J. Am. Chem. Soc. 1999, 121, 9473-9474
9473
Asymmetric Conjugate Reduction of r,â-Unsaturated
Esters Using a Chiral Phosphine-Copper Catalyst
Daniel H. Appella, Yasunori Moritani, Ryo Shintani,
Eric M. Ferreira, and Stephen L. Buchwald*
Department of Chemistry
Massachusetts Institute of Technology
Cambridge, Massachusetts 02139
ReceiVed July 8, 1999
Currently, there are few catalysts that can reduce carbon-
carbon double bonds to generate products with stereocenters â
to carbonyls and with high enantiomeric excess (ee). In this area,
asymmetric conjugate additions of nucleophiles to R,â-unsaturated
ketones have been intensely investigated (Scheme 1); the best
catalysts for these reactions work well for a limited number of
substrates and nucleophiles.1 In some cases, asymmetric hydro-
genation catalysts also provide access to products with stereo-
centers â to carbonyls.2 Asymmetric conjugate reduction of an
R,â-unsaturated carbonyl portion of a molecule can also generate
a stereocenter â to a carbonyl.3 Despite the numerous catalysts
available for conjugate reduction,4 only Pfaltz’s chiral semicorrin
cobalt system is a highly effective catalyst for asymmetric
conjugate reductions. In this system, sodium borohydride is used
as the stoichiometric reducing agent.5,6
Figure 1. Conjugate reduction of ethyl trans-â-methylcinnamate using
p-tol-BINAP of varying ee. Each data point is the average of two
reactions; the line corresponds to a least-squares linear regression of the
data with slope ) 0.909, intercept ) 1.450, and r2 ) 0.998.
Scheme 1
We have begun to investigate whether a copper hydride, with
a chiral phosphine ligand, can be used as a catalyst for asymmetric
(1) (a) Gomez-Bengoa, E.; Heron, N. M.; Didiuk, M. T.; Luchaco, C. A.;
Hoveyda, A. H. J. Am. Chem. Soc. 1998, 120, 7649. (b) Keller, E.; Maurer,
J.; Naasz, R.; Schader, T.; Meetsma, A.; Feringa, B. L. Tetrahedron:
Asymmetry 1998 9, 2409. (c) Nakagawa, Y.; Kanai, M.; Nagaoka, Y.; Tomioka,
K. Tetrahedron 1998, 54, 10295. (d) Takaya, Y.; Ogasawara, M.; Hayashi,
T.; Sakai, M.; Miyaura, N. J. Am. Chem. Soc. 1998, 120, 5579. (e) Yan, M.;
Yang, L.-W.; Wong, K.-Y.; Chan, A. S. C. J. Chem. Soc., Chem. Commun.
1999, 11. (f) Krause, N. Angew. Chem., Int. Ed. 1998, 37, 283 and references
therein.
(2) (a) Asymmetric hydrogenations that generate a chiral center â to a
carbonyl: Yamamoto, K.; Ikeda, K.; Yin, L. K. J. Organomet. Chem. 1989,
370, 319. Saburi, M.; Takeuchi, H.; Ogasawara, M.; Tsukahara, T.; Ishii, Y.;
Ikariya, T.; Takahashi, T.; Uchida, Y. J. Organomet. Chem. 1992, 428, 155.
Uemura, T.; Zhang, X.; Matsumura, K.; Sayo, N.; Kumobayashi, H.; Ohta,
T.; Nozaki, K.; Takaya, H. J. Org. Chem. 1996, 61, 5510. Yamada, I.;
Ohkouchi, M.; Yamaguchi, M.; Yamagishi, T. J. Chem. Soc., Perkin Trans.
1 1997, 1869. Lightfoot, A.; Schnider, P.; Pfaltz, A. Angew. Chem., Int. Ed.
1998, 37, 7, 2897. (b) Asymmetric hydrogenations that simutaneously generate
chiral centers R and â to a carbonyl: Hayashi, T.; Kawamura, N.; Ito, Y. J.
Am. Chem. Soc. 1987, 109, 7876. Burk, M. J.; Gross, M. F.; Martinez, J. P.
J. Am. Chem. Soc. 1995, 117, 9375. Sawamura, M.; Kuwano, R.; Ito, Y. J.
Am. Chem. Soc. 1995, 117, 9602. Imamoto, T.; Watanabe, J.; Wada, Y.;
Masuda, H.; Yamada, H.; Tsuruta, H.; Matsukawa, S.; Yamaguchi, K. J. Am.
Chem. Soc. 1998, 120, 1635.
(3) Hayashi, T.; Yamamoto, K.; Kumada, M. Tetrahedron Lett. 1975, 3.
(4) (a) Cu catalysts: Semmelhack, M. F.; Stauffer, R. D.; Yamashita, A.
J. Org. Chem. 1977, 42, 3180. Tsuda, T.; Yoshida, T.; Kawamoto, T.; Saegusa,
T. J. Org. Chem. 1987, 52, 1624. Ito, H.; Ishizuka, T.; Arimoto, K.; Miura,
K.; Hosomi, A. Tetrahedron Lett. 1997, 38, 8887. (b) Ir catalyst: Apple, D.
C.; Brady, K. A.; Chance, J. M.; Heard, N. E.; Nile, T. A. J. Mol. Catal.
1985, 29, 55. (c) Mo catalysts: Keinan, E.; Perez, D. J. Org. Chem. 1987,
52, 2576. Schmidt, T. Tetrahedron Lett. 1994, 35, 3513. (d) Ni catalysts:
Caporusso, A. M.; Giacomelli, G.; Lardicci, L. J. Org. Chem. 1982, 47, 4640.
Boudjouk, P.; Choi, S.,-B.; Hauck, B. J.; Rajkumar, A. B. Tetrahedron Lett.
1998, 39, 3951. (e) Pd catalysts: Keinan, E.; Greenspoon, N. J. Am. Chem.
Soc. 1986, 108, 7314. Arcadi, A.; Bernocchi, E.; Cacchi, S.; Marinelli, F.
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A. J. Organomet. Chem. 1980, 191, 39. Johnson, C. R.; Raheja, R. K. J. Org.
Chem. 1994, 59, 2287. (g) Rh catalysts: Yoshii, E.; Kobayashi, Y.; Koizumi,
T.; Oribe, T. Chem. Pharm. Bull. 1974, 22, 2767. Ojima, I.; Kogure, T.
Organometallics 1982, 1, 1390. Evans, D. A.; Fu, G. C. J. Org. Chem. 1990,
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Zheng, G. Z.; Chan, T. H. Organometallics 1995, 14, 70.
conjugate reduction using a silane reagent as the stoichiometric
reductant. Achiral phosphine-copper hydride complexes, such
as [(Ph3P)CuH]6, have been shown to act as catalysts for conjugate
reductions of R,â-unsaturated carbonyl compounds in combination
with phenylsilane or phenyldimethylsilane.7,8 We now report that
a catalyst formed from p-tol-BINAP,9 CuCl, and NaOt-Bu affects
the asymmetric conjugate reduction of R,â-unsaturated esters in
the presence of 4 equiv of polymethylhydrosiloxane (PMHS)
relative to the substrate. We felt that using PMHS, a safe and
inexpensive polymer that has been previously employed as a
stoichiometric reductant in metal-catalyzed reductions of ketones10
and imines,11 would greatly enhance the utility of any process
that we would develop.
In practice, we were able to generate an efficient catalyst in
situ by first combining (S)-p-tol-BINAP, CuCl, and NaOt-Bu in
toluene, followed by addition of PMHS. For a series of R,â-
unsaturated esters, conjugate reductions usually took 24 h at room
temperature with 5 mol % catalyst and 4 equiv of PMHS. As
shown in Table 1, products were obtained with good ee’s and in
excellent yields. When the amount of catalyst was lowered to 1
mol %, a longer reaction time was necessary for the reaction to
go to completion, but the ee of the product was unchanged. The
reaction worked best when carried out under air-free conditions,
presumably due to the sensitivity of copper hydrides to oxygen.
(7) (a) Lipshutz, B. H.; Keith, J.; Papa, P.; Vivian, R. Tetrahedron Lett.
1998, 39, 4627. (b) Mori, A.; Fujita, A.; Kajiro, H.; Nishihara, Y.; Hiyama,
T. Tetrahedron 1999, 55, 4573.
(8) [(Ph3P)CuH]6 also functions as a catalyst for conjugate reduction in
the presence of H2: Mahoney, W. S.; Stryker, J. M. J. Am. Chem. Soc. 1989,
111, 8818.
(9) p-tol-BINAP is an abbreviation for 2,2′-bis(di-p-tolylphosphino)-1,1′-
binaphthyl; each enantiomer is commercially available.
(10) (a) Carter, M. B.; Schiøtt, B.; Gutie´rrez, A.; Buchwald, S. L. J. Am.
Chem. Soc. 1994, 116, 11667. (b) Yun, J.; Buchwald, S. L. J. Am. Chem.
Soc. 1999, 121, 5640. (c) Mimoun, H.; de Saint Laumer, J. Y.; Giannini, L.;
Scopelliti, R.; Floriani, C. J. Am. Chem. Soc. 1999, 121, 6158.
(11) (a) Verdaguer, X.; Lange, U. E. W.; Buchwald, S. L. Angew. Chem.,
Int. Ed. 1998, 37, 1103. (b) Hansen, M. C.; Buchwald, S. L. Tetrahedron
Lett. 1999, 40, 2033.
(5) (a) Leutenegger, U.; Madin, A.; Pfaltz, A. Angew. Chem., Int. Ed. Engl.
1989, 28, 60. (b) von Matt, P.; Pfaltz, A. Tetrahedron: Asymmetry, 1991, 2,
691. (c) Misun, M.; Pfaltz, A. HelV. Chim. Acta 1996, 79, 961.
(6) For a recent example of a chiral aldiminato cobalt catalyst for
asymmetric reduction of R,â-unsaturated amides, see: Yamada, T.; Ohtsuka,
Y.; Ikeno, T. Chem. Lett. 1998, 1129.
10.1021/ja992366l CCC: $18.00 © 1999 American Chemical Society
Published on Web 09/24/1999