Asymmetric Synthesis of 1,1-Diarylalkyl Units
FULL PAPER
CN functionality to copper as a coordinating ligand. The re-
action proceeded to give the desired product with a negligi-
ble change in ee value (90% ee).[18] Although we cannot
completely exclude such coordination during the course of
our reaction, judging from the reactivity and enantiodiffer-
entiation exhibited by the catalyst, the contribution is negli-
gible.
This current method was applied to the enantioselective
preparation of the indatraline precursor 8 (Scheme 4). Inda-
traline (4) is a potent psychoactive compound with high in-
hibitory activity for monoamine reuptake.[19] Although sev-
eral racemic syntheses of 4 have been reported, so far only
one catalytic enantioselective synthesis of (+)-4 has been re-
Conclusion
We have developed a conjugate reduction protocol that
allows for the catalytic enantioselective preparation of 1,1-
diarylalkyl units possessing two sterically similar aryl groups.
A series of b,b-diaryl-substituted a,b-unsaturated nitriles
that have a meta or para substituent on the aryl ring have
been successfully reduced with good to excellent enantiose-
lectivities by using a copper–Josiphos catalyst in the pres-
ence of hydrosilane. The advantages of this catalyst system
are the high enantioselectivities for both the E and Z iso-
mers, mild reaction conditions, and the use of an economi-
cally appealing transition metal and hydrosilane. This meth-
odology offers an attractive alternative to conjugate addition
reactions of aryl-based organometallic reagents to a,b-unsa-
turated carbonyl compounds. Finally, we have applied this
method to a catalytic enantioselective formal synthesis of in-
datraline.
À
ported, which employed a rhodium-catalyzed carbenoid C
H insertion reaction.[20] Our synthesis started with the prepa-
ration and subsequent addition of dichloroarylboronic acid
to phenyl alkynyl nitrile to give the unsaturated nitrile (E)-5
in 62% yield from the bromobenzene derivative. The nitrile
was reduced at room temperature under the optimized con-
ditions to give the key intermediate (S)-6, which is the
common intermediate in the synthesis of indatraline by
Davies and Gregg, in 96% ee and 84% yield. Our asymmet-
ric approach can provide either enantiomer of 6 in good ee
simply by changing to the antipode of the ligand or by using
the other stereoisomer of 5 in the asymmetric reduction.
Hydrolysis of (S)-6 with aqueous HCl/AcOH and cyclization
by employing chlorosulfonic acid gave indanone 8 in 80%
yield. The indanone is a versatile precursor for the construc-
tion of optically active 4.[20]
Experimental Section
General procedure for the enantioselective reduction of b,b-diaryl-substi-
tuted a,b-unsaturated nitriles: CuACHTNUGRTENUNG(OAc)2 (1.82 mg, 0.010 mmol) and the
ligand (R)-(S)-3 (6.41 mg, 0.010 mmol, ethanol adduct) were placed in an
oven-dried Schlenk tube and toluene (0.5 mL) was added under a nitro-
gen atmosphere. The reaction mixture was stirred for 10 min at room
temperature and PMHS (90 mL, 1.5 mmol) was added. The reaction was
stirred for 5 min to activate the catalyst. The unsaturated nitrile
(0.5 mmol) in toluene (0.5 mL) was added, followed by tBuOH (191 mL,
2.0 mmol). The reaction was sealed and stirred until the starting material
was completely consumed, as monitored by TLC. The reaction mixture
was quenched with water and transferred to a round-bottomed flask with
the aid of EtOAc (10 mL) and aque-
ous NaOH (2.5m, 1.2 mL) was added.
The biphasic mixture was stirred vigo-
rously for 0.5 h. The layers were sepa-
rated and the aqueous layer was ex-
tracted with EtOAc (3ꢁ20 mL). The
combined organic layers were washed
with brine, dried over MgSO4, and
concentrated in vacuo. The product
was purified by chromatography on
silica gel.
Acknowledgements
This paper was supported by Samsung
Research Fund, Sungkyunkwan Uni-
versity, 2008 and by a Korea Research
Foundation Grant (KRF-2008–531-
C00039) funded by the Korean Gov-
ernment (MOEHRD, Basic Research
Promotion Fund). We thank Prof. S.
Lee and Dr. S. Huh for X-ray analysis
and Solvias for supplying the ligands
used in this study.
Scheme 4. Enantioselective formal synthesis of indatraline.
Chem. Eur. J. 2009, 15, 11134 – 11138
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
11137