Ru-catalyzed asymmetric hydrogenation of α-ketoesters with CeCl 3·7H2O as additive

Article abstract of DOI:10.1021/ol052212c

(Chemical Equation Presented) An efficient asymmetric hydrogenation of α-ketoesters is reported with use of a catalyst prepared from [Ru((S)-3)(benzene)Cl]Cl and CeCl₃-7H₂O. α-Hydroxy esters are obtained in up to 96% ee. The addition of CeCl₃· 7H₂O not only improves the enantioselectivity, but also enhances the stability of the catalyst. As a result, the hydrogenation of methyl benzoylformate affords the product with 92% ee with a substrate/catalyst ratio of 10 000. Hydrolysis of 2 provides the final compound with 83% yield at 99% ee after a single recrystallization from 1,2-dichloroethylene.

Full text of DOI:10.1021/ol052212c

ORGANIC
LETTERS
2005
Vol. 7, No. 24
5425-5427
Ru-Catalyzed Asymmetric Hydrogenation
of -Ketoesters with CeCl3 7H2O as
Additive
r
‚
Yanhui Sun,† Xiaobing Wan,† Jianping Wang,‡ Qinghua Meng,‡ Hongwei Zhang,‡
Lijuan Jiang,‡ and Zhaoguo Zhang*,†,‡
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, and School of Chemistry and Chemical Engineering, Shanghai Jiaotong
UniVersity, Shanghai 200240, China
zhaoguo@sjtu.edu.cn
Received September 13, 2005
ABSTRACT
An efficient asymmetric hydrogenation of
r
-ketoesters is reported with use of a catalyst prepared from [Ru((S)-3)(benzene)Cl]Cl and CeCl3
‚
7H2O. -Hydroxy esters are obtained in up to 96% ee. The addition of CeCl3
r
‚7H2O not only improves the enantioselectivity, but also enhances
the stability of the catalyst. As a result, the hydrogenation of methyl benzoylformate affords the product with 92% ee with a substrate/catalyst
ratio of 10 000. Hydrolysis of 2 provides the final compound with 83% yield at 99% ee after a single recrystallization from 1,2-dichloroethylene.
Optically active R-hydroxy acids and their derivatives are
very important structural motifs in numerous biologically
interesting compounds1 and are often utilized as resolving
agents.2 Accordingly, considerable effort has been devoted
to their preparation via asymmetric synthesis. Besides optical
resolution of the racemates with resolving agents, reductive
approaches have been developed extensively,3 including (1)
reductions by chiral boranes,4 (2) diastereoselective reduc-
tions with the help of chiral auxiliaries,5 (3) homogeneous
hydrogenations and hydrogen transfer reactions,6 (4) hetero-
geneous catalytic enantioselective hydrogenations, especially
hydrogenation with Pt-cinchona modifiers,3,7 and (5) enzy-
matic or biomimetic methods.8 Recently, a few other catalytic
approaches have been reported: namely, carbon-carbon
bond formation reaction,9 kinetic resolution/asymmetric
(5) (a) Solodin, I.; Goldberg, Y.; Zelcans, G.; Lukevics, E. J. Chem.
Soc., Chem. Commun. 1990, 1321. (b) Xiang, Y. B.; Snow, K.; Belley, M.
J. Org. Chem. 1993, 58, 993. (c) Maitra, U.; Mathivanan, P. Tetrahedron:
Asymmetry 1994, 5, 1171.
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1977, 428. (b) Blaser, H.-U.; Jalett, H.-P.; Spindler, F. J. Mol. Catal. A:
Chem. 1996, 107, 85. (c) Pasquier, C.; Eilers, J.; Reiners, I.; Martens, J.;
Mortreux, A.; Agbossou, F. Synlett 1998, 1162. (d) ter Halle, R.; Schultz,
E.; Spagnol, M.; Lemaire, M. Synlett 2000, 680. (e) Jones, M. D.; Raja,
R.; Thomas, J. M.; Johnson, B. F. G.; Lewis, D. W.; Rouzaud, J.; Harris,
K. D. M. Angew. Chem., Int. Ed. 2003, 42, 4326. (f) Gamez, P.; Fache, F.;
Lemaire, M. Tetrahedron: Asymmetry 1995, 6, 705. (g) Gamez, P.; Fache,
F.; Mangeney, P.; Lemaire, M. Tetrahedron Lett. 1993, 34, 6897.
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H.-U.; Schreier, P. J. Org. Chem. 1997, 62, 7841. (b) Drioli, S.; Nitti, P.;
Pitacco, G.; Tossut, L.; Valentin, E. Tetrahedron: Asymmetry 1999, 10,
2713. (c) Kanomata, N.; Nakata, T. J. Am. Chem. Soc. 2000, 19, 4563. (d)
Ohno, A.; Ikeguchi, M.; Kimura, T.; Oka, S. J. Am. Chem. Soc. 1979, 101,
7036. (e) Kanomata, N.; Nakata, T. Angew. Chem., Int. Ed. Engl. 1997,
36, 1207.
† State Key Laboratory of Organometallic Chemistry, Shanghai Institute
of Organic Chemistry.
‡ School of Chemistry and Chemical Engineering, Shanghai Jiaotong
University.
(1) (a) In ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N., Pfaltz,
A., Yamamoto, H., Eds.; Springer: Berlin, Germany, 1999; Vols. I-III.
(b) In Catalysis Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley-
VCH: New York, 2000.
(2) Kinbara, K. Synlett 2005, 732.
(3) Szo¨ri, K.; Sutyinszki, M.; Felfo¨ldi, K.; Barto´k, M. Appl. Catal., A
2002, 237, 275.
(4) (a) Brown, H. C.; Pai, G. G. J. Org. Chem. 1985, 50, 1384. (b) Singh,
V. K. Synthesis 1992, 605. (c) Wang, Z.; La, B.; Fortunak, J. M.; Meng,
X.-J.; Kabalka, G. W. Tetrahedron Lett. 1998, 39, 5501.
10.1021/ol052212c CCC: $30.25
© 2005 American Chemical Society
Published on Web 10/29/2005

oxidation of R-hydroxy esters,10 and dynamic kinetic resolu-
tion of dioxolanediones.11 However, the catalytic reductive
approaches to nonracemic R-hydroxy acids or esters are the
most attractive due to their simplicity and efficiency. Despite
all of these achievements, developing effective, easily
reproducible, highly stereoselective and universal approaches
to R-hydroxy acids or esters is still challenging.
Table 1. Asymmetric Hydrogenation of Methyl
Benzoylformate with (Ru(L*)(benzene)Cl)Cla
In this Letter, we report a Ru-catalyzed homogeneous
hydrogenation reaction of R-ketoesters with various Lewis
acids as additives. Our model reactions were conducted with
[Ru((S)-3)(benzene)Cl]Cl as the catalyst,12 which is efficient
in the hydrogenation of â-ketoesters,12c and which is easily
prepared by heating [Ru(benzene)Cl2]2 and (S)-3 (molar ratio
1:2.2) in a solution of EtOH and CH2Cl2 (1:1, v/v) at 50 °C.
Hydrogenation reactions were carried out with a ketoester/
Ru ratio of 100 at 0.5 M concentration. The reaction was
completed within 20 h at 70 °C with a hydrogen pressure of
50 atm. Under these catalytic conditions, the hydrogenation
of methyl benzoylformate (1a) afforded the product with
good enantioselectivity (85% ee, Table 1, entry 1). (S)-3 is
superior to BINAP and comparable to SEGPhos (Table 1,
entries 1-4).
It is reported that catalytic additives play a crucial role in
improving the reactivity and enantioselectivity of many
asymmetric reactions.13 King et al.14 reported that acid
additives can promote the reaction rates in ruthenium-
catalyzed hydrogenations of â-ketoesters. Utilizing Brønsted
acids as additives, Takaya and co-workers 12b also acquired
elevated enantioselectivities (79% vs to 89% ee) in the
asymmetric hydrogenation of R-ketoesters. Noyori and co-
workers15 found that Ru(II) catalysts in situ modified with
acid facilitate the hydrogenation of simple ketones and
4-oxoesters. They also showed that no reaction takes place
without acid additives. Although it is not quite clear what
these additives do in terms of the reaction mechanism, they
are often beneficial in the ruthenium-catalyzed hydrogenation
of ketones. Therefore, Brønsted acids were tested and results
were positive but still not excellent (87-89% ee, Table 1,
entries 5 and 6).
entry
additive
ee (%)b
1
2c
3d
4e
5
6
7
8
9
10
11
12
13
14
15
16
17c
18f
85
85
84
79
87
89
90
91
85
87
92
96
95
96
95
93
96
96
HBF4 aq
CSA
CuCl
CuCl2
MgCl2‚6H2O
AlCl3
FeCl3
CeCl3‚7H2O
LaCl3‚7H2O
NdCl3‚6H2O
SmCl3‚6H2O
YbCl3‚6H2O
CeCl3‚7H2O
CeCl3‚7H2O/CSA
a All reactions were carried out in MeOH with a substrate concentration
of 0.5 M at 70 °C under 50 atm of H2 for 20 h. Substrate/[Ru(benzene)Cl2]2/
(S)-3/additive: 100/0.5/1.1/5; conversion:100%. b Ee values were determined
by HPLC on a Chiracel OD-H column. The configuration was determined
to be R by comparing the specific rotation with reported data. c Ethyl
benzoylformate (1b) was hydrogenated in EtOH under the same conditions.
d 1b was hydrogenated in EtOH under the same conditions with SEGPhos
as ligand. e [Ru(binap)(benzene)Cl]Cl as the catalyst according to ref 12b.
f 1b was hydrogenated in EtOH under the same conditions. Both CeCl3‚7H2O
and CSA are 5 equiv relative to the catalyst.
Lewis acids are among the most useful reagents in
reactions with ketones as substrates.16 For example, CeCl3‚
7H2O was used in the selective reduction of the carbonyl
group of R,â-unsaturated ketones with NaBH4.17 When Lewis
acids were used as additives in the hydrogenation of our
model substrate 1a with ruthenium as the catalyst (Table 1,
entries 7-16), dramatically improved enantioselectivities
(90-96% ee) were obtained. The best results were achieved
with LnCl3‚XH2O as additives and ee values of the reduced
product were comparable (Table 1, entries 12-16). There
was no detectable difference between the hydrogenations of
methyl and ethyl benzoylformates (Table 1, entries 12 and
17). The reactions with both CeCl3‚7H2O and CSA (1:1)
(CSA: D-camphor-10-sulfonic acid) as additives provided
the same ee value as those with only CeCl3‚7H2O as the
additive (96% ee, Table 1, entries 17 vs 18). For simplicity
and better reproducibility, substrate/[Ru(benzene)Cl2]2/(S)-
3/CeCl3‚7H2O with a ratio of 100/0.5/1.1/5 was employed
as the standard set of reaction conditions.
(9) Yuan, Y.; Zhang, X.; Ding, K. Angew. Chem., Int. Ed. 2003, 42,
5478.
(10) Radosevich, A. T.; Musich, C.; Toste, F. D. J. Am. Chem. Soc. 2005,
127, 1090.
(11) Tang, L.; Deng, L. J. Am. Chem. Soc. 2002, 124, 2871.
(12) (a) Mashima, K.; Kusano, K.; Ohta, T.; Noyori, R.; Takaya, H. J.
Chem. Soc., Chem. Commun. 1989, 1208. (b) Mashima, K.; Kusano, K.;
Sate, N.; Matsumura, Y.; Nozaki, K.; Kumobayashi, H.; Sayo, N.; Hori,
Y.; Ishizaki, T.; Akutagawa, S.; Takaya, H. J. Org. Chem. 1994, 59, 3064.
(c) Sun, Y.; Wan, X.; Guo, M.; Wang, D.; Dong, X.; Pan, Y.; Zhang, Z.
Tetrahedron: Asymmetry 2004, 15, 2185. (d) Wan, X.; Sun, Y.; Luo, Y.;
Li, D.; Zhang, Z. J. Org. Chem. 2005, 70, 1070.
(13) (a) Vogl, E. M.; Groger, H.; Shibasaki, M. Angew. Chem., Int. Ed.
1999, 38, 1570. (b) Chan, Y. N. C.; Osborn, J. A. J. Am. Chem. Soc. 1990,
112, 9400. (c) Togni, A. Angew. Chem., Int. Ed. Engl. 1996, 35, 1475. (d)
Wang, W.-B.; Lu, S.-M.; Yang, P.-Y.; Han, X.-W.; Zhou, Y.-G. J. Am.
Chem. Soc. 2003, 125, 10536. (e) Xiao, D.; Zhang, X. Angew. Chem., Int.
Ed. 2001, 40, 3425. (f) Morimoto, T.; Nakajima, N.; Achiwa, K. Chem.
Pharm. Bull. 1994, 42, 1951. (g) Morimoto, T.; Nakajima, N.; Achiwa, K.
Synlett 1995, 748. (h) Morimoto, T.; Suzuki, N.; Achiwa, K. Heterocycles
1996, 43, 2557. (i) Tani, K.; Onouchi, J.; Yamagata, T.; Kataoka, Y. Chem.
Lett. 1995, 955.
Under the optimized reaction conditions, a variety of
substrates were tested in the asymmetric hydrogenations with
(14) King, S. A.; Thompson, A. S.; King, A. O.; Verhoeven, T. R. J.
Org. Chem. 1992, 57, 6689.
(15) (a) Noyori, R.; Ohkuma, T. Angew. Chem., Int. Ed. 2001, 40, 40.
(b) Ohkuma, T.; Kitamura, M.; Noyori, R. Tetrahedron Lett. 1990, 31, 5509.
(16) Yamamoto, H. Lewis Acids in Organic Synthesis; VCH: Weinheim,
Germany, 2000; Vol. 1.
(17) Gemal, A. L.; Luche, J.-L. J. Am. Chem. Soc. 1981, 103, 5454.
5426
Org. Lett., Vol. 7, No. 24, 2005

[Ru((S)-3)(benzene)Cl]Cl and the CeCl3‚7H2O system (Table
2, column C). Hydrogenation of 4-halo or 4-methyl ben-
Table 2. Asymmetric Hydrogenation of RCOCO2Et with
Additivesa
eeb
Figure 1. The color difference between the catalyst solutions with
and without CeCl3‚7H2O Left: Catalyst in methanol solution with
5 equiv of CeCl3‚7H2O (relative to Ru) as additive. Right: Catalyst
in methanol solution without any additive. Both of the solutions
were stirred in air for 10 days.
entry
Ar
Ph (1b)
A
B
C
1
2
3
4
5
6
7
8
9c
85
87
89
29
75
75
80
40
83
89
90
89
30
88
87
86
-9
92
96
95
88
87
95
94
95
76
84
4-Me-C6H4 (1c)
4-MeO-C6H4 (1d)
2-Me-C6H4 (1e)
4-F-C6H4 (1f)
4-Cl-C6H4 (1g)
4-Br-C6H4 (1h)
2- Cl-C6H4 (1i)
Me (1j)
which indicated that the catalyst was decomposing (Figure
1). When this greenish solution is employed in the hydro-
genation of R-ketoesters, the reaction was very sluggish and
the enantioselectivity was poor. However, the catalyst in the
MeOH solution with 5 equiv of CeCl3‚7H2O (relative to Ru)
remained orange after the solution was stirred in air for 10
days, and hydrogenation of 1a with this solution under the
standard reaction condition gave complete conversion of
substrate and the product with 87% ee.
a All reactions were carried out in EtOH with a substrate concentration
of 0.5 M at 70 °C and 50 atm of H2 for 20 h. Substrate/[Ru(benzene)Cl2]2/
(S)-3/ additive: 100/0.5/1.1/5; conversion 100%. b Ee values were deter-
mined by HPLC on a Chiracel OD-H column. A, no additive; B, CSA as
additive; C, CeCl3‚7H2O as additive. c Ee values were determined by GC
on a â-DEX-325 column.
The stabilizing effect of CeCl3‚7H2O prompted us to
develop a practical asymmetric hydrogenation reaction of
benzoylformate with high TON. [Ru((S)-3)(benzene)Cl]Cl
(37 mg, 0.04 mmol) and CeCl3‚7H2O (75 mg, 0.2 mmol)
were dissolved in 80 mL of MeOH in an autoclave in a
glovebox, and combined with freshly distilled and degassed
methyl benzoylformate (1a) (65.6 g, 400 mmol). The
autoclave was purged three times with H2, and the pressure
of H2 was set to 60 atm. The autoclave was placed to an oil
bath at 100 °C for 10 h to achieve complete conversion.
Routine workup gave 66.0 g of 2a as a white solid (99.3%
yield, 92% ee). The reduced product was hydrolyzed to
mandelic acid and recrystallized from ClCH2CH2Cl to afford
material of >99% ee in 83% yield. This is a promising
procedure for a large-scale or even industrial setting.
In conclusion, using Lewis acid additives, we have
developed an efficient homogeneous asymmetric hydrogena-
tion reaction of R-ketoesters; high enantioselectivities and
TON were achieved. Further applications of this method to
extend the scope of substrates and exploration of the
mechanism are currently underway in our group.
zoylformic acid ethyl esters gave comparable ee values (94-
95% ee, Table 2, entries 2 and 5-7, column C), while
4-methoxy (strong electron-donating substituent), 2-methyl
(stereohindering substituent), and 2-chloro (coordinating
substituent) benzoylformate were reduced with only 88% ee,
87% ee, and 76% ee, respectively (Table 2, entries 3, 4, and
8, column C).
In general, both Brønsted acids and Lewis acids can be
used as additives to improve enantioselectivities in the
asymmetric hydrogenation of R-ketoester, but CeCl3‚7H2O
was found to be the most effective additive examined (Table
2, columns B and C vs A). However, when ethyl pyruvate
(1j, R ) alkyl) was employed as substrate, CeCl3‚7H2O
showed no enantioselectivity improvement although CSA
worked much better (Table 2, entry 9). When the benzoyl-
formates possessed a substituent at the ortho position of the
aromatic ring, the results became complicated. Hydrogenation
of 2-methyl benzoylformate with CSA as additive gave
similar ee values to those without any additive. On the other
hand, much higher ee was obtained with CeCl3‚7H2O as
additive (Table 2, entry 4). Hydrogenation of 2-chloro
benzoylformic ethyl ester gave the product with only 40%
ee with no additive, and 76% ee with CeCl3‚7H2O; however,
in the presence of CSA, a reversed low enantioselectivity
was observed (Table 2, entry 8).
Acknowledgment. We thank the National Natural Sci-
ence Foundation of China, Chinese Academy of Sciences,
and the Science and Technology Commission of Shanghai
Municipality for financial support. We are indebted to Dr.
Xichen Lin (GlaxoSmithKline), Philadelphia, for his helpful
suggestions.
In the course of our exploration of these hydrogenation
reactions, we also found that the cerium chloride hydrate
had some effect on stabilizing the catalyst ([Ru((S)-3)-
(benzene)Cl]Cl). The freshly prepared catalyst in MeOH was
orange and gradually turned green upon contact with air,
Supporting Information Available: Experimental details
and analytical data. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL052212C
Org. Lett., Vol. 7, No. 24, 2005
5427