Highly enantioselective hydrogenation of α-keto esters catalyzed by Ru-tunephos complexes

Article abstract of DOI:10.1055/s-2006-932461

Various enantiomerically pure α-hydroxy esters were synthesized by asymmetric hydrogenation of α-keto esters catalyzed by Ru-C _n-Tunephos complex. Up to 97.1% ee has been achieved for both α-aryl and α-alkyl substituted α-keto esters. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-932461

LETTER
1169
Highly Enantioselective Hydrogenation of a-Keto Esters Catalyzed by
Ru-Tunephos Complexes
H
ighly Enantiose
h
lective
H
ydr
u
ogenation of
n
a
-Keto
E
ste
r
-
s
Jiang Wang, Xianfeng Sun, Xumu Zhang*
Department of Chemistry, The Pennsylvania State University, University Park, PA 16802, USA
Fax +1(814)8638403; E-mail: xumu@chem.psu.edu
Received 25 October 2005
Abstract: Various enantiomerically pure a-hydroxy esters were
O
(CH2)n
O
synthesized by asymmetric hydrogenation of a-keto esters cata-
PPh2
PPh2
PPh2
PPh2
PPh2
MeO
MeO
PPh2
PPh2
lyzed by Ru-Cn-Tunephos complex. Up to 97.1% ee has been
achieved for both a-aryl and a-alkyl substituted a-keto esters.
PPh2
Key words: asymmetric catalysis, enantioselectivity, ruthenium,
hydrogenation, a-keto esters
(S)-BINAP
(S)-BIPHEP
(S)-MeO-BIPHEP
(S)-Cn-TunePhos
n = 1–6
Figure 1
Enantiomerically pure a-hydroxy acid derivatives are
very important chiral building blocks for the synthesis of
a variety of natural products and biologically active mol-
ecules,1 e.g., angiotensin converting enzyme inhibitors:
benazepril,2 delapril hydrochloride,3 and clopidogrel
bisulfate4 (Scheme 1). An effective method for preparing
this class of compounds involves asymmetric hydrogena-
tion of the corresponding a-keto esters.5 Despite the
tremendous progress made on the asymmetric hydro-
genation of b-keto esters, highly enantioselective hydro-
genation of a-keto esters has not been fully explored.6
Recently, we have developed a novel class of bisphos-
phine ligands (Cn-Tunephos, n = 1–6) with tunable dihe-
dral angles.11 These ligands allow us to systematically
study the influence of dihedral angles of atropisomeric bi-
aryl bisphospines on the reactivity and enantioselectivity
of asymmetric hydrogenation reactions. For example, in
the Ru-catalyzed asymmetric hydrogenation of b-keto
esters10 and a-phthalimide ketones,11 C4-Tunephos and
C3-Tunephos have given the best enantioselectivities (up
to 99% ee) among the Cn-Tunephos ligands. We envision
that a tunable chiral pocket is very important for achieving
high enantioselectivity for the hydrogenation of a-keto
esters. Herein we report the systematic study of Ru-
catalyzed asymmetric hydrogenation of a-keto esters us-
ing a series of chiral biaryl bisphosphines (Cn-Tunephos,
n = 1–6) with tunable dihedral angles. Up to 97.1% ee
has been achieved for both a-aryl and a-alkyl substituted
a-keto esters.
CH2COOH
N
O
OH
NH
OEt
OEt
O
O
Benazepril
Scheme 1 Example of an ACE inhibitor
We initiated our study by choosing 6a as the model sub-
strate and screened a number of Ru-Cn-Tunephos com-
plexes to examine both the ligand effects and the
influence of different metal complexes. Some representa-
tive results are shown in Table 1. Hydrogenation of 6a
catalyzed by Ru[(S)-C3-Tunephos](OAc)2 (1)12 proceeded
slowly and resulted in low enantioselectivity (Table 1, en-
try 1). Similar results have been observed for the hydroge-
nation of b-keto esters and changing the carboxylate ion
to halide can enhance reactivity and enantioselectivity.13
Therefore, we explored several Ru-halide complexes for
the hydrogenation reactions. When [RuCl(benzene)(S)-
C3-Tunephos]Cl (2)6b was employed as catalyst, 94.5% ee
was observed at room temperature (Table 1, entry 2).
However, under the same reaction conditions hydrogena-
tion of 6a with [RuCl(cymene)(S)-C3-Tunephos]Cl (3)6b
gave only <10% conversion and 47% ee (Table 1, entry
3). A possible reason is that the dissociation of the h6-
cymene ligand in 3 requires higher energy than that of
the h6-benzene ligand in 2. As expected, the reaction
Although axially C2-symmetric biaryl bisphosphines such
as BINAP,7 BIPHEP8 and MeO-BIPHEP8 (Figure 1) are
effective chiral ligands for many asymmetric hydrogena-
tion reactions, the current substrate scope of asymmetric
hydrogenation is still far from satisfactory. It is well
known that subtle changes in conformation, steric and
electronic properties of the chiral ligands can often lead to
dramatic variation of reactivities and enantioselectivities.
Therefore, considerable efforts have been made toward
the design and synthesis of a variety of atropisomeric
ligands based on the biphenyl, binaphthyl or other biaryl
backbones.9
SYNLETT 2006, No. 8, pp 1169–1172
1
5.
0
5.
2
0
0
6
Advanced online publication: 10.03.2006
DOI: 10.1055/s-2006-932461; Art ID: W30605ST
© Georg Thieme Verlag Stuttgart · New York

1170
C.-J. Wang et al.
LETTER
Table 1 Asymmetric Hydrogenantion of Methyl Benzoylformate 6a
In the proposed transition state model, hydride transfer to
ketones is the stereochemically defining step. The strong
interaction between the R group from a-keto esters and
the equatorial phenyl group makes A a disfavored species
compared with B (Figure 2). According to this model, S-
configuration reductive product was obtained due to the
addition of H to the Re face of the ketone.
H2
O
OH
*
1 mol% catalyst
OMe
OMe
MeOH, 20 h
O
O
6a
7a
Entrya
Catalyst q (o)c
Temp
r.t.
H2 (atm) ee (%)d
equatorial
1
2
3
4b
5
6
7
8
9
1
77
77
77
77
60
74
77
88
94
106
77
5
5
14.0
94.5
47.0
94.0
90.7
92.6
97.1
93.0
92.9
91.7
96.7
O
2
r.t.
PPh2
(CH2)n
P
P
Ru
PPh2
O
3
r.t.
5
axial
3
50 °C
r.t.
50
5
(S)-Cn-TunePhos
quadrant diagram of
4a
4b
4c
4d
4e
4f
5
n = 1–6
Ru-(S)-Cn-Tunephos
r.t.
5
dihedral angle
dihedral angle
r.t.
5
L
S
L
S
r.t.
5
H
R
H
R
repulsion
P
P
P
P
r.t.
5
S
Ru
L
S
L
Ru
O
O
10
11
r.t.
5
O
O
r.t.
5
Cl
OMe
Cl
MeO
Ru[(S)-C3-Tunephos](OAc)2
1
{RuCl(benzene)[(S)-C3-Tunephos]}Cl 2
disfavored (A)
favored (B)
{RuCl(Cymene)[(S)-C3-Tunephos]}Cl
3
L = equatorial phenyl group, large group
S = axial phenyl group, small group
n = 1 4a; n = 2 4b; n = 3 4c
n = 4 4d; n = 5 4e; n = 6 4f
RuCl2[(S)-Cn-Tunephos](DMF)m
4a–4f
Figure 2
[NH2Me2]+[{RuCl[(S)-C3-Tunephos]}2(µ-Cl3)]–
5
a All reactions were completed in 100% conversion except entry 3
(10% conversion).
Under optimized reaction conditions (Table 1, entry 7), a
variety of a-aryl substituted a-keto esters 6a–i were exam-
ined for the hydrogenation reaction with RuCl2[(S)-C3-
Tunephos](DMF)m (4c, Table 2, entries 1–9). High enan-
tioselectivities have been achieved with the exception of
o-fluoro-substituted a-keto ester 6d (Table 2, entry 4).
There is no major electronic effect on the substitution pat-
tern of the substrates (92.4–96.9% ee). A proposed expla-
nation of the low ee (84.6%) with the o-fluoro-substituted
a-keto ester 6d is that competing coordination of the o-
fluoro group exists in the Ru system. For a-alkyl-substi-
tuted a-keto esters 6j–l, high enantioselectivities (95–
96% ee) have also been observed regardless of the steric
hindrance (Table 2, entries 10–12). To provide a key in-
termediate for the synthesis of ACE inhibitors benazepril
(Figure 2), we have carried out the hydrogenation of 6m
and up to 95.8% ee has been achieved, which represents
the highest ee ever reported for the hydrogenation of this
challenging substrate (Table 2, entry 13). Therefore, our
hydrogenation of a-keto esters with 4c provides a broad
substrate scope.15
b The reaction was performed at 50 °C and 50 atm for 10 h.
c Calculated dihedral angles of Cn-Tunephos from CAChe MM2
program.
d Enantiomeric excesses were determined by chiral GC, the con-
figuration of the product is S.
proceeded smoothly at 50 °C with 3 and 94% ee and
100% conversion were observed (Table 1, entry 4). We
have also explored two other Ru-complexes (4, 5) without
the coordination of h6-arene so that reactions can be car-
ried out under milder conditions. Further experiments
showed that up to 97.1% ee was achieved with RuCl2[(S)-
C3-Tunephos](DMF)m (m can be 2, 3 or 4; 4c)10 and
[NH2Me2]+[{RuCl[(S)-C3-Tunephos]}2(m-Cl3)] (5)14 as
the catalysts (Table 1, entries 7 and 11).
To test the effect of dihedral angles of chiral biaryl ligands
on the enantioselectivity of the reactions, a series of (S)-
Cn-Tunephos10 was examined (Table 1, entries 5–10).
While ligands (S)-C1–C6 Tunephos showed similar reac-
tivity, the enantioselectivity varied dramatically. The op-
timal ee (97.1%) was achieved with (S)-C3-Tunephos. To
the best of our knowledge, this is the highest ee reported
for hydrogenation of this kind of substrate. Hydrogenation
of 6a with Ru-BINAP complex only leads to 79% ee.6b
Compared with BINAP, tunable Cn-Tunephos provides an
opportunity to optimize chiral catalytic pockets for a
given substrate.
In conclusion, a family of chiral bisphosphines with
tunable dihedral angles has been employed in the asym-
metric Ru-catalyzed hydrogenation of a-keto esters, and
up to 97.1% ee has been achieved with RuCl2[(S)-C3-
Tunephos](DMF)m (4c) as the catalyst. The highly enan-
tioselective hydrogenation provides a powerful way to
prepare chiral a-hydroxy esters, which are important
Synlett 2006, No. 8, 1169–1172 © Thieme Stuttgart · New York

LETTER
Highly Enantioselective Hydrogenation of a-Keto Esters
1171
(3) (a) Ogihara, T.; Nakamaru, M.; Higaki, J.; Kumahara, Y.;
Hamano, Y.; Minamino, T.; Nakamura, N. Curr. Ther. Res.
1987, 41, 809. (b) Miyake, A.; Itoh, K.; Oka, Y. Chem.
Pharm. Bull. 1986, 34, 2852.
(4) (a) Defreyn, G.; Gachet, C.; Savi, P.; Driot, F.; Cazenave, J.
P.; Maffrand, J. P. Thromb. Haemostasis 1991, 65, 186.
(b) Rodgers, J. E.; Steinhubl, S. R. Expert Rev. Cardiovasc.
Ther. 2003, 1, 507. (c) Castaldi, G.; Barreca, G.; Bologna,
A. WO 2003093276 A1, 2003.
Table 2 Asymmetric Hydrogenantion of a-Keto Esters 6
O
OH
OR2
1 mol% 4c, MeOH
OR2
R1
R1
*
H2 (5 atm), r.t., 20 h
O
O
6
7
Entrya Substrate R1
R2
Yield
ee
(%)e
92
94
91
90
95
92
89
90
91
70
75
90
94
93
(%)f
(5) (a) Orito, Y.; Imai, S.; Niwa, S. Nippon Kagaku Kaishi 1979,
1118. (b) Orito, Y.; Imai, S.; Niwa, S. Nippon Kagaku
Kaishi 1980, 670. (c) Orito, Y.; Imai, S.; Niwa, S. Nippon
Kagaku Kaishi 1982, 137. (d) Blaser, H.-U.; Jalett, H. P.;
Wiehl, J. J. Mol. Catal. 1991, 68, 215. (e) Spindler, F.;
Pittelkow, U.; Blaser, H.-U. Chirality 1991, 3, 370.
(f) Blaser, H.-U.; Jalett, H. P.; Spindler, F. J. Mol. Catal.
1996, 107, 85. (g) Blaser, H.-U.; Müller, M. Stud. Surf. Sci.
Catal. 1991, 59, 73. (h) Webb, G.; Wells, P. B. Catal. Today
1992, 12, 319. (i) Augustine, R. L.; Tanieylan, S. K.; Doyle,
L. K. Tetrahedron: Asymmetry 1993, 4, 1803. (j) Wang, G.;
Heinz, T.; Pfaltz, A.; Minder, B.; Mallat, T.; Baiker, A. J.
Chem. Soc., Chem. Commun. 1994, 2047. (k) Minder, P.;
Schurch, M.; Mallat, T.; Baiker, A.; Heinz, T.; Pfaltz, A. J.
Catal. 1996, 160, 261.
(6) (a) Tang, W.; Zhang, X. Chem. Rev. 2003, 103, 3029; and
references cited therein. (b) Mashima, K.; Kusano, K.; Sato,
N.; Matsumura, Y.; Nozaki, K.; Kumobayashi, H.; Sayo, N.;
Hori, Y.; Ishizaki, T.; Akutagawa, S.; Takaya, H. J. Org.
Chem. 1994, 59, 3064. (c) Chiba, T.; Miyashita, A.; Nohira,
H.; Takaya, H. Tetrahedron Lett. 1993, 34, 2351. (d)Genet,
J. P.; Pinel, C.; Ratovelomanana-Vidal, V.; Mallart, S.;
Pfister, X.; Bischoff, L.; Cano De Andrade, M. C.; Darses,
S.; Galopin, C.; Laffitte, J. A. Tetrahedron: Asymmetry
1994, 5, 675. (e) Benincori, T.; Brenna, E.; Sannicolo, F.;
Trimarco, L.; Antognazza, P.; Cesarotti, E.; Demartin, F.;
Pilati, T. J. Org. Chem. 1996, 61, 6244. (f) Benincori, T.;
Cesarotti, E.; Piccolo, O.; Sannicolo, F. J. Org. Chem. 2000,
65, 2043.
1
6a
6b
6c
6d
6e
6f
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
97.1
94.5
94.1
84.6
93.2
92.4
96.4
95.5
95.0
95.5
96.0
95.3
95.8
94.1
2
p-F-C6H4
m-F-C6H4
o-F-C6H4
p-Cl-C6H4
p-Br-C6H4
p-Me-C6H4
p-MeO-C6H4
m-MeOC6H4
Me
3
4
5b
6b
7
6g
6h
6i
8
9
10
6j
11c
12c
13c
14d
6k
6l
i-Pr
t-Bu
Et
6m
6m
Ph(CH2)2
Ph(CH2)2
Et
Et
a All reactions went to 100% conversion.
b The reaction was performed at 50 °C and 50 atm for 15 h. 91.0% ee
and 90.5% ee were obtained for 6e and 6f, respectively, at r.t. and 5
atm for 20 h.
c EtOH was used as solvent.
d The reaction was carried out by using 0.1 mol% of the catalyst 5 at
50 °C and 50 atm for 48 h.
(7) Noyori, R. Acc. Chem. Res. 1990, 23, 345.
(8) (a) Schmid, R.; Broger, E. A.; Cereghtti, M.; Crameri, Y.;
Foricher, J.; Lalonde, M.; Müller, R. K.; Scalone, M.;
Schoettel, G.; Zutter, U. Pure Appl. Chem. 1996, 68, 131.
(b) Schmid, R.; Foricher, J.; Cereghtti, M.; Schonholzer, P.
Helv. Chim. Acta 1991, 74, 370. (c) Schmid, R.; Cereghtti,
M.; Heiser, B.; Schonholzer, P.; Hansen, H.-J. Helv. Chim.
Acta 1988, 71, 897.
e Isolated yields. For 6j and 6k lower yields were due to the volatility
of the reductive product.
f Enantiomeric excesses were determined by chiral GC; the configu-
ration of the products is S.
chiral building blocks for organic synthesis. Further stud-
ies of other transition metal complexes of these ligands
and their applications are in progress.
(9) (a) Pai, C.-C.; Lin, C.-W.; Lin, C.-C.; Chen, C. C.; Chan, A.
S. C. J. Am. Chem. Soc. 2000, 122, 11531. (b) Benincori,
T.; Brenna, E.; Sannicolo, F.; Trimarco, L.; Antognazza, P.;
Cesarotti, E.; Demartin, F.; Pilati, T. J. Org. Chem. 1996, 61,
6244. (c) Saito, T.; Yokozawa, T.; Ishizaki, T.; Moroi, T.;
Sayo, N.; Miura, T.; Kumobayashi, H. Adv. Synth. Catal.
2001, 343, 264. (d) Duprat de Paule, S.; Jeulin, S.;
Ratovelomanana-Vidal, V.; Genet, J. P.; Champion, N.;
Dellis, P. Eur. J. Org. Chem. 2003, 1931. (e) Pai, C.-C.; Li,
Y.-M.; Zhou, Z.-Y.; Chan, A. S. C. Tetrahedron Lett. 2002,
43, 2789. (f) Gelpke, A. E. S.; Kooijman, H.; Spek, A. L.;
Hiemstra, H. Chem. Eur. J. 1999, 5, 2472. (g) Qiu, L.; Wu,
J.; Chan, S.; Au-Yeung, T. T.-L.; Ji, J.-X.; Guo, R.; Pai, C.-
C.; Zhou, Z.; Li, X.; Fan, Q.-H.; Chan, A. S. C. Proc. Natl.
Acad. Sci. U.S.A. 2004, 101, 5815. (h) Jeulin, S.; Duprat de
Paule, S.; Ratovelomanana-Vidal, V.; Genet, J. P.;
Champion, N.; Dellis, P. Proc. Natl. Acad. Sci. U.S.A. 2004,
101, 5799.
Acknowledgment
This work was supported by National Institute of Health grants.
References and Notes
(1) (a) Hanessian, S. Total Synthesis of Natural Products: The
Chiron Approach; Pergamon Press: New York, 1983.
(b) Seuring, B.; Seebach, D. Helv. Chim. Acta 1977, 60,
1175. (c) Mori, K.; Takigawa, T.; Matsuo, T. Tetrahedron
1979, 35, 933.
(2) (a) Watthey, J. W. H.; Stanton, J. L.; Desai, M.; Babiarz, J.
E.; Finn, B. M. J. Med. Chem. 1985, 28, 1511. (b) Blaser,
H. U.; Jalett, H. P.; Sedelmeier, G. H. EP 0 206 993 A1,
1986. (c) Yanagisawa, H.; Ishihara, S.; Ando, A.; Kanazaki,
T.; Miyamoto, S.; Koike, H.; Iijima, Y.; Oizumi, K.;
Matsushita, Y.; Hata, T. J. Med. Chem. 1988, 31, 422.
(10) (a) Zhang, Z.; Qian, H.; Longmire, J.; Zhang, X. J. Org.
Chem. 2000, 65, 6223. (b) Kitamura, M.; Tokunaga, M.;
Noyori, R. Org. Synth. 1993, 71, 1.
Synlett 2006, No. 8, 1169–1172 © Thieme Stuttgart · New York

1172
C.-J. Wang et al.
LETTER
degassed MeOH (8 mL) in a glovebox and distributed
equally between four vials. Substrate 6a (82 mg, 0.5 mmol)
was then added to the catalyst solution. The resulting
mixture was transferred into an autoclave and charged with
5 atm pressure of H2. The autoclave was stirred at r.t. for
20 h. The autoclave was then cooled to r.t. and the H2 was
carefully released. The reaction solution was then
(11) Lei, A.; Wu, S.; He, M.; Zhang, X. J. Am. Chem. Soc. 2004,
126, 1626.
(12) Kitamura, M.; Tokunaga, M.; Noyori, R. J. Org. Chem.
1992, 57, 4053.
(13) Noyori, R.; Ohkuma, T.; Kitamura, M. J. Am. Chem. Soc.
1987, 109, 5856.
(14) (a) Wu, S.; Wang, W.; Tang, W.; Lin, M.; Zhang, X. Org.
Lett. 2002, 4, 4495. (b) Mashima, K.; Nakanura, T.; Matsuo,
Y.; Tani, K. J. Organomet. Chem. 2000, 1607, 51.
(15) General Procedure for the Asymmetric Hydrogenation
of a-Keto Esters.
evaporated and the residue was purified by column
chromatography to give the corresponding hydrogenation
product (76 mg, 92% yield). 1H NMR (300 MHz, CDCl3):
d = 7.34–7.44 (m, 5 H), 5.18 (d, J = 3.5 Hz, 1 H), 3.76 (s,
3 H), 3.59 (d, J = 3.5 Hz, 1 H). 13C NMR (75 MHz, CDCl3):
d = 174.5, 138.7, 129.0, 128.9, 127.0, 73.3, 53.4.
[Ru(cymene)Cl2]2 (6.2 mg, 0.01 mmol) and (S)-C3-Tunephos
(12.5 mg, 0.021 mmol) were dissolved in degassed DMF
(3 mL) in a Schlenk tube under N2. The solution was heated
at 100 °C for 3.5 h. After the mixture was cooled to 50 °C,
the solvent was removed under vacuum to give the catalysts
as an orange-red solid. The catalyst was dissolved in
[a]D20 +180.5 (c 1.3, CHCl3) for 97.1% ee; Gamma Dex 225,
30 m × 0.25 mm, column temperature: 130 °C, carrier gas:
He, 1 mL/min, t1 = 19.000 min, t2 = 21.593 min.
Synlett 2006, No. 8, 1169–1172 © Thieme Stuttgart · New York