Catalytic asymmetric hydrogenation of α-amino-β-keto ester hydrochlorides using homogeneous chiral nickel-bisphosphine complexes through DKR

Article abstract of DOI:10.1039/b816524f

Homogeneous chiral nickel-bisphosphine complexes catalyze the asymmetric hydrogenation of α-amino-β-keto ester hydrochlorides through dynamic kinetic resolution to efficiently afford anti-β-hydroxy-α-amino esters with high diastereo- and enantioselectivit

Full text of DOI:10.1039/b816524f

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Catalytic asymmetric hydrogenation of a-amino-b-keto ester
hydrochlorides using homogeneous chiral nickel-bisphosphine complexes
through DKRw
Yasumasa Hamada,* Yu Koseki, Takefumi Fujii, Tsukuru Maeda, Takuya Hibino
and Kazuishi Makino
Received (in Cambridge, UK) 22nd September 2008, Accepted 22nd October 2008
First published as an Advance Article on the web 31st October 2008
DOI: 10.1039/b816524f
Homogeneous chiral nickel-bisphosphine complexes catalyze
the asymmetric hydrogenation of a-amino-b-keto ester hydro-
chlorides through dynamic kinetic resolution to efficiently
afford anti-b-hydroxy-a-amino esters with high diastereo- and
enantioselectivities.
Scheme 1 Homogeneous Ni-catalyzed asymmetric hydrogenation.
Nickel, one of abundant and cheap base transition metals, has
attracted a great deal of attention in catalytic organic synthesis.1
apparatus and the addition of molecular sieves 3A to the
reaction media. After extensive experiments, a combination of
In the area of catalytic hydrogenation using nickel catalysts, the
nickel acetate and ferrocenylphosphine 3a15 has been proven
to be the best couple for the hydrogenation. The chiral nickel
heterogeneous catalysts represented by Raney nickel have been
well studied, and the asymmetric synthesis using heterogeneous
catalyst was directly prepared in the reaction media without
nickel catalysts modified by a chiral auxiliary has also been
prior preparation of the catalyst complex.
Using this combination, the effects of solvents and ligands
investigated.2 Recently, the first use of homogeneous nickel-
bisphosphine complexes for the catalytic hydrogenation of
were examined as shown in Table 1. Most of the solvents were
simple alkenes has been reported.3,4 Although homogeneous
ineffective for this hydrogenation. Fortunately, when acetic
acid in the presence of sodium acetate16 (1 equiv.) was
asymmetric syntheses,5 the asymmetric hydrogenation using
chiral nickel-bisphosphine complexes have been used in various
employed, the reaction proceeded to give the product in
65% yield with a complete anti-selectivity and 82% ee (entry
3). Encouraged by this result, a further investigation revealed
these complexes remains a formidable challenge. In addition,
the development of sustainable methods using abundant and
cheap base transition metals is desirable.
We6–8 and others9 have reported the efficient asymmetric
that a mixture of trifluoroethanol and acetic acid (1:4) was
suitable for this hydrogenation that led to the full conversion
hydrogenations of a-amino-b-keto ester hydrochlorides using
chiral ruthenium, rhodium, and iridium catalysts for the
Table 1 Effects of solvent and ligands
enantio- and diastereoselective synthesis of anti-b-hydroxy-a-
amino acids through dynamic kinetic resolution (DKR).10–12
anti-b-Hydroxy-a-amino acids are valuable constituents of a
variety of natural products and medicinally important com-
pounds.13 We now describe the successful asymmetric hydro-
genation using homogeneous chiral nickel-bisphosphine
catalysts through DKR for the stereoselective synthesis of
anti-b-hydroxy-a-amino esters from chirally labile a-amino-b-
keto ester hydrochlorides.
Our investigation commenced with the screening of nickel
Entry Solvent
Ligand t/h Yield (%) anti/syna eeb (%)
salts and chiral ligands for the reaction of the readily available
substrate 114 as shown in Scheme 1. The initial experiments
were confronted with the problem of reproducibility because
the activity of the nickel catalysts was sensitive to the presence
of air and moisture. This problem was overcome by using an
argon-filled glove-bag during the assembling of the reaction
1
2
3
4
5
6
7
8
PhCH3
TFE
AcOH
3a
3a
3a
12 NR
12 NR
12 65
12 NR
12 71
12 100
12 87
—
—
499/1
—
499/1
499/1
499/1
—
—
—
82
—
71
81
84
—
—
9
EtOH/AcOH (1/4) 3a
TFE/AcOH (4/1) 3a
TFE/AcOH (1/1) 3a
TFE/AcOH (1/4) 3a
TFE/AcOH (1/4) 3b
TFE/AcOH (1/4) 3c
TFE/AcOH (1/4) 3d
TFE/AcOH (1/4) 3e
TFE/AcOH (1/4) 3f
TFE/AcOH (1/4) 3g
6
Trace
9
24 NR
48 48
24 NR
26 NR
24 100
—
10
11
12
13
96/4
—
—
Graduate School of Pharmaceutical Sciences, Chiba University,
Yayoi-cho, Inage-ku, Chiba, 263-8522, Japan.
E-mail: hamada@p.chiba-u.ac.jp; Fax: +81-(0)43-290-2987;
Tel: +81-(0)43-290-2987
—
—
92
499/1
a
b
Estimated by 1H NMR spectra. Determined after N-benzoylation.
w Electronic supplementary information (ESI) available: Experimental
details and spectral data. See DOI: 10.1039/b816524f
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Table 2 Nickel precursors
Table 3 Various b-hydroxy-a-amino acide esters
Entry
Ni precursor
Yielda (%)
anti/syna
eea (%)
1
2
3
4
5
6
7
8
Ni (OAc)2ꢁ4H2O
Ni (acac)2ꢁ2H2O
NiCl2
NiCl2ꢁ6H2O
NiCl2(PPh3)2
NiBr2
84
62
80
87
50
84
86
17
499/1
499/1
499/1
499/1
499/1
499/1
499/1
87/13
85
86
85
86
84
85
85
82
Entry
R
R0
Time Yielda anti/syn eeb (%)
1
2
3
4
5
6
o-tolyl
7 d
90 499/1 81
98 499/1 92
83 499/1 93
88 499/1 89
91 499/1 92
91 499/1 92
H
Me
F
Cl
Br
24 h
24 h
24 h
24 h
24 h
Ni(NO3)2ꢁ6H2O
[Ni(cod)2]
a
Determined after N-benzoylation.
7
8
Me
24 h
24 h
4 d
82 499/1 93
90 499/1 92
94 499/1 91
80 499/1 91
82 499/1 88
t-Bu
OBn
NO2
9d
10c
11
of the substrate with an excellent enantioselectivity and com-
plete diastereoselectivity (entry 7). Interestingly, when the
trifluoroethanol in the mixed solvent was substituted with
ethanol (entry 4) or trifluoroethanol itself was used as the
solvent (entry 2), no reaction was observed. With the best
solvent in hand, we reexamined the nickel salts (Table 2).
Although all the examined bivalent nickel salts were found to
be applicable and gave a comparable stereoselectivity, we
employed nickel acetate tetrahydrate with a nonhygroscopic
property from a practical point of view.17 In order to enhance
the enantioselectivity, we next examined several chiral phos-
phine ligands. Most of the commercially available chiral
phosphines resulted in little or no reaction, while the Josiphos
type ligands produced the active catalysts.18 Among them, the
substituents on the two phosphorus atoms influenced the
activity of the catalysts (Table 1, entries 7–13). The aromatic
group with electron-donating group(s) at the phosphorus on
the ferrocenyl ring and cyclohexyl group at the side chain were
essential for the catalytic activity along with an excellent
diastereoselectivity and enantioselectivity. Finally, when the
hydrogenation was performed using a combination of nickel
acetate (5 mol%) and the (R,S)-ferrocenyl ligand 3g in the
presence of sodium acetate in a mixture of trifluoroethanol
and acetic acid under 100 atm of hydrogen for 24 h, the
substrate was smoothly converted and the anti-b-hydroxy-a-
amino acid ester 2 was obtained in quantitative yield with
complete diastereoselectivity and 92% ee.19
24 h
CO2Me 48 h
12d
4 d
90 499/1 89
13
14d
15
16
2-Naphthyl
2-Thienyl
Cyclohexyl
t-Butyl
24 h
7 d
92 499/1 90
79 499/1 95
24 h 8 (16)e 499/1 81
24 h
21 499/1 54
a
b
Isolated yield after N-benzoylation. Determined after N-benzoylation.
c
d
e
NO2/NH2 = Z9/1. 10 Mol% catalyst was used. Yield in AcOH.
10, 11). Conventionally, the Raney nickel catalyst has been used
for dehalogenation and desulfurization, but the homogeneous
nickel complex catalyzes the hydrogenation without any inter-
action in the presence of halogen and sulfur atoms to afford the
corresponding b-hydroxy-a-amino acid esters with excellent
enantioselectivity (entries 4–6, 14). Although a nitro group is
sensitive to reducing conditions, the hydrogenation of the nitro-
containing substrate chemoselectively proceeded to give the
corresponding product along with a small amount of the aniline
derivative (entry 10). In contrast to the aromatic substrates, the
reaction of the aliphatic substrates was slow and the enantio-
selectivities were moderate (entries 15 and 16). In order to
explore the potential of the homogeneous chiral nickel-bispho-
sphine complex, we examined the asymmetric hydrogenation of
several substrates. The ketonic substrates, methyl benzoylace-
tate and acetophenone, were smoothly hydrogenated but the
enantioselectivities of the products were low or moderate.
Although the activity of the chiral nickel-catalyst in the above
asymmetric hydrogenation is moderate, the results of the pre-
sent reaction are noteworthy because this represents not only
the first use of homogeneous chiral nickel-phosphine complexes
in asymmetric hydrogenation, but also the first example of
nickel-catalyzed dynamic kinetic resolution.
For the scope and limitations of the hydrogenation under the
optimized conditions, a series of substrates 4 with different
substituents were subjected to hydrogenation as shown in
Table 3. Excellent diastereoselectivities and enantioselectivities
were obtained for the aromatic substrates. Compared to the
iridium-catalyzed hydrogenation,8 somewhat superior results
with respect to the enantioselectivity and reactivity were ob-
tained using the hindered substrate and halogen-containing
substrates. The o-tolyl substrate did not react during the Ir-
catalyzed hydrogenation, but was a good substrate for the
nickel-catalyzed hydrogenation (entry 1). In the case of the Ir-
catalyzed hydrogenation, the existence of an electron-withdraw-
ing group on the aromatic ring hampered the hydrogenation
and caused a low enantioselectivity. However, these were
excellent substrates for the present hydrogenation (entries 4–6,
We have succeeded in the development of a successful
asymmetric hydrogenation using homogeneous chiral nickel-
bisphosphine catalysts for the stereoselective synthesis of
anti-b-hydroxy-a-amino esters. This reaction represents the first
asymmetric hydrogenation using homogeneous chiral nickel-
bisphosphine complexes. The present hydrogenation is superior
to the iridium-catalyzed hydrogenation regarding the substrate
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generality and enantioselectivity. It is noteworthy that such a
complicated asymmetric hydrogenation smoothly proceeds with
a combination of the cheap base metal, nickel, and commercially
available phosphine ligands without using any precious transi-
tion-metal catalyst. Further investigations on the mechanistic
details and potential applications of asymmetric hydrogenation
using homogeneous chiral nickel catalysts are actively underway.
This paper is dedicated to Professor E. J. Corey on the occasion
of his 80th birthday. This work was financially supported in part
by a Grant-in-Aid for Scientific Research (B) from the Ministry of
Education, Culture, Sports, Science and Technology, Japan.
(c) Ratovelomanana-Vidal and J.-P. Genet, Can. J. Chem., 2000,
78, 846; (d) K. Faber, Chem. Eur. J., 2001, 7, 5004; (e) H. Pellissier,
Tetrahedron, 2003, 59, 8291; (f) K. Faber, Chem. Eur. J., 2008, 14,
8060.
12 R. Noyori, T. Ikeda, T. Ohkuma, M. Widhalm, M. Kitamura,
H. Takaya, S. Akutagawa, N. Sayo, T. Saito, T. Taketomi and
H. Kumobayashi, J. Am. Chem. Soc., 1989, 111, 9134.
13 K. Makino and Y. Hamada, J. Synth. Org. Chem., 2006, 63, 1198.
14 (a) For preparation of a-amino-b-keto esters, see: K. Makino,
N. Okamoto, O. Hara and Y. Hamada, Tetrahedron: Asymmetry,
2001, 12, 1757; (b) O. Hara, M. Ito and Y. Hamada, Tetrahedron
Lett., 1998, 39, 5537; (c) D. J. Krysan, Tetrahedron Lett., 1996, 37,
3303; (d) J. Singh, T. D. Gordon, W. G. Earley and B. A. Morgan,
Tetrahedron Lett., 1993, 34, 211.
15 (a) A. Togni, C. Breutel, A. Schnyder, F. Spindler, H. Landert and
A. Tijiani, J. Am. Chem. Soc., 1994, 116, 4062; (b) A. Togni,
Angew. Chem., Int. Ed. Engl., 1996, 35, 1475.
16 Sodium acetate serves as the base for the generation of the acid-free
substrate.
17 The examined nickel salts were purchased and used as received.
The anhydrous nickel salts prepared from commercial nickel
chloride and nickel acetate had a hygroscopic tendency.
18 The examined bisphosphines are follows: (+)-DIOP, (S,S)-Chiraphos,
(R,R)-Me-Duphos, (R,R)-Et-BPE, (R,R)-Quinox P*, (S)-PHOX,
(R,S)-PPFA, (R,R)-Walphos, (R,S)-Taniaphos, (S)-BINAP, and 1,2-
bis(dicyclohexylphosphino)ethane.
Notes and references
1 Modern Organonickel Chemistry, ed. Y. Tamaru, Wiley-VCH,
Weinheim, 2005.
2 (a) A. Tai and T. Sugimura, in Chiral Catalysts Immobilization and
Recycling, eds. D. E. De Vos, I. F. J. Vankelecom and P. A. Jacobs,
Wiley-VCH, Weinheim, 2000, p. 173; (b) T. Osawa, T. Harada and
O. Takayasu, Top. Catal., 2000, 13, 155; (c) M. Studer, H.-U. Blaser
and C. Exner, Adv. Synth. Catal., 2003, 345, 45; (d) T. Osawa, in
ref. 1, p. 273.
3 For a review on nickel-catalyzed hydrogenation, see: E. Bouwman,
in Handbook of Homogeneous Hydrogenation, eds. J. G. De Vries
and C. J. Elsevier, Wiley-VCH Verlag GmbH & Co. KGaA,
Weinheim, 2007, p. 93.
4 (a) I. M. Angulo, A. M. Kluwer and E. Bouwman, Chem. Commun.,
1998, 2689; (b) I. M. Angulo, S. M. Lok, V. F. Q. Norambuena,
M. Lutz, A. L. Spek and E. Bouwman, J. Mol. Catal. A, 2002, 187,
55; (c) I. M. Angulo, E. Bouwman, R. van Gorkum, S. M. Lok,
M. Lutz and A. L. Spek, J. Mol. Catal. A, 2003, 202, 97.
5 R. Shintani and T. Hayashi, in ref. 1, p. 240.
6 K. Makino, T. Goto, Y. Hiroki and Y. Hamada, Angew. Chem.,
Int. Ed., 2004, 43, 882.
7 K. Makino, T. Fujii and Y. Hamada, Tetrahedron: Asymmetry,
2006, 17, 481.
8 (a) K. Makino, Y. Hiroki and Y. Hamada, J. Am. Chem. Soc.,
2005, 127, 5784; (b) K. Makino, M. Iwasaki and Y. Hamada, Org.
Lett., 2006, 8, 4573.
9 (a) C. Mordant, P. Dunkelmann, V. Ratovelomanana-Vidal and
J.-P. Genet, Chem. Commun., 2004, 1296; (b) C. Mordant,
P. Dunkelmann, V. Ratovelomanana-Vidal and J.-P. Genet, Eur.
J. Org. Chem., 2004, 3017.
19 Typical procedure for asymmetric hydrogenation (the reaction was
carried out in a glassware placed in a stainless autoclave apparatus):
A glass test tube was charged with Ni(OAc)2ꢁ4H2O (8.7 mg, 0.035
mmol), (R,S)-ferrocenyl ligand (3g, 24.9 mg, 0.035 mmol), the a-
amino-b-keto ester hydrochloride (1, 161 mg, 0.70 mmol), sodium
acetate (57.4 mg, 0.70 mmol), and molecular sieves 3A
(70 mg), and then was flushed with argon. After trifluoroethanol
(0.7 mL) and acetic acid (2.8 mL) were added, the resulting mixture
was degassed by three freeze–thaw cycles. The glass test tube was
transferred to a stainless steel autoclave in an argon-filled glove bag.
The mixture was stirred at 25 1C under hydrogen pressure (100 atm)
for 24 h. After hydrogen was carefully released, MeOH (3.5 mL)
and aqueous HCl (1 M in H2O, 1.4 mL) was added and the mixture
was concentrated in vacuo to dryness below 40 1C. The resulting
residue was dissolved in MeOH and the mixture was concentrated
in vacuo. This operation was repeated three times. The residue was
used for next step without any purification. Benzoic anhydride (158
mg, 0.70 mmol) followed by a solution of Et3N (0.3 mL, 2.1 mmol)
in THF (2.1 mL) were added dropwise to a solution of the above
crude product in THF (3.5 mL) at 0 1C. After stirring the mixture at
25 1C for 12 h, the reaction was quenched with saturated aqueous
NH4Cl, and the mixture was extracted with EtOAc. The organic
layer was washed with saturated aqueous NH4Cl, saturated aqu-
eous NaHCO3, and brine, dried over Na2SO4, filtered, and con-
centrated in vacuo. The residue was purified by silica gel column
chromatography to give the N-benzoyl derivative of 2 (204 mg,
10 (a) For reviews on asymmetric hydrogenation, see: T. Ohkuma,
M. Kitamura and R. Noyori, in Catalytic Asymmetric Synthesis, ed.
I
Ojima, Wiley-VCH, Weinheim, 2nd edn, 2000, p. 1;
(b) H.-U. Blaser, C. Malan, B. Pugin, F. Spindler, H. Steiner and
M. Studer, Adv. Synth. Catal., 2003, 345, 103; (c) Modern Reduction
Methods, eds. P. G. Andersson and I Munslow, Wiley-VCH, 2008.
11 (a) For reviews on dynamic kinetic resolution, see: R. Noyori,
M. Tokunaga and M. Kitamura, Bull. Chem. Soc. Jpn., 1995, 68,
36; (b) R. S. Ward, Tetrahedron: Asymmetry, 1995, 6, 1475;
1
98%). The diastereomeric ratio was determined by H NMR. The
enantiomeric excess was determined by chiral HPLC.
ꢀc
This journal is The Royal Society of Chemistry 2008
6208 | Chem. Commun., 2008, 6206–6208