A homogeneous catalyst for reduction of optically active esters to the corresponding chiral alcohols without loss of optical purities

Article abstract of DOI:10.1002/adsc.200900114

A ruthenium complex was found to catalyze the hydrogen reduction of esters under mild and neutral conditions. A variety of optically active esters can be reduced to the corresponding alcohols in excellent yield without loss of their optical purity or causing undesirable side reactions. Hydrogen reduction needs such simple operations - reaction, concentration, and purification - that the violent quench step and extraction step, which accompany conventional sodium borohydride or lithium aluminum hydride reduction, can be omitted.

Full text of DOI:10.1002/adsc.200900114

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DOI: 10.1002/adsc.200900114
A Homogeneous Catalyst for Reduction of Optically Active
Esters to the Corresponding Chiral Alcohols without Loss of
Optical Purities
Wataru Kuriyama,a,* Yasunori Ino,a Osamu Ogata,a Noboru Sayo,a
and Takao Saitoa
a
Takasago International Corporation, Corporate Research & Development Division, 4-11, 1-Chome, Nishi-Yawata,
Hiratsuka City, Kanagawa 254-0073, Japan
Fax : (+81)-463-25-2093; e-mail: wataru_kuriyama@takasago.com
Received: February 19, 2009; Revised: October 15, 2009; Published online: December 22, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900114.
Abstract: A ruthenium complex was found to cata-
lyze the hydrogen reduction of esters under mild
and neutral conditions. A variety of optically active
esters can be reduced to the corresponding alcohols
in excellent yield without loss of their optical purity
or causing undesirable side reactions. Hydrogen re-
duction needs such simple operations – reaction,
concentration, and purification – that the violent
quench step and extraction step, which accompany
conventional sodium borohydride or lithium alumi-
num hydride reduction, can be omitted.
metal hydride compounds, and to simplify the subse-
quent operations.
To the best of our knowledge, there are few pub-
lished articles that refer to catalytic reduction of opti-
cally active esters to the corresponding chiral alco-
hols. In a recent article, a Nishimura catalyst, which
consists of Rh/Pt oxide, catalyzed the hydrogenation
of chiral a-hydroxy or a-amino esters at 258C under
10 MPa hydrogen pressure without racemization.[3]
However, application of the catalyst was limited, be-
cause at the same time a phenyl group was hydrogen-
ated to a cyclohexyl group.
Keywords: chiral alcohols; esters; homogeneous
catalyst; hydrogenation; reduction; ruthenium
More recently, homogeneous ruthenium-amino-
phosphine complexes were reported to demonstrate
excellent performance in the catalytic reduction of
esters. They showed high activity and selectivity
under basic and relatively mild conditions.[4] However
the article gave no description of chiral esters and op-
Chiral alcohols are versatile intermediates for physio- tical purity.
logically active compounds.[1] A wide variety of chiral
We began to develop a homogeneous catalytic
secondary alcohols having the hydroxy group on system for the reduction of chiral esters because ho-
chiral centers are efficiently synthesized by asymmet- mogeneous catalysts seemed the most likely to have
ric syntheses such as catalytic asymmetric hydrogena- both activity and selectivity. Herein, we report a new
tion or asymmetric biocatalytic reduction of the corre- ruthenium-catalyzed hydrogen reduction of various
sponding ketones.[2a–f] Another technique is dynamic kinds of optically active esters to the corresponding
kinetic resolution of racemic secondary alcohols by chiral alcohols with virtually perfect retention of their
the combination of metal catalysts and enzymes.[2g] optical purities.
Chiral primary alcohols have often been obtained via
We first investigated whether the reported highly
stoichiometric metal hydride reduction of the corre- active catalytic system, which employed the complex
sponding chiral esters, which are generally easily RuCl2(aminophosphine)2 and a base,[4a] could catalyze
available from the chiral pool or through asymmetric the reduction of chiral esters (Table 1). Unfortunately,
syntheses. Conventionally, sodium borohydride or the procedure did not work for that purpose. The cat-
lithium aluminum hydride reductions have been em- alyst reduced some kinds of chiral esters, but with a
ployed for this purpose. They are reliable in the labo- considerable loss in enantiomeric excess. Undesirable
ratory, but an alternative method is desirable for large side reactions were also observed. This system
scale synthesis to avoid the use of extremely reactive showed higher catalytic activity for reduction of an a-
92
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2010, 352, 92 – 96

A Homogeneous Catalyst for Reduction of Optically Active Esters
Table 1. Hydrogenation reduction of chiral esters with RuCl2(aminophosphine)2/base.[a]
Entry
1[c]
Substrate
Product
Yield [%] (Dee)[b]
93[d] (62)
2
3
70[d] (>98)
Trace[e] (–)
0[f] (–)
4
[a]
Standard reaction conditions: substrate (5.0 mmol), 1 (0.05 mmol), and NaOMe (0.5 mmol) in THF (2 mL) under 5 MPa
H2 at 808C for 16 h.
[b]
[c]
[d]
[e]
[f]
Dee=(ee of substrate)À(ee of product). ee of substrate/product; entry 1 (78.9/17.4), entry 2 (>99/1).
1 (0.01 mmol).
Isolated yield.
GC analysis.
Only starting ester was detected by GC analysis.
alkylated ester, but a significant drop in optical purity ligands would make it easy to tune the catalyst. We
was observed (entry 1, Dee=62). In the case of an a- attempted to modify the catalytic system for hydrogen
amino acid ester protected by a Boc group, which is reduction of esters, although it was likely to be chal-
one of the most useful protecting groups for the lenging because it was reported that the ester was not
amino moiety, the reduction itself proceeded, but op- simultaneously hydrogenated.[8]
tical purity was lost and a side reaction formed an ox-
We conducted a screening test to investigate the
(di-
ACHTUNGTRENaNUNG mine) complexes under basic conditions by using
azolidinone ring (entry 2).[5] When unprotected b-hy- ligand effect of precursor RuCl2(bisphosphine)
ACHTUNGTRENNUNG
droxy and b-amino acid esters were examined, only
traces or no product was obtained (entries 3 and 4). methyl benzoate as the substrate (Table 2).[9] Ligand
In entry 3, although the starting material was con- combination strongly influenced catalyst activity.
sumed, a trace of amino alcohol was obtained, proba- Among the combinations examined, dppp-dpen
bly because of its instability under basic conditions. showed the best performance. Substituents on the eth-
Considering these results, we decided that more neu- ylene moiety of ethylenediamine significantly im-
tral conditions were required for the ester reduction proved the catalytic activity (entries 8 and 9). RuCl2
to succeed.
Milstein et al. reported a ruthenium complex which choice.
(dpen)[10] was considered the precursor of
ACHUTGTNRNEUG(N dppp)ACHTUTGNRENNUGN
catalyzed hydrogen reduction of esters without addi-
The complex was converted according to a known
tion of a base. They proposed that ester coordination method into RuH
G
E
ACHTUNGTRENNUNG
to ruthenium is involved in the catalytic cycle.[6] Con- plexes RuH
G
N
R
ACHTUNGTRENNUNG
cerning metal-ligand bifunctional catalysts with the BH4)
(dppp)
E
effect,[7]
RuH
(h1-BH4)(bisphosphine)
ACHUTGTNRENNUG CAHTUNGTRENNUNG
À
“N H”
amine) and RuH
U
plexes have been reported to catalyze the asymmetric tion of a-substituted chiral esters (Table 3). These
hydrogenation of ketones without addition of a complexes successfully catalyzed hydrogen reductions
ACTHNUTRGNEUNG
base.[8] In this article, we focused on RuH(h1- of various kinds of a-alkyl, substituted amino, and
BH4)(bisphosphine)
ACHTUNGTRNE(NUNG diamine) complexes because the protected hydroxy esters without addition of a base.
easy availability of various bisphosphine and diamine The corresponding chiral alcohols were produced in
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93

Wataru Kuriyama et al.
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Table 2. Hydrogen reduction of methyl benzoate with
Table 3. Hydrogen reduction of a-substituted chiral esters
with ruthenium complex 14.[a]
RuCl2(bisphosphine)ACTHNUTRGNEUNG
(diamine)/base.[a]
Entry
Product
Cat.
(R,R)-14
Yield [%] (Dee)[b]
1a
1b
G
95 (<2)
95 (1)
E
2a
2b
C
92 (1)
96 (<1)
3
4
N
94 (<1)
89 (<1)
Entry
P^P
N^N
3[b]
2[b]
1
2
3
4
5
6
7
8
9
4
5
6
7
8
7
7
7
7
9
9
9
9
15
22
4
49
27
76
1
70
62
85
37
59
21
97
0
5
G
89 (<1)
9
10
11
12
13[c]
6a
6b
95 (<1)
90 (<1)
97
97
7a
7b
0[c] (–)
Trace
0[c] (–)
[a]
Standard reaction conditions: methyl benzoate (4 mmol),
RuCl2(bisphosphine)(diamine) (0.008 mmol) and
NaOMe (0.4 mmol) in THF (3 mL) under 5 MPa H2 for
8a
8b
30[d] (6) [<1][e]
AHCTUNGTRENNUNG
45[d] (5) [2][e]
3 h.
[a]
Standard reaction conditions: substrate (5.0 mmol) and
14 (0.05 mmol) in THF (2 mL) under 5 MPa H2 at 808C
for 16 h. Purification: silica gel column chromatography.
Dee=(ee of substrate)À(ee of product). ee of substrate/
product; entry 1a (78.9/77.4), 1b (78.9/77.6), entry 2a
(product 98.9), entry 2b (product 99.1), entry 3 (product
99.1), entry 4 (product>99.8), entry 5 (61.3/61.3),
entry 6a (98.5/98.3), entry 6b (98.5/98.3), entry 8a (99.0/
93.4, remaining ester 98.3), entry 8b (99.0/93.7, remaining
ester 97.7).
[b]
[c]
GC area %.
Racemic mixture.
[b]
[c]
[d]
[e]
GC analysis.
GC area%.
(ee of starting methyl lactate)À(ee of remaining sub-
stance).
(h1-BH4)
Scheme 1. Synthesis of [RuHACHTUGNTRENNNGU AHCTUNRTGENN(GUN dppp)CAHTNUGTRENN(UGN dpen)].
case of the unprotected a-functionalized esters (en-
tries 7a–8b). In comparison with the results with
(R,R)-14 and those with (S,S)-14, virtually no steric
excellent yields without loss of optical purity and un- effect between non-racemic DPEN and chiral sub-
desirable side reactions. The tert-butoxycarbonyl strates was observed.
moiety was tolerated. A variety of Boc-protected a-
Next, b-substituted esters were examined (Table 4).
amino acid esters were reduced effectively (entries 2a, In this case, even unprotected b-amino and b-hydroxy
2b, 3 and 4). N-Phenylalanine ester was also reduced esters were reduced to the corresponding amino alco-
(entry 5). The protected lactic acid ester gave the cor- hols and diols (entries 1a, 1b, 4a and 4b). Although
responding monoprotected diol without hydrogenoly- 100% conversion was obtained as determined by GC
sis of the benzyl moiety (entries 6a and 6b). But no analysis in entries 1a and 1b, small-scale distillation
product or only moderate yields were obtained in the produced only moderate yields (we expect that scal-
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A Homogeneous Catalyst for Reduction of Optically Active Esters
Table 4. Hydrogen reduction of b-substituted chiral esters
with ruthenium complex 14.[a]
Scheme 3. Hydrogen reduction of deuterium-labelled methyl
b-hydroxybutyrate
Entry
Alcohol
Cat.
Yield[b] [%] Dee[c]
Table 5. Hydrogen reduction of benzoic acid esters with
ruthenium complex (R,R)-14.[a]
1a
1b
A
AHCTUNGTRENNUNG
64[d] (<1)
53[d] (<1)
2a
2b
C
96 (<1)
92 (1)
3a
3b
N
96 (<2)
95 (<1)
Entry
R
3[b]
2’[b]
1
2
3
4
Me
i-Pr
t-Bu
Ph
97
34
<1
8
<1
66
>99
84
4a
4b
N
98 (19)
95 (24)
5a
5b
87 (<1)
92 (<1)
[a]
Standard reaction conditions: benzoic acid ester
(4 mmol), (R,R)-14 (0.008 mmol) in THF (3 mL) under
5 MPa H2 for 16 h.
[a]
[b]
GC area %.
[b]
[c]
Dee=(ee of substrate)À(ee of product). ee of substrate/
product; entry 1a (product 99.6), entry 1b (product 99.7),
entry 2a (product 99.7), entry 2b (product 98.7), entry 3a
(87.7/86.2), entry 3b (87.7/87.0), entry 4a (98.9/80.2),
entry 4b (98.9/75.1), entry 5a (98.9 max./98.8), entry 5b
(98.9 max./98.8).
Last, we investigated the application of this catalyt-
ic system to variety of alkyl and aryl esters by using
benzoic acid esters as the substrates (Table 5).
In the hydrogen reduction of methyl benzoate,
0.2 mol% of the catalyst afforded almost full conver-
sion, however, as the steric bulkiness of the R group
increased, the product ratio decreased (entry 1; Me
group 97%, entry 2; i-Pr group 34%, entry 3; t-Bu
[d]
Purification by distillation.
ing up the operation would improve the yield). Enan- <1%). In the reduction of phenyl benzoate, this cata-
tiomeric excesses were almost perfectly retained lyst gave a lower yield than methyl and isopropyl ben-
through the reaction process, except for the reduction zoate (entry 4).
of the unprotected b-hydroxy ester (entries 4a and
To summarize, a new catalytic system for the hydro-
4b). This might be caused via the hydrogen transfer gen reduction of esters has been developed. This
process shown in Scheme 2.[11] Once the hydroxy promising method was carried out without addition of
group was protected, no racemization was observed a base to give various types of chiral alcohols from
(entry 5).
the corresponding esters, which are easy to obtain
To confirm the hypothesis, we reduced deuterium- from the chiral pool or through asymmetric syntheses.
labelled methyl b-hydroxybutyrate. Methyl b-hydroxy- In many cases, yields were excellent without loss of
ACHTUNGTRENNUNGbutyrate with 69% deuterium-labelling gave 1,3-buta- optical purity. Using this catalytic system, the trouble-
nediol with 59% deuterium-labelling. This result sug- some and annoying operations incidental to ordinary
gests that transfer hydrogenation occurred during the metal hydride reduction can be avoided. The catalytic
reduction (Scheme 3).
process could contribute to sustainable chemistry by
reducing the waste generated and energy consumed
during the reactions and subsequent operations.
Experimental Section
Catalyst Preparation
Scheme 2. Racemization process through transfer hydroge-
nation.
RuH
(2.0 g, 2.51 mmol) was placed in a 200-mL 3-neck flask
(h1-BH4) (S,S)-dpen)[10]
ACHTUNGTRENUGN ACHUTNGTRNNEU(GN dppp)ACHTNURTGENG[UNN (S,S)-dpen]: RuCl2AHTCUNGERTN(NUNG dppp)ACHTNUTGRNUEGN
Adv. Synth. Catal. 2010, 352, 92 – 96
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95

Wataru Kuriyama et al.
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equipped with a Dimroth condenser. The atmosphere was
replaced with nitrogen gas, followed by addition of a toluene
and ethanol (30 mL) solution of NaBH4 (2.4 g, 62.8 mmol).
The mixture was stirred at 658C for 5 min., and at room
temperature for 1 h. The reaction mixture was concentrated
under vacuum, followed by addition of toluene (90 mL).
The suspension was stirred at 408C for 10 min, and filtered
through a Celite column and the column was washed with
toluene (45 mL). The solution was concentrated under
vacuum, until approximately 95 mL of toluene had been re-
moved. To the mixture, was added hexane (70 mL). The pre-
cipitate was filtered off and washed with hexane (10 mL ꢁ
628. For dynamic kinetic resolution: g) O. Pꢂmies, J.-E.
Bꢃckvall, Chem. Rev. 2003, 103, 3247–3261.
[3] M. Studer, S. Burkhardt, H.-U. Blaser, Adv. Synth.
Catal. 2001, 343, 802- 808.
[4] a) L. A. Saudan, C. M. Saudan, C. Debieux, P. Wyss,
Angew. Chem. 2007, 119, 7617–7620; Angew. Chem.
Int. Ed. 2007, 46, 7473–7476; b) L. Saudan, C. Saudan,
WO Patent 2008/65588A1, 2008.
[5] V. B. Birman, H. Jiang, X. Li, L. Guo, E. W. Uffman, J.
Am. Chem. Soc. 2006, 128, 6536–6537.
[6] J. Zhang, G. Leitus, Y. Ben-David, D. Milstein. Angew.
Chem. 2006, 118, 1131–1133; Angew. Chem. Int. Ed.
2006, 45, 1113–1115.
3) to afford RuHACHTUNGTRENNUNG ACHUTNRTGEG(NNNU dppp)ACHTUNGTREN[NUGN (S,S)-dpen] as light brown
(h1-BH4)
solid; yield: 1.25 g (63%). 1H NMR (300 MHz, C6D6): d=
À14.98 (t, J=25.8 Hz, 1H), À0.68 (br, 4H), 1.28–1.56 (m,
1H), 1.58–1.91 (m, 1H), 2.20–2.42 (m, 3H), 2.49–2.62 (m,
1H), 2.67–2.87 (m, 2H), 3.58–3.73 (m, 1H), 3.88–4.03 (m,
1H), 4.25–4.40 (m, 1H), 4.56–4.70 (m, 1H), 6.47–8.18 (m,
30H); 31P NMR (121.5 MHz, C6D6): d=57.51.
[7] Mechanistic studies for metal ligand bifunctional catal-
ysis; a) M. Yamakawa, H. Ito, R. Noyori, J. Am. Chem.
Soc. 2000, 122, 1466–1478; b) K. Abdur-Rashid, S. E.
Clapham, A. Hadzovic, J. N. Harvey, A. J. Lough, R. H.
Morris, J. Am. Chem. Soc. 2002, 124, 15104–15118;
c) C. A. Sandoval, T. Ohkuma, K. MuÇiz, R. Noyori, J.
Am. Chem. Soc. 2003, 125, 13490–13503; d) R. J. Ham-
ilton, C. G. Leong, G. Bigam, M. Misklzie, S. H. Ber-
gens, J. Am. Chem. Soc. 2005, 127, 4152–4153; e) A.
Hadzovic, D. Song, C. M. MacLaughlin, R. H. Morris,
Organometallics 2007, 26, 5987–5999; f) R. J. Hamilton,
S. H. Bergens, J. Am. Chem. Soc. 2008, 130, 11979–
11987, and references cited therein.
[8] a) T. Ohkuma, M. Koizumi, K. MuÇiz, G. Hilt, C.
Kabuto, R. Noyori, J. Am. Chem. Soc. 2002, 124, 6508–
6509; b) R. Guo, R. H. Morris, D. Seng, J. Am. Chem.
Soc. 2005, 127, 516–517; c) T. Ohkuma, C. A. Sandoval,
R. Srinivasan, Q. Lin, Y. Wei, K. MuÇiz, R. Noyori, J.
Am. Chem. Soc. 2005, 127, 8288–8289.
RuH
similar procedure.
ACHTUNGTRENNUNG ACHTUNGTRENNUNG(dppp)ACTHNUGTRENUN[GN (R,R)-dpen] was synthesized by a
(h1-BH4)
General Procedure for Hydrogen Reduction of Chiral
Esters
To a 100-mL stainless steel autoclave equipped with a
Teflon-coated stirrer bar, was charged ruthenium complex
14 (0.05 mmol). The atmosphere was replaced with nitrogen
gas, followed by addition of a THF (2 mL) solution of the
substrate ester (5 mmol). The vessel was purged three times
with hydrogen gas (0.5 MPa), and then pressurized with hy-
drogen (5 MPa). The mixture was stirred at 808C for 16 h.
[9] L. Saudan and C. Saudan conducted a screening test on
RuCl2ACTHNURGTENN(UG bis(triarylphosphine))ACHTUNTGREN(NUNG diamine)complexes under
References
basic conditions by using methyl benzoate as the sub-
strate, see ref.[4b]
[1] V. Farina, J. T. Reeves, C. H. Senanayake, J. J. Song,
Chem. Rev. 2006, 106, 2734–2793.
[10] The complex was synthesized according to the litera-
ture: H. Doucet, T. Ohkuma, K. Murata, T. Yokowasa,
M. Kozawa, E. Katayama, A. F. England, T. Ikaraiya,
R. Noyori, Angew. Chem. 1998, 110, 1792–1796;
Angew. Chem. Int. Ed. 1998, 37, 1703–1707; and 1H
and 31P NMR spectra data were identical with those of
reported: E. Lindner, H. A. Mayer, I. Warad, K. Ei-
chele, J. Organomet. Chem. 2003, 665, 176–185.
[2] For catalytic asymmetric hydrogenation; a) R. Noyori,
T. Ohkuma, Angew. Chem. 2001, 113, 40–75; Angew.
Chem. Int. Ed. 2001, 40, 40–73; b) R. Noyori, Angew.
Chem. 2002, 114, 2108–2123; Angew. Chem. Int. Ed.
2002, 41, 2008–2022; c) W. Tang, X. Zhang; Chem.
Rev. 2003, 103, 3029–3069; d) H. Shimizu, I. Nagasaki,
T. Saito, Tetrahedron 2005, 61, 5405–5432. For asym-
metric biocatalytic reduction: e) E. Santaniello, P. Fer-
raboschi, P. Grisenti, A. Manzocchi, Chem. Rev. 1992,
92, 1071–1140; f) Enzyme Catalysis in Organic Synthe-
sis A Comprehensive Handbook, Volume II, (Eds.: K.
Drauz, H. Waldmann), VCH, Weinheim, 1995, pp 595–
[11] A similar trans-RuHACHTNUTGRNEUNG
(h1-BH4)(phosphinite)diamine
complex was reported to catalyze the transfer hydroge-
nation between acetophenone and IPA: R. Guo, X.
Chen, C. Elpelt, D. Song, R. H. Morris, Org. Lett. 2005,
7, 1757–1759.
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Adv. Synth. Catal. 2010, 352, 92 – 96