ORGANIC
LETTERS
2005
Vol. 7, No. 11
2285-2288
Rhodium-Catalyzed Asymmetric
1,4-Addition of Arylboronic Acids to
Coumarins: Asymmetric Synthesis of
(R)-Tolterodine
Gang Chen, Norihito Tokunaga, and Tamio Hayashi*
Department of Chemistry, Graduate School of Science, Kyoto UniVersity, Sakyo,
Kyoto 606-8502, Japan
Received April 6, 2005
ABSTRACT
Rhodium-catalyzed asymmetric 1,4-addition of arylboronic acids to coumarins proceeded with high enantioselectivity in the presence of a
rhodium catalyst (3 mol %) generated from Rh(acac)(C2H4)2 and (R)-Segphos to give the corresponding (R)-4-arylchroman-2-ones in over 99%
ee. This asymmetric reaction was applied to the synthesis of (R)-tolterodine.
Some of the enantiomerically enriched compounds possess-
ing a chiral diarylmethane unit are known to be biologically
active, and their preparation by asymmetric synthesis has
recently attracted growing attention.1,2 One of the straight-
forward methods of constructing a stereogenic carbon center
connected with two different aryl groups and one alkyl group
is asymmetric conjugate addition of an aryl nucleophile to
electron-deficient olefins substituted with another aryl group
at the â-position. Although the rhodium-catalyzed asym-
metric conjugate addition3 has been successfully applied to
a variety of electron-deficient olefins, including R,â-unsatur-
ated ketones,4,5 esters,6 amides,7 alkenylphosphonates,8 ni-
troalkenes,9 and alkenyl sulfones,10 its application to the
â-aryl-substituted substrates remains to be studied.11 Herein
we report that coumarin derivatives are suitable substrates
for the rhodium-catalyzed asymmetric conjugate addition to
give 4-arylchroman-2-ones, in which the stereogenic carbon
center at the 4 position is substituted with two aryl groups,
(4) (a) Takaya, Y.; Ogasawara, M.; Hayashi, T.; Sakai, M.; Miyaura, N.
J. Am. Chem. Soc. 1998, 120, 5579. (b) Takaya, Y.; Ogasawara, M.;
Hayashi, T. Tetrahedron Lett. 1999, 40, 6957. (c) Hayashi, T.; Takahashi,
M.; Takaya, Y.; Ogasawara, M. Org. Synth. 2002, 79, 84. (d) Hayashi, T.;
Takahashi, M.; Takaya, Y.; Ogasawara, M. J. Am. Chem. Soc. 2002, 124,
5052. (e) Hayashi, T.; Tokunaga, N.; Yoshida, K.; Han, J.-W. J. Am. Chem.
Soc. 2002, 124, 12102. (f) Yoshida, K.; Ogasawara, M.; Hayashi, T. J.
Org. Chem. 2003, 68, 1901. (g) Hayashi, T.; Ueyama, K.; Tokunaga, N.;
Yoshida, K. J. Am. Chem. Soc. 2003, 125, 11508. (h) Tokunaga, N.;
Yoshida, K.; Hayashi, T. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5445. (i)
Shintani, R.; Tokunaga, N.; Doi, H.; Hayashi, T. J. Am. Chem. Soc. 2004,
126, 6240.
(5) (a) Kuriyama, M.; Tomioka, K. Tetrahedron Lett. 2001, 42, 921. (b)
Kuriyama, M.; Nagai, K.; Yamada, K.-i.; Miwa, Y.; Taga, T.; Tomioka,
K. J. Am. Chem. Soc. 2002, 124, 8932. (c) Reetz, M. T.; Moulin, D.;
Gosberg, A. Org. Lett. 2001, 3, 4083. (d) Amengual, R.; Michelet, V.; Geneˆt,
J.-P. Synlett 2002, 1791. (e) Pucheault, M.; Darses, S.; Geneˆt, J.-P.
Tetrahedron Lett. 2002, 43, 6155. (f) Pucheault, M.; Darses, S.; Geneˆt,
J.-P. Eur. J. Org. Chem. 2002, 3552. (g) Itooka, R.; Iguchi, Y.; Miyaura,
N. J. Org. Chem. 2003, 68, 6000. (h) Boiteau, J.-G.; Imbos, R.; Minnaard,
A. J.; Feringa, B. L. Org. Lett. 2003, 5, 681 and 1385. (i) Shi, Q.; Xu, L.;
Li, X.; Jia, X.; Wang, R.; Au-Yeung, T. T.-L.; Chan, A. S. C.; Hayashi, T.;
Cao, R.; Hong, M. Tetrahedron Lett. 2003, 44, 6505. (j) Iguchi, Y.; Itooka,
R.; Miyaura, N. Synlett 2003, 1040. (k) Boiteau, J.-G.; Minnaard, A. J.;
Feringa, B. L. J. Org. Chem. 2003, 68, 9481. (l) Ma, Y.; Song, C.; Ma, C.;
Sun, Z.; Chai, Q.; Andrus, M. B. Angew. Chem., Int. Ed. 2003, 42, 5871.
(m) Duursma, A.; Boiteau, J.-G.; Lefort, L.; Boogers, J. A. F.; de Vries, A.
H. M.; de Vries, J. G.; Minnaard, A. J.; Feringa, B. L. J. Org. Chem. 2004,
69, 8045.
(1) As a pertinent review: Bolm, C.; Hildebrand, J. P.; Mun˜iz, K.;
Hermanns, N. Angew. Chem., Int. Ed. 2001, 40, 3284.
(2) For recent examples: (a) Paras, N. A.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2002, 124, 7894. (b) Prat, L.; Mojovic, L.; Levacher, V.; Dupas,
G.; Que´guiner, G.; Bourguignon, J. Tetrahedron: Asymmetry 1998, 9, 2509.
(c) Lautens, M.; Rovis, T. J. Org. Chem. 1997, 62, 5246.
(3) For reviews: (a) Hayashi, T. Synlett 2001, 9, 879. (b) Fagnou, K.;
Lautens, M. Chem. ReV. 2003, 103, 169. (c) Hayashi, T.; Yamasaki, K.
Chem. ReV. 2003, 103, 2829. (d). Hayashi, T. Pure Appl. Chem. 2004, 76,
465.
10.1021/ol0507367 CCC: $30.25
© 2005 American Chemical Society
Published on Web 05/04/2005