Enhanced enantioselectivity in the heterogeneous catalytic hydrogenation of acetoacetate esters into the corresponding 3-hydroxybutyrates using commercial nickel powder

Article abstract of DOI:10.1016/j.tetasy.2014.11.003

Heterogeneous catalytic hydrogenation of acetoacetic acid esters over tartaric acid/NaBr-modified Ni powder was determined to be a critical function of the steric bulk of the ester moiety to afford quantitatively 3-hydroxybutyrate in 94% enantiomeric excess when ethyl and i-butyl esters are used, providing a facile route to optically active 3-hydroxybutyrates.

Full text of DOI:10.1016/j.tetasy.2014.11.003

Tetrahedron: Asymmetry 25 (2014) 1630–1633
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Enhanced enantioselectivity in the heterogeneous catalytic
hydrogenation of acetoacetate esters into the corresponding
3-hydroxybutyrates using commercial nickel powder
Tsutomu Osawa a, , Tomoko Kizawa , Shinji Ikeda , Takayuki Kitamura , Yoshihisa Inoue ,
Victor Borovkov
a
⇑
b
b
b
c
b,c,
⇑
Graduate School of Science and Engineering for Research, University of Toyama, Gofuku, Toyama 930-8555, Japan
Metek Co., Ltd, 1 Warada-cho, Kamitoba, Minami-ku, Kyoto 601-8133, Japan
Department of Applied Chemistry, Osaka University, 2-1 Yamada-oka, Suita 565-0871, Japan
b
c
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 1 October 2014
Accepted 5 November 2014
Heterogeneous catalytic hydrogenation of acetoacetic acid esters over tartaric acid/NaBr-modified Ni
powder was determined to be a critical function of the steric bulk of the ester moiety to afford quantita-
tively 3-hydroxybutyrate in 94% enantiomeric excess when ethyl and i-butyl esters are used, providing a
facile route to optically active 3-hydroxybutyrates.
Ó 2014 Elsevier Ltd. All rights reserved.
1
. Introduction
Chirality is one of the most essential issues in living organisms
heterogeneous catalysis, seems to be the most promising for indus-
trial application for the following reasons: the facile preparation,
easy separation, convenient recovery, and reuse of the catalyst,
as well as the use of economically and environmentally benign
procedures. In general, in the case of heterogeneous enantio-selec-
tive catalysts, the most systematically studied systems that give
due to the asymmetric nature of basic molecular building blocks
such as amino acids and sugars. As a consequence, the majority
of metabolic reactions involve chiral compounds. One such mole-
cule is (R)-3-hydroxybutyrate, which is a member of the so-called
2
1–23
24,25
high enantioselectivities are Pt
and Pd
modified with cin-
‘
ketone bodies’. Hydroxybutyrate is involved in the ketogenesis
chona alkaloids and Ni modified with tartaric acid. For the purpose
of obtaining hydroxybutyrate, the most suitable catalytic system is
the last one. In this catalytic system, the chiral catalyst is prepared
by modifying Raney or metallic Ni with tartaric acid and NaBr is
conventionally used. The best result obtained thus far was
achieved in the case of modified metallic Ni by systematically
examining the Ni source and modifying the hydrogenation condi-
tions for methyl acetoacetate to afford quantitatively methyl
process in liver mitochondria, and acts as an energy source for
many peripheral tissues, particularly in the heart, skeletal muscle,
and brain in the case of glucose starvation.1–3 Therefore, its blood
level is an important diagnostic tool for monitoring various patho-
logical conditions. Furthermore, hydroxybutyrate serves not only
as a component of biodegradable plastics that are used in tissue
4
–6
engineering,
but also as a chiral building block for the synthesis
7
–10
26
of a wide variety of fine (bio)chemicals, such as antibiotics,
pharmaceuticals,
being a component for improving drug delivery to the brain.
Currently, there are several main approaches to synthesize
enantiopure hydroxybutyrate, which include bacterial depolymer-
ization of poly(hydroxyalkanoate),16 biosynthesis from glucose,
hydroxybutyrate with up to 91% enantiomeric excess (ee). This
1
1–13
12,14
and nutritional supplements,
as well as
type of catalyst has two additional advantages for its use in
industry; it does not require the less reproducible dissolution of
an Al–Ni alloy (in the case of Raney Ni) or the somewhat dangerous
pre-activation by hydrogen gas at elevated temperatures,27 and
still retains its original hydrogenation activity and enantio-
1
5
17
18
28
enzymatic reduction of b-ketoesters, and asymmetric catalytic
differentiation ability for 3 months. The only drawback of this
hydrogenation of b-ketoesters.1
9,20
Of these biological and
catalyst is the enantioselectivity upon hydrogenation, which is
not high enough for pharmaceutical applications (95% ee).29 Herein
we report a convenient, highly efficient, and versatile technique for
obtaining enantiomeric hydroxybutyrate with up to 94% ee by
carefully choosing the steric bulk of the ester moiety of the
substrate in the catalytic hydrogenation over tartaric acid-NaBr/
Ni under the optimized conditions (see Scheme 1 and Section 4).
chemical routes to hydroxybutyrate, the last one, in particular
⇑
Corresponding authors. Tel.: +81 76 445 6611; fax: +81 76 445 6549 (T.O.); tel.:
81 6 6879 4128; fax: +81 6 6879 7923 (V.B.).
+
E-mail addresses: osawa@sci.u-toyama.ac.jp (T. Osawa), victrb@chem.eng.
osaka-u.ac.jp (V. Borovkov).
http://dx.doi.org/10.1016/j.tetasy.2014.11.003
0
957-4166/Ó 2014 Elsevier Ltd. All rights reserved.

T. Osawa et al. / Tetrahedron: Asymmetry 25 (2014) 1630–1633
1631
(
R,R)-tartaric acid-
and electronic effects on the enantiodifferentiating hydrogenation
over tartaric acid/NaBr-modified Ni powder to generally afford
considerably high ee values. The catalytic reaction was carried
out at two different temperatures, that is, 100 and 110 °C, which
are known to be optimal for the hydrogenation of methyl acetoac-
etate over the modified Ni powder catalyst in terms of the yield
OR
H
OR
H3C
H
OR
modified Ni
+
H3C
O
O
OH
O
OH
O
major product
minor product
Scheme 1. Enantiodifferentiating hydrogenation of normal and branched alkyl and
aryl acetoacetates to the corresponding (R)-3-hydroxybutyrates over a chiral Ni
catalyst prepared by directly modifying commercially available Ni powder with
2
6
and ee, to give the results shown in Table 1, where the corre-
sponding data obtained by using conventional modified Raney Ni
(
R,R)-tartaric acid and NaBr without any pre-treatment (for R, see Table 1).
1
9,33,34
catalyst
are included for the sake of comparison.
The acetoacetate substrates used herein were divided into three
main categories according to the branching of the ester group: 1°,
2
. Results and discussion
2
°, and 3°, see Table 1. Within the same category, the ester groups
One of the key steps in the catalytic hydrogenation is the enan-
of different chain lengths were employed. Methyl acetoacetate,
which belongs to the first category and has been used as a bench-
mark substrate of this type of catalytic reaction, was hydrogenated
to give methyl (R)-hydroxybutyrate in 100% conversion and 91% ee
and 89% ee at both 100 and 110 °C, respectively, which was in good
agreement with the literature. It should be noted that the ee
value obtained with this catalyst is consistently higher by 5% than
that of the Raney Ni-based catalysts, thus reflecting the enhanced
enantio-differentiating efficiency of metallic Ni powder.
As can be seen from Table 1, further elongation and branching
of the alkyl ester chain significantly influenced the catalytic perfor-
mance of the Ni powder, which is in sharp contrast to the relatively
modest effect in the case of Raney Ni. Thus, the conversion at
tiotopic face-differentiating supramolecular complexation of pro-
chiral acetoacetate with enantiomeric tartaric acid adsorbed on
the Ni surface, which is followed by the asymmetric hydrogenation
of the carbonyl group in acetoacetate with activated hydrogen on
1
9
2
6
the Ni surface. Of these two successive key processes, the first
one plays the dominant role in determining the product’s ee. In
general, the geometry and stability of chiral supramolecular sys-
tems are affected by several factors, including the relative size of
the complexation partners,3
0–32
and hence the steric bulk and
conformation of the substrate molecule should play important
roles upon adsorption on the Ni surface as well as the subsequent
enantiomeric face-differentiating hydrogenation. Indeed, some of
these effects have been observed upon catalytic hydrogenation of
homologous acetoacetate derivatives over chirally modified Raney
1
00 °C gradually decreased from 100% to 97% and then rather
suddenly to 85–78% by elongating the alkyl group from Me to Et
and then to Pr and Bu, but was not affected by incorporating an
aromatic group (100% conversion). Alkyl branching had a very sim-
ilar effect. The i-Bu ester with remote branching (1° group)
1
9,33,34
Ni.
However, since biologically important enantiopure
hydroxybutyrate is of our prime interest herein, a series of
branched and unbranched alkyl, as well as benzyl acetoacetate
were employed as prochiral substrates for examining their steric
resulted in a slight decrease in the conversion to 96%, while
a
Table 1
Comparison of the enantiodifferentiating hydrogenation over tartaric acid/NaBr-modified Ni powder versus tartaric acid/NaBr-modified Raney Ni catalysts
Ester group (R)
T (°C)
Ni powdera
ee (%)
eee (%)
Raney Nib,c,d
eeg (%)
f
eee (%)
Conv. (%)
D
D
ee (%)
Conv. (%)
D
Ref
1
°
CH
CH
3
60
h
98
86
86
ꢀ0
ꢀ0
b
d
1
00
10
85
00
10
100
100
91
89
„0
„0
+5
1
2
CH
3
2
97
h
87
88
d
c
1
1
97
94
85
100
78
100
96
100
100
100
94
92
92
91
93
91
94
92
89
88
+3
+3
+1
+2
+2
+2
+3
+3
À2
À1
+6
+4
+5
+6
+2
+2
+2
+2
CH
CH
CH
CH
2
2
2
2
CH
CH
3
100
10
100
10
100
10
100
h
88
88
88
c
c
d
1
(CH
2
2
) CH
3
h
1
CH(CH
3
)
2
95
1
6 5
C H
1
1
1
10
60
00
2
°
°
CH(CH
3
)
2
h
95
h
87
88
85
+1
+2
À1
b
d
b
96
92
+1
+4
+
7
10
100
80
100
84
91
91
93
92
93
+2
0
+4
+1
+4
i
CH(CH
3
2
)CH
2
CH
3
100
10
100
1
CH(CH
CH
3
)
2
1
10
60
00
10
100
3
C(CH
3
)
3
h
h
88
84
+2
À2
b
b
1
1
77
64
84
72
À7
À17
a
b
c
d
e
f
This work.
Ref. 25.
Ref. 33.
Ref. 34.
Difference in ee relative to the value obtained for methyl acetoacetate substrate at an identical temperature with the same catalyst.
Difference in ee relative to the value obtained for methyl acetoacetate with Raney Ni catalyst at an identical temperature (100 °C).
Some of the values are calculated based on the specific rotation measurements and reported values of maximum optical rotation of the corresponding isomers.
Not reported.
g
h
i
A racemic substrate was used. The ee values were calculated based on the chirality of the b-carbon of 3-hydroxybutyrate.

1
632
T. Osawa et al. / Tetrahedron: Asymmetry 25 (2014) 1630–1633
branching (2° group) led to 96–80% conversion, depending upon
the alkyl chain length. However, raising the temperature to
definite enantioface-selective fixation of the prochiral substrate
for the unidirectional approach of activated hydrogen.
1
10 °C significantly increased the conversion in almost all
examples. The sterically more demanding t-Bu group (3° group)
considerably decelerated the reaction down to 64% conversion at
3
. Conclusion
1
10 °C. In sharp contrast, Raney Ni-based catalysts are known to
In conclusion, high enantioselectivities of up to 94% have been
give almost identical conversions of 95–98%, irrespective of the
substrate structure. These observations could be attributed to
the difference in surface morphology between the Ni powder
achieved in enantiodifferentiating heterogeneous catalysis over
chirally modified Ni and by judicious choice of the prochiral sub-
strate. These results pave the way to the facile industrial produc-
tion of biologically important enantiopure hydroxybutyrate
derivatives.
3
4
2
6
3
5
and Raney Ni, which leads to the structural selectivity due to
the distinct accessibility of substrate to the catalyst surface where
the corresponding hydrogenation reaction takes place. This conclu-
sion is compatible with the hydrogenation mechanism proposed
previously for tartaric acid/NaBr-modified Ni catalyst,19 in which
the substrate is held near the catalyst surface through hydrogen-
bonding interactions with tartaric acid anchored to the Ni surface.
The effect of the alkyl chain length and branching on enantiose-
lectivity is somewhat less pronounced but is noticeable. In
particular, the ee value was appreciably improved from the original
4. Experimental
Nickel powders (5 lm) purchased from Aldrich were directly
subjected to chiral modification without any pretreatment, such
as hydrogen activation. The chiral modification was performed
under the conditions optimized previously for this type of cata-
2
6
8
9–91% for Me to 92–94% upon elongation to Et and to 91–93%
lyst.
Thus, the non-activated nickel powders (0.5 g) were
3
upon further elongation to n-Pr and n-Bu. This trend may be attrib-
uted to the ambivalent roles of the steric bulk in enhancing the
enantiomeric face-selectivity upon complexation and subsequent
hydrogenation and also discouraging the tight complexation with
tartaric acid, which would be balanced when the Et ester is used.
This view may be rationalized by the fact that the more bulky
i-Pr group yields a reduced 91–92% ee, while the more bulky t-Bu
ester gives the lowest 72–84% ee. For secondary branched short
alkyl esters, no such unfavorable effect on the enantioselectivity
was observed. Thus, the n-Pr and i-Pr esters afforded comparable
immersed in an aqueous solution (50 cm ) of (R,R)-tartaric acid
(0.5 g) and NaBr (2.0 g) at 100 °C, the pH of which was pre-adjusted
to 3.2 with an aqueous 1 M NaOH solution. NaBr was added to the
modification solution to block the non-enantiodifferentiating sites
of tartaric acid/Ni catalyst, thus preventing the generation of race-
mic products. After immersion for 1 h, the modification solution
was removed by decantation and the catalyst was successively
washed once with deionized water (10 cm ), twice with methanol
3
9
3
3
3
(25 cm ), and twice with tetrahydrofuran (THF) (10 cm ). The
modified catalyst was added to a mixture of alkyl acetoacetate
(43 mmol for methyl ester and 21.5 mmol for other esters), acetic
9
1–92% ee, while i- and s-Bu esters gave slightly higher 92–94%
3
and 91–93% ee, respectively. The introduction of the aromatic
substituent also reduces the ee value down to 88–89%, indicating
that the p-interactions do not play any significant role in the stabil-
ization of the supramolecular complex or the asymmetric attack of
an activated hydrogen molecule, while excessive bulk discourages
the prochiral faceselectivity of the supramolecular complex. This
bulkiness-controlled enantioselectivity is in contrast to the almost
acid (0.1 g), and THF (10 cm ) placed in an autoclave equipped
with a magnetically coupled mechanical stirrer. The hydrogenation
was run for 20 h at 100 or 110 °C and at a hydrogen pressure of
9 MPa. The hydrogenation product, a mixture of alkyl (R)- and
(S)-3-hydroxybutyrates, was isolated from the reaction mixture
by distillation. The conversion was determined by gas-liquid chro-
matography (GLC) on a GL Science model GC-4000 equipped with a
CP Chirasil DEX-CB capillary column (0.25 mm  25 m) at 90 °C,
while the enantioselectivity was determined by chiral GLC after
acetylation of the reaction product using acetyl chloride and pyri-
dine. A portion of the acetylated sample was subjected to the chiral
GLC analysis on a CP Chirasil DEX-CB column (0.25 mm  25 m)
operated at 90 °C. The ee value was calculated from the peak inte-
gration of the corresponding enantiomer peaks. The reproducibility
of the ee value was found to be within ±2%.
invariant ee values (Dee = ±2%) regardless of the ester structure,
which have been reported for the Raney Ni catalyst (Table 1).
Furthermore, the sensitivity to steric bulk observed for the Ni pow-
der-based catalyst allowed for considerable enhancement of the
enantiodifferentiating performance of catalytic heterogeneous
hydrogenation by 6–7% in comparison with the conventional
Raney Ni-based catalysts.
So far, there have been several models proposed for the inter-
mediate host-guest complex of chiral tartaric acid with prochiral
acetoacetate substrate on the metallic surface.36 For example,
according to Tai’s mechanism, the two hydroxyl groups of the tar-
taric acid molecule attached to the Ni surface interact with two
carbonyl groups of the b-ketoester via hydrogen bonding.3 Mean-
while, Osawa et al. proposed a different type of interaction
between tartaric acid and b-ketoester. In this case the carbonyl
group of the b-ketoester interacts with one hydroxyl group of
tartaric acid, while the ester carbonyl moiety is bonded to sodium
ion, which is an important component of the reaction mixture to
ensure high enantioselectivity of hydrogenation.38 However, none
of these reports explicitly explain the role of substrate bulk in
general and in particular the effect of the ester substituent on
the catalytic efficiency. Although the specific host–guest
interaction mechanism and the role of the ester group in the
activated catalyst complex are yet to be understood in detail, the
results obtained clearly indicate that the most plausible rationale
of the observed behavior is a structural ‘key-and-lock’ principle
based upon the geometrical complementarity between the
adsorbed tartaric acid and acetoacetate derivative resulting in the
References
1.
Voet, D.; Voet, J. G. Biochemistry, 2nd ed.; John Wiley & Sons: New York,
Chichester, Brisbane, Toronto, Singapore, 1995.
2. Laffel, L. Diab. Metab. Res. Rev. 1999, 15, 412–426.
3. Laeger, T.; Metges, C. C.; Kuhla, B. Appetite 2010, 54, 450–455.
7
4
5
.
.
Kose, G. T.; Ber, S.; Korkusuz, F.; Hasirci, V. J. Mater. Sci.: Mater. Ned. 2003, 14,
21–126.
Chen, G.-Q.; Wu, Q. Biomaterials 2005, 26, 6565–6578.
1
6. Keshavarz, T.; Roy, I. Curr. Opin. Microbiol. 2010, 13, 321–326.
7
8
.
.
Seebach, D.; Zuger, M. Helv. Chim. Acta 1982, 65, 495–503.
Seebach, D.; Roggo; Zimmermann, S. J. In Stereochemistry of Organic and
Bioorganic Transformation; Bartmann, W., Sharpless, K. B., Eds.; VCH:
Germany:Weinheim, 1987; Vol. 17, pp 85–126.
9.
Hatanaka, M.; Nitta, H. Tetrahedron Lett. 1987, 28, 69–72.
1
1
0. Georg, G. I.; Akgun, E. Tetrahedron Lett. 1990, 31, 3267–3270.
1. Dohi, S.; Hiraide, A.; Shiba, Y.; Suzuki, M. US 6136862 A, 2000.
12. Veech, R. L.; King, M. US 20060280721 A1, 2006.
1
1
1
3. Andrews, M. T.; Drewes, L. R.; Beilman, G. EP 2146711 A1, 2010.
4. Clarke, K. WO 2011101171 A1, 2011.
5. Venishetty, V. K.; Samala, R.; Komuravelli, R.; Kuncha, M.; Sistla, R.; Diwan, P. V.
Nanomed. Nanotechnol. Biol. Med. 2013, 9, 388–397.
1
1
6. Lee, S. Y.; Lee, Y.; Wang, F. Biotechnol. Bioeng. 1999, 65, 363–368.
7. Gao, H.-J.; Wu, Q.; Chen, G.-Q. FEMS Microbiol. Lett. 2002, 213, 59–65.

T. Osawa et al. / Tetrahedron: Asymmetry 25 (2014) 1630–1633
1633
1
1
8. Moore, J. C.; Pollard, D. J.; Kosjek, B.; Devine, P. N. Acc. Chem. Res. 2007, 40,
412–1419.
9. Tai, A.; Sugimura, T. In Chiral Catalyst Immobilization and Recycling; De Vos, D.
E., Vankelecom, I. F. J., Jacobs, P. A., Eds.; Wiley–VCH, 2000; pp 173–209 and
references therein.
29. Clarke, K.; Veech, R. L. US 20110237666, 2011.
30. Borovkov, V. V.; Lintuluoto, J. M.; Inoue, Y. J. Am. Chem. Soc. 2001, 123, 2979–
2989.
31. Borovkov, V. V.; Yamamoto, N.; Lintuluoto, J. M.; Tanaka, T.; Inoue, Y. Chirality
2001, 13, 329–335.
1
2
2
2
2
0. Sugimura, T.; Nakagawa, S.; Tai, A. Bull. Chem. Soc. Jpn. 2002, 75, 355–363.
1. Mallat, T.; Orglmeister, E.; Baiker, A. Chem. Rev. 2007, 107, 4863–4890.
2. Balázsik, K.; Sz o} ri, K.; Sz o} ll o} si, G.; Bartók, M. Chem. Commun. 2011, 1551–1552.
3. Sz o} ll o} si, G.; Makra, Z.; Kovács, L.; Fülöp, F.; Bartók, M. Adv. Synth. Catal. 2013,
32. Borovkov, V. V.; Hembury, G. A.; Inoue, Y. Angew. Chem., Int. Ed. 2003, 42, 5310–
5314.
33. Tai, A.; Harada, T. In Tailored Metal Catalysts; Iwasawa, Y., Ed.; D. Reidel
Publishing Company, 1986; pp 265–324.
3
55, 1623–1629.
34. Tai, A.; Harada, T.; Hiraki, Y.; Murakami, S. Bull. Chem. Soc. Jpn. 1983, 56, 1414–
1419.
2
4. Sz o} ll o} si, G.; Busygin, I.; Hermán, B.; Leino, R.; Bucsi, I.; Murzin, Y. D.; Fülöp, F.;
Bartók, M. ACS Catal. 2011, 1, 1316–1326.
5. Makra, Z.; Sz o} ll o} si, G. Catal. Commun. 2014, 46, 113–117.
35. Tai, A.; Kikukawa, T.; Sugimura, T.; Inoue, Y.; Abe, S.; Osawa, T.; Harada, T. Bull.
Chem. Soc. Jpn. 1994, 67, 2473–2477.
2
2
6. Osawa, T.; Kizawa, T.; Takano, F.; Ikeda, S.; Kitamura, T.; Inoue, Y.; Borovkov, V.
ChemCatChem 2014, 6, 170–178.
7. Osawa, T.; Lee, I.-Y. S.; Ikeda, S.; Kitamura, T.; Inoue, Y.; Borovkov, V. Appl. Catal.
A: Gen. 2012, 445–446, 269–273.
8. Osawa, T.; Kizawa, T.; Lee, I.-Y. S.; Ikeda, S.; Kitamura, T.; Inoue, Y.; Borovkov, V.
Catal. Commun. 2011, 15, 15–17.
36. Osawa, T.; Harada, T.; Takayasu, O. Curr. Org. Chem. 2006, 10, 1513–1531.
37. Tai, A. J. Synth. Org. Chem. 2000, 58, 568–577.
38. Osawa, T.; Harada, T.; Takayasu, O. Top. Catal. 2000, 13, 155.
39. Harada, T.; Tai, A.; Yamamoto, M.; Ozaki, H.; Izumi, Y. Proc. 7th Int. Cong. Catal.
1981, 364–375.
2
2