Enantioselective Synthesis of Axially Chiral Biaryls
A R T I C L E S
Figure 1. Ligands and biologically active natural products containing the axially chiral biaryl structural motif.
tions including the oxidative dimerization of phenols4,33-37 and
metal-catalyzed [2 + 2 + 2] formal cycloadditions have also
been reported.5,38-40
reactions could be used to synthesize axially chiral binaphthyl
compounds in the presence of a chiral ferrocene ligand.48,49
The Suzuki-Miyaura cross-coupling of aryl boronic acids
with aryl halides offers a number of advantages over Negishi
and Kumada cross-coupling methods to form biaryl bonds,
especially in terms of functional group tolerance and the stability
and lack of air sensitivity of the boronic acid coupling
partner.50,51 Uemura,52-54 Nelson,55 Colobert,56 and Lipshutz57
demonstrated that axially chiral biaryl products are formed in
high yields and excellent selectivities in Pd-catalyzed Suzuki-
Miyaura reactions with aryl halides bearing chiral auxiliaries.
Later Nicolaou employed chiral phosphines to modulate the
selectivity of a diastereoselective Suzuki-Miyaura reaction used
in the synthesis of vancomycin.9
Palladium-catalyzed reactions involving Kumada, Negishi,
Hiyama, and Suzuki-Miyaura cross-coupling have emerged as
one of the most powerful and general means of constructing
biaryl bonds.41-44 There has been growing interest in imple-
menting enantioselective variants of these reactions in order to
access enantiopure, axially chiral biaryls. Generally, in order
for a biaryl compound to exhibit atropisomerism, there must
be at least three ortho substituents about the biaryl axis;45 this
high degree of steric hindrance presents a serious challenge to
many cross-coupling transformations.
Hayashi reported the first use of a chiral ligand in redox-
neutral asymmetric biaryl coupling reactions with a transition
metal catalyst. It was demonstrated that axially chiral binaphthyl
compounds could be formed via the Ni-catalyzed Kumada cross-
coupling reaction between aryl bromides and aryl Grignard
reagents in the presence of a chiral ferrocenylphosphine
ligand.46,47 Espinet later demonstrated that Pd-catalyzed Negishi
Our group reported one of the earliest procedures for the
preparation of functionalized biaryl compounds via the asym-
metric Suzuki-Miyaura coupling reaction.58 A number of
enantioenriched biaryl phosphonates could be synthesized in
yields of 74% or greater and enantiomeric excesses up to 92%
with the use of catalytic amounts of a Pd source and the (S)-
KenPhos ligand (Scheme 1). At around the same time, Cam-
midge disclosed the Pd-catalyzed synthesis of axially chiral
binaphthalene compounds with the use of a chiral ferrocene-
derived monophosphine ligand.59 Since then, a variety of
ligands48,60-66 have been examined for the asymmetric Pd-
catalyzed Suzuki coupling reaction. Recent noteworthy examples
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