical methods
for constructing atropisomers of biaryls. However, longstanding challenges
remain in this field. For example, substrate scope is often narrow
and specialized, functional groups and heterocycles can lead to reduced
reactivity and selectivity, bulky ortho-substituents
are usually needed, and reported methods are generally inapplicable
to tetra-ortho-substituted biaryls. We have developed
an unprecedented highly enantioselective N-heterocyclic carbene (NHC)-Pd
catalyzed Suzuki–Miyaura cross-coupling reaction for the synthesis
of atropisomeric biaryls. These reactions enable efficient coupling
of aryl halides (Br, Cl) or aryl triflates with various types of aryl
boron compounds (B­(OH)2, Bpin, Bneo, BF3K),
tolerate a remarkably broad scope of functional groups and heterocycles
(>41 examples), employ low loading of catalyst (0.2–2 mol
%),
and proceed under mild conditions. The protocol provided general and
efficient access to various atropisomeric biaryls and heterobiaryls
in excellent enantioselectivities (up to 99% ee) with no need
of using bulky ortho-substituted substrates and was
effective for the synthesis of tetra-ortho-substituent
biaryls. Moreover, the method was successfully applied to the diastereo-
and enantioselective synthesis of atropisomeric ternaphthalenes. Critical
to the success of the reaction is the development and application
of an extremely bulky C2-symmetric chiral
NHC, (R,R,R,R)-DTB-SIPE, as the ligand for palladium. To the best of
our knowledge, this is the first highly enantioselective (>90%
ee)
example of a chiral NHC-metal-catalyzed C­(sp2)–C­(sp2) cross-coupling reaction.