C O M M U N I C A T I O N S
Stereospecific cross-coupling proceeds smoothly with a series
of enantioenriched benzylic ethers (Table 2). We examined three
ligands, rac-BINAP, Xantphos, and DPEphos, with each substrate.12
In general, the highest yields were obtained by using rac-BINAP
for substituted naphthalenes and DPEphos for substituted hetero-
cycles. Benzyl ether 4 reacted similarly to the methyl ether 1 (entry
2).13,14 In all cases, the reaction was stereospecific and provided
product in enantiomeric excesses similar to those of the starting
ether. This method accomplishes smooth translation of stereochem-
ical information from a secondary carbinol to a tertiary stereocenter.
This strategy is particularly practical since there are many outstand-
ing methods for the enantioselective synthesis of secondary
carbinols.15,16
We sought to apply this reaction in the synthesis of enantioen-
riched diarylethanes, a structural motif which exhibits a diverse
range of biological properties, including anticancer, antidepressant,
and antiviral activity.17 While creative approaches to the enanti-
oselective synthesis of this moiety exist,18 most require inclusion
of functional group handles that are later removed. Classical
resolution by crystallization of diastereomeric salts is frequently
the most practical method for the preparation of enantioenriched
diarylmethanes. We envisioned a direct synthesis of enantioenriched
diarylethanes from readily available diarylmethanols.19 Under our
standard reaction conditions, nickel-catalyzed cross-coupling of
diarylmethanol 13 proceeded with high stereochemical integrity and
in good yield to afford 14 (Scheme 1).
subsequent functionalization of the benzothiophene ring was
accomplished using literature methods.23b
In summary, selective formation of tertiary stereogenic centers
has been achieved using a stereospecific nickel-catalyzed cross-
coupling reaction. This strategy provides a new synthesis of
enantioenriched 1,1-diarylalkanes, important pharmacophores in
medicinal chemistry. Efforts to expand the scope of this transforma-
tion and elucidate the mechanistic details are underway.
Acknowledgment. This work was supported by the UC Irvine
Academic Council on Research, Computing, and Library Resources.
We thank Frontier Scientific for donations of boronic acids.
Supporting Information Available: Experimental procedures and
spectroscopic and analytical data for all new compounds. This material
References
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Scheme 1. Synthesis of Enantioenriched Diarylethanes
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(11) Absolute configurations of 1 and 2 were assigned based on comparison of
optical rotations to literature values. See Supporting Information for details.
(12) See Supporting Information for details.
(13) Notably, substitution occurs R to the naphthalene ring, not the phenyl
ring. Consistent with this observation, simple benzylic ethers do not
undergo cross-coupling under these reaction conditions (see Supporting
Information for details). These observations are consistent with the
greater stability of arylalkylmetal complexes containing extended
aromatic systems.
To highlight the potential applications of this method, we
examined cross-couplings of ethers 15 and 17. Benzylic ether 15
underwent cross-coupling with high stereochemical fidelity to
provide enantioenriched diarylethane 16. Racemic 16 is a potent
inhibitor of tubulin polymerization.20 During the course of the
reaction, a portion of the material underwent deprotection of the
para-methoxy group.21 Therefore, the unpurified reaction mixture
was treated with methyl iodide to reinstall the ether and obtain a
high yield of 16. Benzothiophene 19, an anti-insomnia agent, was
also prepared in enantioenriched form.22 Cross-coupling of diaryl-
methanol 17 provided the requisite tertiary stereogenic center;
(14) Substitution of methylmagnesium iodide with n-propylmagnesium iodide
in cross-coupling reactions with ether 5 provided cross-coupled product,
albeit in variable yield (between 14-65%).
9
390 J. AM. CHEM. SOC. VOL. 133, NO. 3, 2011