dine9) and natural products (e.g., podophyllotoxin10). Their
asymmetric synthesis has been reported by the chiral diene/
rhodium-catalyzed asymmetric 1,4-addition of arylboronic
acids to â-aryl-substituted R,â-unsaturated aldehydes and
esters,4h,5c,d which gave the corresponding â,â-diaryl-
substituted products in 90-93% ee11,12 (Scheme 1). Herein
Table 1. Rhodium-Catalyzed Asymmetric 1,4-Addition of
Phenylboronic Acid (2m) to Arylmethylene Cyanoacetate 1a
Scheme 1
entry
ligand
yielda (%)
eeb (%)
1
2
3
4
(R,R)-Ph-bod*
(R,R)-Bn-bod*
(S,S)-diene
99
94
96
33c
99 (R)
81 (R)
71 (S)
46 (S)
we wish to report that arylmethylene cyanoacetates 1 are
suitable substrates for the rhodium/chiral diene-catalyzed
asymmetric 1,4-addition of arylboronic acids 2, which gave
the corresponding 3,3-diaryl-2-cyanopropanoates 3 in up to
99% ee. This methodology was used for the asymmetric
synthesis of (R)-tolterodine, an important urological drug.9
A rhodium complex coordinated with chiral diene ligand
(R,R)-Ph-bod*,4c,e which is a C2-symmetric bicyclic diene
bearing two phenyl groups on the double bonds, was found
to be highly catalytically active and enantioselective for the
addition of phenylboronic acid (2m) to 4-methoxyphenyl-
methylene cyanoacetate (1a) (entry 1 in Table 1). Thus, the
reaction was completed in 1 h at 20 °C in the presence of 3
mol % of the rhodium catalyst to give 99% yield of 3,3-
(R)-binap
a Isolated yield of a 1:1 mixture of diastereomers. b Determined after
the deesterification giving 4am. c 60% 1a recovered.
diayl-2-cyanopropanoate 3am. Its enantiomeric purity was
determined to be 99% (R) by HPLC analysis (Chiralcel OD-
H) of 3,3-diarylpropanenitrile 4am, which is readily obtained
in a high yield by decarbomethoxylation of 3am. Other
rhodium/diene complexes, where the dienes are (R,R)-Bn-
bod*4c,e and Carreira’s (S,S)-diene,5 were as catalytically
active as the Rh/(R,R)-Ph-bod*, but the enantioselectivity
was lower (entries 2 and 3). Rhodium/phosphine complexes
were much less catalytically active. For example, (R)-binap13
catalyst gave 3am in 33% yield under otherwise the same
reaction conditions (entry 4).
As illustrated in Table 2, the present catalytic asymmetric
1,4-addition is applicable to a broad range of arylboronic
acids and arylmethylene cyanoacetates. The 1,4-addition
proceeded in high yield (>90%) with excellent enantio-
selectivity (96-99% ee) for all of the substrate combinations
we examined. Arylmethylene cyanoacetates substituted with
a methoxy group at the 4-, 3-, and 2-positions on the phenyl
are all good substrates, giving the corresponding arylation
products 3 with over 96% ee in the reaction with phenyl-,
4- or 3-methylphenyl-, and 4-bromophenyl boronic acids.
The enantioselectivities are also very high for arylmethylene
cyanoacetates where the aryl groups are 2-methylphenyl,
2-naphthyl, and 4-chlorophenyl.
(5) (a) Fischer, C.; Defieber, C.; Suzuki, T.; Carreira, E. M. J. Am. Chem.
Soc. 2004, 126, 1628. (b) Defieber, C.; Paquin, J.-F.; Serna, S.; Carreira,
E. M. Org. Lett. 2004, 6, 3873. (c) Paquin, J.-F.; Defieber, C.; Stephenson,
C. R. J.; Carreira, E. M. J. Am. Chem. Soc. 2005, 127, 10850. (d) Paquin,
J.-F.; Stephenson, C. R. J.; Defieber, C.; Carreira, E. M. Org. Lett. 2005,
7, 3821. (e) Fessard, T. C.; Andrews, S. P.; Motoyoshi, H.: Carreira, E.
M. Angew. Chem., Int. Ed. 2007, 46, 9331.
(6) (a) La¨ng, F.; Breher, F.; Stein, D.; Gru¨tzmacher, H. Organometallics
2005, 24, 2997. (b) Grundl, M. A.; Kennedy-Smith, J. J.; Trauner, D.
Organometallics 2005, 24, 2831. (c) Wang, Z.-Q.; Feng, C.-G.; Xu, M.-
H.; Lin, G.-C. J. Am. Chem. Soc. 2007, 129, 5336. (d) Helbig, S.; Sauer,
S.; Cramer, N.; Laschat, S.; Baro, A.; Frey, W. AdV. Synth. Catal. 2007,
349, 2331.
(7) One of the reviewers kindly suggested that the following report should
be cited as an early example of the chiral diene ligand: Sato, Y.; Takimoto,
M.; Mori, M. Tetrahedron Lett. 1996, 37, 887.
(8) McRae, A. L.; Brady, K. T. Expert Opin. Pharmacother. 2001, 2,
883.
(9) (a) Hills, C. J.; Winter, S. A.; Balfour, J. A. Drugs 1998, 55, 813.
(b) Wefer, J.; Truss, M. C.; Jonas, U. World J. Urol. 2001, 19, 312. (c)
Rovner, E. S.; Wein, A. J. Eur. Urol. 2002, 41, 6.
(10) Gordaliza, M.; Garc´ıa, P. A.; Miguel del Corral, J. M.; Castro, M.
A.; Go´mez-Zurita, M. A. Toxicon 2004, 44, 441.
The presence of both cyano and ester groups at the
R-position of the reaction substrates is essential for the high
reactivity and enantioselectivity in the present reaction, which
is demonstrated by the results summarized in Table 3.
Arylmethylene malononitrile 5a and malonate 5b, which are
(11) Higher enantioselectivity (99% ee) has been reported in the reaction
of ArZnCl/ClSiMe3 with 3-arylpropenals calyzed by a rhodium-binap
complex: Tokunaga, N.; Hayashi, T. Tetrahedron: Asymmetry 2006, 17,
607.
(12) The catalytic asymmetric synthesis of â,â-diaryl-substituted carbonyl
compounds has been also reported by use of chiral phosphine-palladium
catalysts: (a) Nishikata, T.; Yamamoto, Y.; Gridnev, I. D.; Miyaura, N.
Organometallics 2005, 24, 5025. (b) Nishikata, T.; Yamamoto, Y.; Miyaura,
N. Tetrahedron Lett. 2007, 48, 4007.
(13) Takaya, H.; Mashima, K.; Koyano, K.; Yagi, M.; Kumobayashi,
H.; Taketomi, T.; Akutagawa, S.; Noyori, R. J. Org. Chem. 1986, 51, 629.
590
Org. Lett., Vol. 10, No. 4, 2008