the synthesis of diaryl or aryl alkyl ethers. In recent years,
improved protocols have been developed by adding proper
copper ligands to promote reactions under relatively much
milder conditions. However, limitations such as a limited
substrate scope, high temperature, and requirement of a high
loading of catalyst still exist.4,5 The Pd-catalyzed protocol is
an alternative for copper-catalyzed methods and has been
applied under milder conditions with a broader substrate
scope. However, in some cases low yields were obtained for
the Pd-catalyzed coupling of aryl halides with primary or
secondary alcohols due to the competing β-hydrogen elim-
ination. Thus specially designed ligands are needed for these
catalysts to achieve better performance in such reactions.6dÀj
Although great progress has been made in the Cu and Pd
catalyzed coupling of aryl halides with alcohols, little atten-
tion has been focused on the asymmetric O-arylation reac-
tion since no chiral carbon center directly was involved in the
process of aryl C(sp2)ÀO bond formation. The significance
in developing novel methods in an enantioselective manner
from readily available starting materials has attracted broad
interest in the synthetic community. Many transition-metal
catalyzed asymmetric aryl CÀC or CÀN bond formations
have been achieved through an “indirect” manner such as
desymmetrization7,8 or kinetic resolution.9,10 During the
course of developing asymmetric aryl CÀheteroatom coupling
reactions, our group recently developed some copper-
catalyzed asymmetric aryl C(sp2)ÀN coupling reactions
through the asymmetric desymmetrization or kinetic re-
solution strategies.11 We believed that such strategies may
also be applicable to the asymmetric aryl C(sp2)ÀO
coupling of aryl halides with a hydroxyl group. To the
best of our knowledge, only one example of copper-catalyzed
asymmetric aryl C(sp2)ÀO coupling was recently reported,
which induced an axis chirality in diaryl ether formation
with moderate enantioselectivity.12 No example of a trans-
ition metal catalyzed asymmetric O-arylation reaction for
the formation of a chiral carbon center has been reported
to date. It is perhaps due to the limitations in substrate
scope and ligand selection in Cu or Pd catalyzed CÀO
couplings, which bring more challenges in developing
asymmetric reactions as compared with that of CÀN or
CÀC couplings. In this paper, we disclose the research
results of the first desymmetrization with a Pd-catalyzed
asymmetric O-arylation reaction, which offered a general
approach for the enantioselective synthesis of biologically
important (3,4-dihydro-2H-chromen-3-yl)methanol struc-
tures (Scheme 1).13
Scheme 1. Design of Pd-Catalyzed Asymmetric Aryl CÀO
Coupling through Desymmetrization Strategy
(7) For reviews, see: (a) Garcıa-Urdiales, E.; Alfonso, I.; Gotor, V.
´
Our investigation commenced by examining the desym-
metric coupling of 2-(2-iodobenzyl)propane-1,3-diol (1a)
in the presence of Pd(OAc)2, Cs2CO3, and chiral ligands.
The challenges in aryl CÀO coupling were shown by the
results in the ligand selection. A wide range of commer-
cially available chiral ligands, including bidentated diphos-
pine ligands L1ÀL3, N,P ligand L4, and monodentated
ligand L5, failed toinduce any desiredproduct or enantios-
electivity in the coupling reaction (Table 1, entries 1À5).
Finally, we were pleased to find that a commercial
spirocyclic biphosphine ligand L6 afforded the desired
coupling product 2a in 66% yield and 63:37 enantiomeric
ratios (Table 1, entry 6).14 Further optimization of the
spirocyclic ligands led to the conclusion that a bulky aryl
Chem. Rev. 2005, 105, 313. (b) Willis, M. C. J. Chem. Soc., Perkin Trans.
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John Wiley & Sons, Inc., 2007; pp 275À309. (e) Atodiresei, I.; Schiffers, I.;
Bolm, C. Chem. Rev. 2007, 107, 5683.
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