Direct asymmetric reduction of levulinic acid to gamma-valerolactone: synthesis of a chiral platform molecule

Article abstract of DOI:10.1039/c5gc01099c

Levulinic acid was directly converted to optically active (S)-gamma-valerolactone, a proposed biomass-based chiral platform molecule. By using a SEGPHOS ligand-modified ruthenium catalyst in methanol as a co-solvent, eventually, 100% chemoselectivity, and 82% enantioselectivity were achieved. The effect of the catalyst composition and reaction parameters on the activity and selectivity was investigated in detail. The conversion of a "real" biomass derived levulinic acid to optically active GVL without decreasing the enantioselectivity was also demonstrated.

Full text of DOI:10.1039/c5gc01099c

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DOI: 10.1039/C5GC01099C
Green Chemistry
ARTICLE
Direct asymmetric reduction of levulinic acid to
gamma-valerolactone: synthesis of a chiral platform molecule
József M. Tukacs,a Bálint Fridrich,a Gábor Dibó,b Edit Székelya and László T. Mikaa,*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Levulinic acid was directly converted to optically active (S)-gamma-valerolactone, a proposed biomass-based chiral
platform molecule. By using SEGPHOS ligand-modified ruthenium catalyst in methanol as co-solvent, eventually, 100%
chemoselectivity, and 82% enantioselectivity were achieved. The effect of catalyst composition and reaction parameters
on the activity and selectivity were investigated in details. The conversion of a “real” biomass derived levulinic acid to
optically active GVL without decreasing the enantioselectivty was also demonstrated.
www.rsc.org/
homogeneous catalysis.6f,12,13 Recently, several catalytic
systems have been reported for the conversion of LA to GVL.
However, the asymmetric reduction of LA to optically active 4-
HVA, which subsequently turns to optically active GVL via ring
closure dehydration (Scheme 1) has not been reported yet.
The one-pot conversion of LA to optically active GVL could
result in a green process representing the elegant approach of
biomass waste valorization to a value-added chiral building
block.
Introduction
Currently, one of the most pressing challenges for the chemical
industry is the gradual replacement of fossil resources with
renewable ones. Since it is difficult to estimate the exact
reserves of fossil resources, which provides more than 95% of
our carbon based chemicals, the development of novel
strategies to provide carbon-based building blocks should be
accelerated. The selective biomass transformation, as one of
most preferred solution, offers several alternative production
of value-added chemicals and has led to the identification of
key platform molecules e.g. 5-hydroxymethyl furfural,1
levulinic acid (LA),2 and γ-valerolactone (GVL),3 which could
replace the currently used fossil-based building blocks or serve
as a “green” and renewable feedstock for their production.
Due to its outstanding physical and chemical properties,
Horváth et al. have first suggested GVL as a sustainable liquid.3
Later, it was shown that GVL can be used for the production of
fuels,4 fuel additives,3 alkanes,5 and fine chemicals.6 In
addition, GVL was also utilized as a green solvent for the
conversion of carbohydrates to LA and subsequently to GVL.7
Obviously, the most efficient protocol for the manufacture
of GVL is the conversion of the carbohydrate content of
biomass7b,8 including cellulose9 and/or biomass wastes10 to LA
followed by the selective hydrogenation of LA to 4-
hydroxyvaleric acid (4-HVA) by using either heterogeneous11 or
Optically active γ-lactones occur naturally14 and can be
used as chiral building blocks for the synthesis of several
biologically active compounds.15 The optically active GVL can
be found in the synthetic schemes of several agricultural or
pharmaceutical compounds16 e.g. the aggregation pheromone
Sulcatol,17 the antihypertensive WS75624B,18 the antileukemic
Steganacin,19 and the insecticide Geodiamolide (Fig. 1).20
O
OH
+ H2
-H2O
chiral catalyst
COOH
levulinic acid
COOH
(R or S)-4-HVA
O
O
(R or S)-GVL
Scheme 1
OMe
Antihipertensive
(WS75624B)
MeO
R1
R2
O
O
OH
N
COOH
N
O
O
S
2
H
OH
OH
OH
Sulcatol
(aggregation pheromone)
a. Department of Chemical and Environmental Process Engineering, Budapest
University of Technology and Economics, Budapest, Hungary Fax: +36 1 463 3197;
L. T. Mika: Tel.: +36 1 463 1263, e-mail: laszlo.t.mika@mail.bme.hu.
b. János Selye University, Faculty of Education, Department of Chemistry,
Bratislavská str. 3322, Komárno SK-94501, Slovakia.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
O
(R or S)-GVL
O
OH
O
OEt
O
OAc
H
O
O
MeO
-
OH
H
O
MeO
[NR4]+
CHIRAL
SOLVENT
COO
Geodiamolide
(insecticide)
MeO Antileukemic
(Steganacin)
Fig. 1 Selected application of optically pure GVL.
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Accordingly, we propose here that the enantiopure GVL can be
used as a promising chiral starting material for the synthesis of
fine chemicals and other valuable intermediates i.e. chiral
pentane-1,4-diol, 5-methyl-3-methylenedihydrofuran-2(3H)-
one and its derivatives, unsaturated esters, and ionic liquids
etc. (Fig. 1). Since chiral solvents are of utmost importance in
chiral recognition,21 due to its good solvating properties, the
optically active GVL could serve as a renewable and non-toxic
chiral reaction media in asymmetric synthesis, as well. It was
demonstrated that chiral ionic liquids were successfully
applied in asymmetric synthesis.22 GVL can easily be converted
to ILs,6a,b the application of chiral 4-hydroxyvalerate-based
ionic liquids are also proposed as a chiral reaction media is
proposed, as well.
The enantioselective reduction of prochiral substrates
including ketones is of utmost importance for the synthesis of
optically pure substances both on laboratory and industrial
scale, as well.23 Although, several catalyst systems have been
developed for the asymmetric reduction of the carbonyl group,
most of them were tested on aromatic ketones e.g.
acetophenone. It was revealed that the enantioselectivity
could be dramatically influenced by the functional groups in
the vicinity of the carbonyl group.23d Compared to the
reduction of aromatic substrates, reduction of aliphatic
ketones resulted in slightly lower yield and small ee value.24,25
Several methods have been developed for the reduction of the
carbonyl group of γ-oxo carboxylates; however, to our best
knowledge, no direct asymmetric hydrogenation of the free
carboxylic acid has been reported yet.
Results and discussion
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DOI: 10.1039/C5GC01099C
Firstly, concerning the ring opening and/or closing, the stability
of the chiral center of GVL is a crucial point for further
synthetic schemes. The ring opening of GVL under acidic
conditions leads to the formation of 4-HVA. Subsequently, 4-
HVA forms GVL via ring closure under neutral condition.
Accordingly, the stability of the chiral center of GVL is of
utmost importance and was investigated by using 18O-labelling
technique as follows: 0.3 mmol of (S)-GVL having 98.5% ee was
treated with 2.7 mmol of H218O (97 atom % 18O) in the
presence of 1 mmol HCl at room temperature. The in situ NMR
showed peaks at 176.6 ppm in 13C-NMR, and 1.2 ppm (3H, d, J
1
= 5.9 Hz), 1.6 ppm (2H, m), 3.75 ppm (1H, s, J = 5.9 Hz) in H-
NMR spectra. These data proved the equilibrium reaction
between GVL and [4-HVA]. To neutralize the solution,
equimolar amount of sodium hydroxide was added to the
reaction mixture after 1 h. The incorporation of 18O-isotope
into the (S)-GVL was verified by GC-MS. Chiral GC analysis of
18O-labelled GVL established that the ring opening and
reclosing had no effect on the enantiopurity of (S)-GVL, as
expected (Fig. 2).
It was demonstrated, that LA was efficiently converted to
GVL in the presence of bidentate phosphine-modified Ru
catalysts without any added solvent and TOF = 100–21000 h–1
values were obtained. In the case of BINAP ligand, 98.6%
conversion was achieved with TOF = 6978 h–1.12c Firstly,
reduction of LA (1 mL, 9.85 mmol) was attempted by using a
catalyst in situ formed from Ru(acac)3 (1.56 µmol) and (R)-
BINAP (15.6 µmol) under 60 bar H2, at 140 °C and 500 rpm.
After 12 h, full conversion was obtained with ee = 26%. The
reaction was repeated in a 120-mL Parr high-pressure reactor
(equipped with a propeller stirrer) loaded with 30 mL (293.02
mmol) of LA, 0.023 mmol of Ru(acac)3 and 10-fold excess
(0.233 mmol) of (R)-BINAP under identical conditions to
monitor the possible change of ee with increasing conversion
(Fig. 3). By using the propeller stirrer, the rate of hydrogen
transfer from gas to liquid phase was significantly higher. Thus,
the reaction time required for full conversion of LA to GVL was
decreased to 2.5 h, however, it was perceived that the ee
value was almost the same (ee = 23%). To conclude, the ee
Karnik et al. reported the stoichiometric synthesis of
optically active γ-lactones from (S)-menthyl or (S)-bornyl esters
of 4-carboxylates by using NaBH4, however, the yield of (S)-
GVL was moderate.26 Hilterhaus et al. suggested
a
chemoenzymatic reaction sequence to produce (S)-GVL via
ethyl levulinate (EL). Expectedly, due to the enzymatic
conversion, the ee values and overall yields were high
(~90%).27 So far, a few studies on the reduction of alkyl
levulinates in the presence of Ru-based catalysts to optically
active GVL were published.28,29 Vinogradov et al. reported the
Ru/BINAP-catalyzed asymmetric hydrogenation of LA by
applying HCl in ethanol under 60 bar H2 at 60 °C.29a It was also
shown that, instead of the reduction of LA, the in situ formed
EL was reduced. Jacobs et al. demonstrated that the bakers’
yeast assisted reduction of alkyl levulinates and subsequent
HCl-catalyzed hydrolysis of the corresponding hydroxy esters
resulted in (S)-GVL with a yield of 73%.30 It is important to note
that the ester hydrolysis step requires mineral acid.
Noteworthily, HCl is released from the reaction to the
atmosphere resulting in serious environmental concerns or
rather, the aqueous HCl is extremely corrosive.
OH
18OH
O
18O
+ H2O
- H+
C
OH
(S)-GVL
O
O
We report here the direct conversion of levulinic acid to
optically active γ-valerolactone via asymmetric hydrogenation
using various Ru-based catalyst systems.
(S)-GVL
Fig. 2 Chromatograms of (S)-GVL before and after ring opening, and MS spectrum of 18O-
(S)-GVL.
2 | J. Name., 2012, 00, 1-3
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demonstrating the inactivity of the high-pressure Hastelloy-C
60
50
40
30
20
10
0
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reactor. When LA was used as substratDeOaI:n1d0.1s0o3l9v/eCn5tGCw0it1h09o9uCt
any additive, all substrates were converted to GVL using 1.
However, the enantioselectivity was modest (ee = 11%).
Similarly, ee = 13% was achieved when methanol was used as
a co-solvent (ESI† Table S1, entries 1-2). Importantly, the
composition of the reaction mixture was continuously
changing from LA to LA/GVL/H2O and finally a GVL/H2O
mixture was obtained. When different alcohols were used as
co-solvents, either with or without a base, the ee was not
influenced significantly (ESI† Table S1, entries 4–10). Although,
by replacing DPEN to DAIPEN, higher enantioselectivity was
proposed,23d however, in our hand no further increase could
be achieved (ESI† Table S1, entry 4).
100
80
60
40
20
0
0.0
0.5
1.0
1.5
2.0
2.5
Time (h)
Fig. 3 Solvent free asymmetric reduction of LA to optically active GVL. Conditions: [Ru] =
7.6×10–4 mol dm –3, [(R)-BINAP] = 7.6×10–3 mol dm –3, T = 140 °C, p = 60 bar, RPM = 600
By using bidentate phophine-modified Ru catalyst, both
the electronic and steric effects of the bis(diarylphosphine)
backbone significantly enhanced the reactivity, and improved
the stereorecognition.32 Recently, Saito et al. introduced a new
ligand family (SEGPHOS) with smaller dihedral angle
representing an outstanding catalytic performance for the
Table 1 Conversion rates and ee values obtained for the hydrogenation of LA to
GVL in the presence of various SEGPHOS-based Ru catalysts.
Conv
(%)
Entry
Catalyst
ee
1
2
3
4
5
6
7
(R)-RuCl2[(p-cymene)(SEGPHOS)]
(R)-RuCl2[(p-cymene)(DM-SEGPHOS)]
(R)-RuCl2[(p-cymene)(DTMB-SEGPHOS)]
RuCl2[(S)-(DM-SEGPHOS)][(S,S)-DPEN]
RuCl2[(S)-(DM-SEGPHOS)][(S)-DAIPEN]
Ru(OAc)2((S)-SEGPHOS)
100
100
95
18
9
reduction of carbonyl compounds.33 By using
a
13
16
13
12
56
substrate/catalyst ratio of 1000, ethyl levulinate was
hydrogenated at 50 °C for 20 h, and ethyl 4(R)-
hydroxypentanoate was obtained with a yield of 99%.33b The
conversion of LA to GVL in methanol, as the preferred
solvent,33b was screened and further improved by using
various SEGPHOS-based Ru catalysts (Table 1). When
mononuclear (R)-RuCl2[(p-cymene)(SEGPHOS)] precursor was
applied, full conversion was achieved with ee = 18 % (similar
yields were obtained under solvent-free conditions where
BINAP-based catalysts were used). When various substituents
on the SEGPHOS ligand were used, a small decrease on the ee
values was observed (Table 1, entries 1–3). Comparing DPEN
and DAIPEN analogues of Noyori’s catalyst, no significant
change in the ee was detected (Table 1, entries 4–5); similar
results were observed when (S)-Ru(OAc)2(SEGPHOS) precursor
was applied. However, the use of (S)-[(RuCl(SEGPHOS))2(μ-
Cl)3][NH2(CH3)2] (3) (Fig. 4) precursor resulted in a dramatic
increase in the enantioselectivity. The reduction of 9.8 mmol
of LA in the presence of 0.004 mmol 3 leads to the complete
formation of (S)-GVL with of ee = 56% (Table 1, entry 7), that
was 4.5 and 2.5 times higher than that obtained by the use of
Noyori’s catalyst in methanol or Ru/BINAP catalyst under
solvent-free condition.
Since the asymmetric induction could be strongly affected
by the solvent, we screened the conversion of LA (9.8 mmol)
to GVL by using various alcohols, methylene chloride and
supercritical CO2 at 60 bar H2 and 140 °C. Although, full
conversion was obtained in all cases, the enantiomeric excess
varied in a wide range depending on the solvent (Fig. 5).
Without any added solvent, no chiral induction occurred, and
negligible values were obtained when methylene chloride or
supercritical carbon-dioxide was used. However, significantly
higher enantioselectivities were obtained in alcohols, a protic
reaction media, in accord with literature data concerning the
reduction of non-aromatic ketones (Saito et al).33b
Hydrogenation of 9.8 mmol LA in 1.4 mL methanol resulted in
100
100
100
100
(S)-[(RuCl(SEGPHOS))2(μ-Cl)3][NH2Me2]
Reaction conditions: 1 mL (9.8 mmol) LA in 1.4 mL MeOH, T = 140 °C,
t = 20 h, p = 60 bar, catalyst: 0.004 mmol, S/C = 2400.
-
Ph
Ph
O
Ph
P
O
Ph
Cl
P
O
O
O
O
[NH2(CH3)2]+
Cl Ru Cl Ru Cl
P
Ph
Ph
P
Cl
Ph
O
O
Ph
Fig. 4. (S)-[(RuCl(SEGPHOS))2(μ-Cl)3][NH2Me2] catalyst (3)
values were not affected by the conversion rate. Moreover,
addition of (R,R)-1,2-diphenyl-1,2-diaminoethane (R,R-DPEN)
neither had significant effect on the final ee values. When 9.85
mmol of LA was reduced in the presence of 0.001 mmol
Ru(acac)3, 0.01 mmol (R)-BINAP, and 0.02 mmol of (R,R-DPEN),
similarly 26.4 % ee was obtained under identical conditions.
Although the ee value was moderate, to our best knowledge,
so far the solvent-free asymmetric reduction of levulinic acid
to optically active GVL has not been reported yet.
It was established that in situ generated and preformed
complexes can be used for the reduction, however, the latter
showed higher activity and selectivity.23d Noyori et al.
demonstrated that dialkyl ketones e.g. 4-phenylbutan-2-one
was reduced with ee = 51%23d by applying XylBINAP/(S,S)-
DPEN-modified Ru catalyst (1) (ESI Fig. S1). Significantly higher
selectivity with opposite sense of asymmetric induction was
achieved for the RuCl2[(S)-XylBINAP][(R,R)-DAIPEN] (2) (ESI Fig.
S1) catalyzed reduction of cyclopropyl ketones.31 Accordingly,
we performed the reduction of LA in the presence of 1 and 2.
Firstly, in the absence of catalyst no conversion was detected
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ee = 56% (Fig. 5). When 9.8 mmol of LA was reduced in 0.7 mL
methanol in the presence of 0.004 mmol of 3, the ee
decreased to 43%. By using 3 mL methanol, the ee was 53%.
Supposedly, methanol acts as co-solvent and may have an
effect on the formation and stabilization of the catalytically
active species. Importantly, the ring closure of 4-
hydroxypentanoic acid resulted in the formation of equimolar
amount of water and GVL. Accordingly, the application of a
water-free solvent is inefficient, however the initial water
content may have an effect on the ee. When, the reaction was
performed in 96% ethanol, a slight decrease of ee (37%) was
found.
View Article Online
DOI: 10.1039/C5GC01099C
56 %
50
40
30
20
10
0
42 %
18 %
9 %
1 %
1 %
0 %
MeOH EtOH iPrOH BuOH DCM scCO2 Neat
Subsequently, the effect of the reaction temperature on
the activity and selectivity was investigated (Fig. 6). The Ru-
catalyzed asymmetric reductions are usually performed in a
range of 20–40 °C, although, the SEGPHOS-based catalysts
operate at higher (65 °C) temperature. Noteworthily,
hydrogenation of LA was unsuccessful below 80 °C by
homogeneous Ru catalyst, and minimum 140 °C was necessary
to get reduction product.12a Interestingly, ethyl and methyl
levulinate was converted to the corresponding alcohols at 30
°C28 and 60 °C,29 respectively. When, 9.8 mmol LA in 1.4 mL
MeOH was reduced, negligible conversion (8%) and ee (3%)
was observed at 80 °C and 60 bar H2 for 20 h; and only a slight
increase was observed at 120 °C. Although, full conversion was
obtained over 130 °C, the maximum ee value was 56% at 140
°C (Scheme 2, (a)).
Fig. 5 Asymmetric hydrogenation of LA to GVL in different solvents. Conditions: [Ru] =
0.004 mol dm –3, T = 140 °C, p = 60 bar, RPM = 400
100
80
60
40
20
0
100
90
80
70
60
50
40
30
20
10
0
80
100
120
140
160
T (oC)
Supposedly, the reduction of LA to GVL in the presence of
HCl with Ru-BINAP-HCl system undergoes via in situ formation
of ethyl levulinate in ethanol. Although no in situ spectroscopic
data were included, ethyl levulinate, ethyl 4-hydroxyvalerate
and GVL were detected in the product mixture.29a When LA
was reduced by catalyst 1, the concentration of methyl
levulinate in the final reaction mixture was below the
detection limit. For comparison, methyl levulinate (9.8 mmol)
in methanol (1.4 mL) was reduced under identical conditions
resulting in full conversion and with ee = 27% cf. Scheme 2 (b)
which is significantly lower than the value obtained for LA
(56%). In addition, the methyl levulinate was reduced at lower
temperature. Although, the in situ equilibrium formation of
methyl levulinate from methanol and LA cannot be completely
excluded, however if LA was hydrogenated to (S)-4-
hydroxyvaleric acid it will spontaneously dehydrate to (S)-GVL.
Unexpectedly, for the reduction of LA, significant improvement
in enantioselectivity was detected by varying the Ru
concentration between 0.002–0.016 mol dm–3 (Fig. 7.). For
example, 9.8 mmol LA was hydrogenated in 1.4 mL of
methanol as co-solvent at [Ru] = 0.016 mol dm–3 at 60 bar and
150 °C, full conversion was obtained with ee = 82% for (S)-GVL.
This selectivity fits to the ee values obtained for dialkyl
ketones, however further increase of the amount of catalyst
had no effect on the selectivity.
Fig. 6 Asymmetric hydrogenation of LA to GVL at different temperatures. Conditions: 9.8
mmol LA in 1.4 mL MeOH, [Ru] = 0.004 mol dm–3, pH2 = 60 bar, RPM = 400
OH
(a)
-H2O
O
COOH
COOH
O
O
O
0.004 mmol 1
(S)-GVL
+
COOH
9.8 mmol
150 °C, 60 bar H2
1.4 mL MeOH
OH
- H2O
Conversion: 100 %
ee: 56 %
O
(R)-GVL
OH
OH
(b)
- MeOH
- MeOH
O
COOCH3
COOCH3
O
O
O
0.004 mmol 1
(S)-GVL
+
COOCH3
9.8 mmol
150 °C, 60 bar H2
1.4 mL MeOH
Conversion: 100 %
ee: 27 %
O
(R)-GVL
Scheme 2 Reduction of LA and methyl levulinate.
100
90
82
80
72
70
60
60
50
40
30
17
20
The use of “real” biomass based levulinic acid to chiral γ-
valerolactone is fundamentally important to show and
establish that no “chemical” (product or side product) formed,
which could interfere with chiral induction of the catalyst. In
10
0
2.5
5.0
7.5 10.0 12.5 15.0 17.5 20.0
cRu x 103 (mol x dm-3)
Fig. 7 Influence of catalyst concentration on ee. Reaction conditions: 9.8 mmol LA in 1.4
mL MeOH, pH2 = 60 bar, T = 150 °C, RPM = 400
order to investigate the catalyst’s applicability, firstly
D-
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fructose (4 g, 22.2 mmol) was converted to LA under optimized case of pre-prepared Ru-based catalyst, the reactor was
View Article Online
conditions.8b As result: 1.65 g of LA was isolated as a light charged with 1.14 g (1 mL, 9.8 mmol) levulinic acid, 1.46 mL
DOI: 10.1039/C5GC01099C
brown and viscous liquid. 1 mL of this product was mixed with methanol, and 0.0048 mmol ruthenium-based chiral complex
1.4 mL of methanol and subsequently hydrogenated by using 3 resulting in a colorful solution. In both cases, the reaction
at 60 bar H2 and 150 °C. Quantitative formation of GVL was mixture was pressurized up to the desired pressure and heated
achieved with ee = 78 % after 20 h (Scheme 3. A). Finally, to to the given temperature. After completing the reaction, the
demonstrate the conversion of a “real” biomass waste reactor was cooled down to ambient temperature, and stirring
containing wheat straw, rice husk, corn straw, nut and pea-pod was stopped. The conversion was determined by 1H-NMR
was treated as follows: 3 g of dried biomass waste was heated spectroscopy by the signals of methyl protons of levulinic acid
in 2 M H2SO4 at 170 °C for 8 h. After our published workup (δ: 2.11 ppm, s, 3H) and GVL (δ: 1.41 ppm, d, 3H). The NMR
procedure was performed,8b c.a. 1 mL of deep dark brow measurements were performed on a Bruker-Avance 250 MHz
solution was obtained. After vacuum distillation 560 mg of LA instrument. The enantiomeric excess (ee) was determined on
was isolated as colorless liquid (Yield: 18 %). It was an HP-CHIRAL-20B capillary column (30 m × 0.25 mm × 0.25
subsequently reduced under optimized conditions (0.75 mL µm) with a Finigan Trace GC Ultra (Thermo Electron
MeOH, 0.009 mmol 3, 60 bar H2, 150°C) resulting in 100% Corporation) using H2 as a carrier gas. For the analysis, 10 µL of
conversion of LA with enantioselectivity for (S)-GVL 80 % the reaction mixture was dissolved in 1 mL methanol.
(Scheme 3. B). Indeed, GVL with high enantiomeric excess can
be produced from biomass based levulinic acid under
optimized conditions.
Conclusions
The reproducibility of the experiments were confirmed by
repeating the reduction of LA (9.8 mmol) at 60 bar H2 and 140
°C (Table 1, entry 7). Complete conversion was achieved after
20 h with ee = 55.2%. When LA (9.8 mmol) in 1.4 mL of
methanol was reduced by using 3 ([Ru] = 0.016 mol dm–3)
under 60 bar of H2 at 150 °C, full conversion with ee = 83% was
achieved. After removal of methanol and H2O by vacuum
distillation 712 mg of colorless (S)-GVL was obtained. Isolated
yield: 62.4% (ee = 83%).
We demonstrated that levulinic acid could be directly
converted to optically active (S)-GVL, a proposed chiral
platform molecule. In contrast to previously published
procedures, no alkyl levulinate was necessary to synthesize
optically active GVL. It was revealed that in the presence of a
catalyst in situ generated from Ru(III)-acetylacetonate and (S)-
BINAP, levulinic acid was converted to (S)-GVL with ee = 26%
without adding any solvent and/or additive. By applying (S)-
{[RuCl(SEGPHOS)]2(μ-Cl)3}–[NH2(CH3)2]+ catalyst precursor in
methanol, the enantiomeric excess was increased resulting in
enantioselectivity of 82%. The conversion of “real” biomass
waste to optically active GVL was also demonstrated.
Experimental
Levulinic acid, catalyst precursors, (S)-GVL, were purchased
from Sigma-Aldrich Ltd., Budapest, Hungary and used as
received. Solvents were obtained from Molar Chemicals Ltd.,
Budapest, Hungary and used without further purification
(ESI†).
Hydrogenation reactions were performed in a magnetically
stirred 25 mL high-pressure Hastelloy-C reactor (Parr Inst, IL
USA) equipped with manometer, safety relief and magnetic
stirring bar using external heating. In a hydrogenation
experiment using in situ generated Ru-based catalysts, the
high-pressure reactor was charged with 1.14 g (1 mL, 9.8
mmol) levulinic acid, 1.4 mL methanol, 0.62 mg (0.00156
mmol) ruthenium(III)-acetylacetonate and 10 eq (0.0156
mmol) of the corresponding chiral phosphine ligand. In the
Acknowledgements
This work was funded by the Budapest University of
Technology and Economics under project number KMR_12-1-
2012-0066. E. Székely and L.T. Mika are grateful to the support
of János Bolyai Research Scholarship of the Hungarian
Academy of Sciences. The authors would like to thank Prof
István T. Horváth (City University of Hong Kong) and Prof.
József Bakos (University of Pannonia) for helpful discussions..
Notes and references
1
2
P. Gallezot, Chem. Soc. Rev., 2012, 41, 1538.
CH2OH
OH
O
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1 mL (9.8 mmol) of LA
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A
Conv.: 100 %
ee = 75 %
OH
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distilaltion
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Scheme 3 Conversion of D-fructose (A) and mixed biomass waste (B) to (S)-GVL
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
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Page 7 of 7
Green Chemistry
View Article Online
DOI: 10.1039/C5GC01099C
Direct asymmetric reduction of levulinic acid to amma-
valerolactone: synthesis of a chiral platform molecule
József M. Tukacs,a Bálint Fridrich,a Gábor Dibó,b Edit Székelya and László T. Mika*.a
aBudapest University of Technology and Economics, Department of Chemical and Environmental Process
Engineering, Budafoki str. 8., Budapest, Hungary, H-1111. Tel: +361463 1263, e-mail: laszlo.t.mika@mail.bme.hu
b János Selye University, Faculty of Education, Department of Chemistry, Bratislavská str. 3322, Komárno SK-
94501, Slovakia.
Table of Contents Entry
Biomass-originated levulinic acid was directly converted to optically active (S)-gamma-
valerolactone, a proposed biomass-based chiral platform molecule.
1