Enantioselective hydrogenation of β-ketoesters with monodentate ligands

Article abstract of DOI:10.1002/anie.200460190

Efficient and stable chiral monodentate phosphine ligands can be used in the ruthenium-catalyzed enantioselective hydrogenation of β-ketoesters (see scheme). The catalysts are remarkably temperature-tolerant, and enantioselectivities of up to 95% ee are possible, even at 100-120 °C. R = C₆H₅, p-CH₃OC₆H₄, p-CF₃OC₆H₄, iPr, Et, C₆D ₅.

Full text of DOI:10.1002/anie.200460190

Communications
Enantioselective Hydrogenation
Enantioselective Hydrogenation of b-Ketoesters
with Monodentate Ligands**
Kathrin Junge, Bernhard Hagemann, Stephan Enthaler,
Günther Oehme, Manfred Michalik, Axel Monsees,
Thomas Riermeier, Uwe Dingerdissen, and
Matthias Beller*
Transition-metal-catalyzed asymmetric reactions offer an
efficient and elegant possibility for the synthesis of enantio-
merically pure compounds.[1] Among the different catalytic
methods, enantioselective hydrogenations have been used
extensively in the last two decades and are likely to provide
the most important access to pharmaceutical intermediates.[2]
In this regard, the hydrogenation of b-ketoesters yields chiral
b-hydroxyesters, which are useful building blocks for the
synthesis of biologically active compounds and natural
products (Scheme 1).[3]
Scheme 2. Selection of recently developed monodentate ligands.
phoramidites 2),[14] Pringle and co-workers (phosphonites
3),[15] and others.[16] Parallel to the workof Zhang and Chi
[17]
and Gladiali and co-workers,[18] we have introduced new
monodentate phosphines based on a 4,5-dihydro-3H-dinaph-
tho[2,1-c;1’,2’-e]phosphepine structure 4.[19,20] Similar to phos-
phites and phosphoramidites, these ligands give high enan-
tioselectivities (up to 95% ee) in the hydrogenation of a-
dehydroamino acid methyl esters. Despite the more compli-
cated synthesis, these ligands have advantages with regard to
stability against water and other nucleophiles under typical
reaction conditions. Herein we report the use of 2a, 3a–b, and
4a–f in the hydrogenation of b-ketoesters. So far, these
monodentate ligands have not been used for the synthesis of
chiral b-hydroxyesters.
Initial studies of the influence of reaction conditions were
carried out with methyl acetoacetate (5a) as substrate and our
standard ligand 4-phenyl-4,5-dihydro-3H-dinaphtho[2,1-
c;1’,2’-e]phosphepine (4a). Typically the catalytic reactions
were run in methanol as solvent in the presence of [Ru(cod)-
(methallyl)2] (1 mol%) and the ligand (2 mol%).
For full conversion within a reasonable time, the reactions
had to be run under pressure (60 bar) at 60–808C (Table 1,
entries 4,6). We were pleased to find that under these
conditions, good enantioselectivities (up to 84% ee) were
achieved. Notably, the best result was obtained at a relatively
high temperature (808C; Table 1, entry 6), which is advanta-
geous in terms of the increased rate and selectivity of the
reaction.
Next we focused our attention on the influence of
different ligands in the hydrogenation of methyl acetoacetate
(5a). Apart from the phenyl ligand 4a, the p-methoxyphenyl
derivative 4b, the p-trifluoromethylphenyl derivative 4c, the
isopropyl derivative 4d, the ethyl derivative 4e, and the
deuterated phenyl derivative 4 f were used (Table 2). All
ligands 4a–f were prepared in good yields by straightforward
Grignard reaction of 1-chloro-4,5-dihydro-3H-dinaphtho[2,1-
c;1’,2’-e]phosphepine with the corresponding aryl and alkyl
halides.[21] Furthermore, monodentate state-of-the-art ligands
Scheme 1. Catalytic hydrogenation of b-ketoesters 5a–c.
Pioneering workby Noyori and co-workers established
the use of binap as a highly selective ligand for this trans-
formation.[4] More recent developments of chiral ligands were
reported by the groups of Genet,[5] Weissensteiner and
Spindler,[6] Imamoto,[7] Knochel,[8] Zhang,[9] and others.[10]
Virtually all known ligands that induce significant enantiose-
lectivity in the hydrogenation of b-ketoesters are optically
active diphosphines.[11]
Interestingly, monodentate ligands (Scheme 2) have
recently become increasingly important for catalytic asym-
metric hydrogenations of amino acid precursors.[12] In this
case, important contributions were made by Reetz et al.
(phosphites 1),[13] de Vries, Feringa, and co-workers (phos-
[*] Dr. K. Junge,Dipl.-Ing. B. Hagemann,S. Enthaler,
Prof. Dr. G. Oehme,Prof. Dr. M. Michalik,Prof. Dr. M. Beller
Leibniz-Institut für Organische Katalyse
Universität Rostock e.V. (IfOK)
Buchbinderstrasse 5–6,18055 Rostock (Germany)
Fax: (+49)381-46693-24
E-mail: matthias.beller@ifok.uni-rostock.de
Dr. A. Monsees,Dr. T. Riermeier,Dr. U. Dingerdissen
Degussa AG,Rodenbacher Chaussee 4
63457 Hanau (Wolfgang) (Germany)
[**] The authors thank M. Heyken,H. Baudisch,Dr. W. Baumann,S.
Buchholz,and Dr. C. Fischer (all IfOK) for analytical and technical
support. Generous financial support for this project from the state
Mecklenburg-Vorpommern (Landesforschungsschwerpunkt),the
Fonds der Chemischen Industrie,and the Bundesministerium für
Bildung und Forschung (BMBF) is gratefully acknowledged.
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DOI: 10.1002/anie.200460190
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Angewandte
Chemie
Table 1: Hydrogenation of 5a in the presence of [Ru(cod)(methallyl)2]/
4a.[a]
the exchange of hydrogen by deuterium atoms. We were
curious to see if this minor change also influences the
enantioselectivity. Thus, the pentadeuterated ligand 4 f was
prepared in good yield by a similar method to that described
above. A comparison of 4a and 4 f under identical reaction
conditions led to (R)-methyl 3-hydroxybutyrate in > 95%
yield with 84 and 59% ee, respectively.
Entry
Solvent
t [h]
p [bar] T [8C]
Conversion [%]
ee [%]
1
2
3
4
5
6
7
8
9
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
acetone
toluene
THF
16
16
16
16
16
16
16
16
16
20
40
60
80
60
60
60
60
60
60
60
60
60
40
80
60
60
60
25
46
51
95
28
95
4
53 (R)
68 (R)
74 (R)
69 (R)
34 (R)
84 (R)
5 (R)
This is, to the best of our knowledge, the first example of
an isotope influence on the stereoselectivity of catalytic
asymmetric reactions. Because of this finding, we also
compared the hydrogenation reaction in the presence of 3a
and its deuterated analogue 3b. In this case, we noted even an
increase in the selectivity upon substitution of the hydrogen
atoms with deuterium atoms (28 versus 56% ee, respectively;
Table 2, entries 2,3). As the mechanism for the ruthenium-
catalyzed asymmetric hydrogenation of b-ketoesters is still
vague,[23] we do not have a clear rational explanation for the
observed change in ee values. We believe that the phenyl ring
also coordinates to the metal center during the catalytic cycle
and therefore affects the outcome of the reaction. A
comparison of catalytic reactions with the deuterated ligand
4 f in the presence of methanol (5a: 64% ee) and deuterated
methanol (5a: 73% ee) demonstrates that deuteration of the
solvent also influences the selectivity of the model reaction.
Finally we applied ligands 4a,b,f in the hydrogenation of
different b-ketoesters (Table 3).
1
<1
2 (S)
8 (R)
[a] Conditions: solvent (20 mL), 5a (3.8 mmol),[Ru(cod(methallyl)
(38 mmol), 4a (76 mmol).
]
2
from other groups such as (R)-monophos (2a) and the Pringle
ligand 3a were applied.[22]
Importantly, in the presence of the monodentate phos-
phonate and phosphoramidite, only low enantioselectivity
was observed (10–28% ee; Table 2, entries 1,2). More sur-
Table 2: Hydrogenation of 5a in the presence of different ligands.[a]
In general, all substrates were hydrogenated with excel-
lent conversion and yield. The best selectivities were obtained
Table 3: Hydrogenation of different b-ketoesters 5a–d.[a]
Entry
Ligand
t [h]
T [8C]
Conversion [%]
ee [%]
1
2
3
4
5
6
7
8
9
2a
3a
3b
4a
4b
4b
4c
4d
4e
4e
4 f
16
16
16
16
48
16
16
16
16
16
16
80
60
60
80
80
80
80
60
60
80
80
85
>99
>99
95
10 (S)
28 (S)
56 (S)
84 (R)
93 (R)
92 (R)
51 (R)
60 (R)
10 (R)
64 (R)
59 (R)
Entry
4
5
R1
R2
t [h] T [8C] Yield [%]
ee [%]
98
>99
>99
>99
96
95
95
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
a
a
a
a
b
b
b
b
b
b
b
b
b
b
b
b
f
a
b
c
Me
Et
CH2Cl
C6H5
Me
Me
Me
Et
Et
Me
Me
Et
16
16
24
16
16
8
8
16
8
8
16
8
8
16
8
80
80
80
80
80
100
120
80
100
120
80
100
120
80
100
120
60
95
97
81
>99
97
99
96
99
99
99
98
73
77
>99
99
99
98
95
99
84 (R)
86 (R)
13 (S)
73 (S)
92 (R)
93 (R)
93 (R)
94 (R)
95 (R)
94 (R)
6 (S)[b]
23 (S)[b]
38 (S)[b]
94 (S)[b]
95 (S)[b]
91 (S)[b]
64 (R)
59 (R)
78 (R)
9 (S)[b]
64 (S)[b]
d
a
a
a
b
b
b
c
Et
10
11
Me
Me
Me
Me
Me
Me
Et
Et
Et
Et
Et
[a] Conditions: methanol (20 mL), 5a (3.8 mmol),[Ru(cod)(methallyl) 2]
(38 mmol), 4a–f, 2a,or 3a,b (76 mmol),60 bar.
Et
CH2Cl
CH2Cl
CH2Cl
C6H5
C6H5
C6H5
Me
Me
Et
CH2Cl
C6H5
prisingly, the structurally analogous phosphonate 3a gave a
significantly lower enantioselectivity than 4a. In this case, the
formal exchange of two oxygen atoms by sterically similar
CH2 groups led to an increase in enantioselectivity from 28%
(S) to 84% (R) (Table 2, entries 2,4). This clearly demon-
strates the importance of electronic effects for achieving high
selectivity in the test reaction. These findings inspired us to
study the effect of variations of substituents on the phenyl
group in 4a more closely.
c
c
d
d
d
a
a
b
c
Et
8
Me
Me
Me
Et
48
16
16
16
16
f
f
f
f
80
80
80
80
97
d
Et
>99[c]
Among the different ligands, 4b gave the highest enan-
tioselectivity (up to 93% ee) (Table 2, entry 5). Only the
introduction of electron-donating (p-methoxy) groups at C4
of the phenyl ring led to a slight increase in selectivity. One of
the smallest structural variations possible within the ligand is
[a] Conditions: solvent (20 mL), 5 (3.8 mmol),[Ru(cod)(methallyl)
]
2
(38 mmol), 4a,b,f (76 mmol) 60 bar; methanol was used as a solvent for
methyl esters and ethanol for ethyl esters. [b] Owing to the change in
priority of the substituents,the configuration of the stereocenter is
changed. [c] Conversion; reaction run at 80 bar pressure of H2.
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22.7 ppm (CH3); elemental analysis: calcd (%) for C5H10O3 (118.17):
C 59.15, H 8.54; found: C 59.01, H 8.59.
by using the 4-methoxyphenyl-substituted dinaphthophos-
phepine ligand 4b at temperatures of 100–1208C. Whereas 3-
oxobutyrate and 3-oxopentanoate gave enantioselectivities of
93–95% ee, the 4-chloro-3-oxobutyrate led only to 38% ee.[24]
The phenyl-substituted b-ketoester gave up to 95% ee. In
agreement with the previous findings, the deuterated ligand
4 f showed a significantly different selectivity than that of
ligand 4a in every hydrogenation. Hence, the observed
deuterium effect on the selectivity seems to be general for
this type of reaction.
In conclusion, we have shown for the first time that
monodentate phosphine ligands can be used efficiently for the
ruthenium-catalyzed hydrogenation of b-ketoesters. The
catalysts are remarkably temperature-tolerant: Enantioselec-
tivities of up to 95% ee were possible, even at 100–1208C. A
comparison of 4a with structurally related 2a and 3a
demonstrates the superiority of phosphines over phosphites,
phosphonates, and phosphoramidites. Interestingly, the use of
deuterated phenyl compounds 3b and 4 f led to the observa-
tion of an isotope effect on the enantioselectivity of the
reaction, which may be of interest to asymmetric reactions in
general.
Received: April 1, 2004
Keywords: b-ketoesters · asymmetric catalysis · hydrogenation ·
.
ruthenium
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Experimental Section
Unless otherwise noted, all chemicals are commercially available and
were used without further purification. The b-ketoesters 5a–d were
distilled under an argon atmosphere. Products were fully character-
ized (b.p., IR, MS, elemental analysis, NMR).
General procedure: in situ preparation of ruthenium catalyst:[5]
[Ru(cod)(methallyl)2] (0.038 mmol) and ligand 2a, 3, or
4
(0.076 mmol) were placed in a dried 25-mL Schlenktube under an
argon atmosphere, and anhydrous and degassed acetone (5 mL) was
added. After the dropwise addition of a solution of HBr in methanol
(0.33 mL, 0.29m) a brown precipitate was formed. Stirring was then
continued over 30 min, the solvent was removed in vacuo, and
methanol (20 mL) or ethanol (for substrates 5c and 5d) was added.
Asymmetric hydrogenation of b-ketoesters 5a–d: Catalytic
hydrogenation experiments were carried out in a Parr stainless-steel
autoclave (100 mL). In a typical experiment, the autoclave was
charged with a mixture of the catalyst [L2RuBr2] prepared in situ and
5a (3.80 mmol) in methanol (20 mL) under a stream of argon. The
autoclave was stirred under 40–80 bar pressure of hydrogen at 60–
1208C for 16–48 h. The autoclave was cooled to room temperature,
and the hydrogen was released. The reaction mixture was filtered
over silica gel, and the enantiomeric excess was determined by GC
(Lipodex E) or HPLC (Chiracel OD-H). Most of the hydrogenation
products have been described previously. Methyl 3-hydroxybutyrate
(6a): GC (25 m Lipodex E, 958C isothermal): tr = 4.9 (S), 5.7 min (R);
methyl 3-hydroxyvalerate (6b): GC (25 m Lipodex E, 858C isother-
mal): tr = 10.9 (S), 11.6 min (R); ethyl 3-hydroxy-4-chlorobutyrate
(6c): GC (25 m Lipodex E, 958C isothermal): tr = 20.4 (R), 20.6 min
(S); ethyl 3-hydroxy-3-phenylpropionate (6d): HPLC (OD-H,
hexane/ethanol 95:5, 0.5 mLminÀ1), tr = 10.1 (S), 11.5 min (R).
6a: B.p. 63–668C/10 Torr; IR (KBr): n˜ = 3439 br, 3140 w, 2974 w,
2967 m, 2937 m, 1737 br vs, 1439 vs, 1410 s, 1377 s, 1298 s, 1269 s, 1195 s,
1178 s, 1170 w, 1126 w, 1089 w, 1082 w, 946 s, 886 s, 862 m, 719 m, 598 m,
593 s, 475 cmÀ1 w; MS (70 eV): m/z (%): 103 (16) [MÀMe]+, 100 (3)
[MÀOH]+, 87 (16) [MÀOMe]+, 85 (5), 74 (50), 71 (26), 61 (12), 59
(10) [COOCH3]+, 45 (55) [CHOHCH3]+, 43 (100), 42 (26), 31 (14)
[CH3O]+, 29 (17), 15 (21); 1H NMR (400 MHz, CDCl3): d = 4.10–4.06
(m, 1H; CH), 3.58 (s, 3H; OCH3), 3.30 (s, 1H; OH), 2.34 (m, 2H;
CH2), 1.11 ppm (d, J = 6.3 Hz, 3H; CH3); 13C NMR (100.6 MHz,
CDCl3): d = 173.2 (CO), 64.2 (C-OH), 51.7 (CH3O), 43.0 (CH2),
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[19] a) K. Junge, G. Oehme, A. Monsees, T. Riermeier, U. Dinger-
dissen, M. Beller, Tetrahedron Lett. 2002, 43, 4977 – 4980; b) K.
Junge, G. Oehme, A. Monsees, T. Riermeier, U. Dingerdissen,
M. Beller, J. Organomet. Chem. 2003, 675, 91 – 96.
[20] These ligands are commercially available from Degussa AG/
Catalyst and Initiators.
[21] Importantly, an alternative synthesis of ligand 4a by double
metallation of 2,2’-dimethylbinaphthyl with n-butyl lithium in
the presence of tetramethylethylenediamine (TMEDA) and
direct quenching with commercially available dichlorophenyl-
phosphane gave the corresponding ligand with only 80–95%
purity (impurities: lithium salts and organic by-products). This
decreased purity led to
a lower enantioselectivity in the
reduction of 5a and the product was obtained with opposite
absolute configuration. We do not know currently which
impurity is responsible for the different outcome. In this respect,
it is also interesting that the addition of lithium and magnesium
salts influences the enantioselectivity of the reduction of 5a in
the presence of 4a by 5–10%.
[22] We also tried phosphites similar to the Reetz ligand in b-
ketoester hydrogenation, but these ligands did not prove to be
stable under our conditions (80–1208C, methanol).
[23] A. Wolfson, I. F. J. Vankelecom, S. Geresh, P. A. Jacobs, J. Mol.
Catal. A 2003, 198, 39 – 45.
[24] In the case of 5c, dehydrochlorination was observed as a side
reaction at higher temperature.
Angew. Chem. Int. Ed. 2004, 43, 5066 –5069
www.angewandte.org
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5069