C.-J. Wang et al. / Tetrahedron Letters 47 (2006) 1901–1903
1903
of this challenging substrate is one of the best results
Acknowledgement
reported to date.
This work was supported by National Institute of
Health grants.
Although the Ru-BINAP system has been recognized as
an efficient and general catalyst for hydrogenation of b-
alkyl substituted b-keto esters, only inferior ee values
were obtained for analogous b-aryl substituted b-keto
esters.3 Asymmetric hydrogenation of b-aryl substituted
b-keto esters remains a challenging task. Only limited
C2-symmetric bisphosphine ligands have been reported
to show good to excellent ee in the Ru-catalyzed hydro-
genation of b-aryl substituted b-keto esters recently.10
For example, up to 99% ee has been reported with bis-
phosphinites ligands10f and 4,40-substituted BINAP
ligands.10g
References and notes
1. (a) Girard, A.; Greck, C.; Ferroud, D.; Genet, J. P.
Tetrahedron Lett. 1996, 37, 7967; (b) Ali, I. S.; Sudalai, A.
Tetrahedron Lett. 2002, 43, 5435; (c) Wirth, D. D.; Miller,
M. S.; Boini, S. K.; Koenig, T. M. Org. Process Res. Dev.
2000, 4, 513; (d) Hodgetts, K. J. Tetrahedron Lett. 2001,
42, 3763.
2. For recent reviews of asymmetric hydrogenation, see: (a)
Tang, W.; Zhang, X. Chem. Rev. 2003, 103, 3029; (b)
McCarthy, M.; Guiry, P. J. Tetrahedron 2001, 57, 3809;
(c) Catalytic Asymmetric Synthesis; Ojima, I., Ed.; Wiley-
VCH: Weinheim, Germany, 2000; (d) Comprehensive
Asymmetric Catalysis; Jacobsen, E. N., Pfalts, A.,
Yamamoto, H., Eds.; Springer: Berlin, Germany, 1999.
3. Noyori, R.; Ohkuma, T.; Kitamura, M.; Takaya, H. J.
Am. Chem. Soc. 1987, 109, 5856.
4. Burk, M. J.; Harper, T. G. P.; Kalberg, C. S. J. Am. Chem.
Soc. 1995, 117, 4423.
5. Yamano, T.; Taya, N.; Kawada, M.; Huang, T.; Imam-
oto, T. Tetrahedron Lett. 1999, 40, 2577.
6. (a) Tang, W.; Zhang, X. Angew. Chem., Int. Ed. Engl.
2002, 41, 1612; (b) Tang, W.; Zhang, X. Org. Lett. 2002, 4,
4159; (c) Tang, W.; Liu, D.; Zhang, X. Org. Lett. 2003, 5,
205.
7. RuCl2(TangPhos)(DMF)m A was prepared according to
the method in the literature: Forman, G. S.; Ohkuma, T.;
Hems, W. P.; Noyori, R. Tetrahedron Lett. 2000, 41,
9471.
8. Ru(TangPhos)Br2 B was prepared according to the
method in the literature: Geneˆt, J. P.; Pinel, C.; Mallart,
S.; Juge, S.; Thorimbert, S.; Laffitte, J. A. Tetrahedron:
Asymmetry 1991, 2, 555.
9. Kitamura, M.; Ohkuma, T.; Takaya, H.; Noyori, R.
Tetrahedron Lett. 1988, 29, 1555.
10. (a) Duprat de Paule, S.; Jeulin, S.; Ratovelomanana-Vidal,
V.; Genet, J. P.; Champion, N. S.; Dellis, P. Eur. J. Org.
Chem. 2003, 10, 1931; (b) Pai, C. C.; Lin, C. W.; Lin, C.
C.; Chen, C. C.; Chan, A. S. C. J. Am. Chem. Soc. 2000,
122, 11513; (c) Saito, T.; Yokozawa, T.; Ishizaki, T.;
Moroi, T.; Sayo, N.; Miura, T.; Kumobayashi, H. Adv.
Synth. Catal. 2001, 343, 264; (d) Ratovelomanana-Vidal,
V.; Girard, C.; Touati, R.; Tranchier, J. P.; Ben Hassine,
B.; Genet, J. P. Adv. Synth. Catal. 2003, 345, 261; (e)
Ireland, T.; Grossheimann, G.; Wieser-Jeunesse, C.;
Knochel, P. Angew. Chem., Int. Ed. 1999, 38, 3212; (f)
Zhou, Y.-G.; Tang, W.; Wang, W.-B.; Li, W.; Zhang, X.
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Lin, W. Angew. Chem., Int. Ed. 2004, 43, 2501.
To our delight, Ru-TangPhos complexes have also
shown excellent enantioselectivities for b-aryl substi-
tuted b-keto esters. The results are summarized in Table
2. Compared with the hydrogenation of b-alkyl substi-
tuted b-keto esters, high temperature and high pressure
are the key factors for achieving higher ees for b-aryl
substituted b-keto ester (Table 2, entries 1–5). Under
the optimized reaction condition, a series of b-aryl
substituted b-keto esters proceeded smoothly to give
the desired hydrogenation products. For b-aryl substi-
tuted b-keto esters with electron-donating group on
the phenyl ring, 94.2–97.5% ee were observed (Table 2,
entries 4 and 10–13). The best results were obtained in
the hydrogenation of substrates with electron-withdraw-
ing group on the phenyl ring, and up to 99.5% ee was
achieved for 3-(4-chloro-phenyl)-3-oxo-propionic acid
ethyl ester (3b) and 3-(4-Bromo-phenyl)-3-oxo-propio-
nic acid ethyl ester (3c) (Table 2, entries 6–9). Complete
conversion and very high ee value (99.0%) were still
observed even when the hydrogenation of 3b was carried
out with 0.1 mol % catalyst loading. To the best of our
knowledge, this is the first report that electron-donating
chiral bis(trialkylphosphine) ligand can achieve very
high enantioselectivities in the hydrogenation of both
b-alkyl and b-aryl substituted b-keto esters.
In conclusion, we have applied the Ru-TangPhos cata-
lyst for the asymmetric hydrogenation of b-keto esters,
and up to 99.8% ee has been observed for both b-alkyl
substituted and b-aryl substituted b-keto esters. These
results demonstrate that the Ru-Tangphos catalyst has
a potential for practical synthesis of a variety of chiral
b-hydroxy esters. Further applications of the Ru-Tang-
Phos catalyst are underway and progress will be dis-
closed in the future.