A simple and practical approach to enantiomerically pure (S)-3-hydroxy-γ-butyrolactone: Synthesis of (R)-4-cyano-3-hydroxybutyric acid ethyl ester

Article abstract of DOI:10.1016/j.tetasy.2005.07.012

The oxidation of α- or β-(1,4) linked disaccharides or oligosaccharides with cumene hydroperoxide in the presence of a base gave (S)-3,4-dihydroxybutyric acid, which was cyclized under acidic conditions to furnish (S)-3-hydroxy-γ-butyrolactone. This was subsequently converted into (R)-cyano-3-hydroxybutyric acid ethyl ester, an intermediate for statin based drugs and other related compounds.

Full text of DOI:10.1016/j.tetasy.2005.07.012

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 2717–2721
A simple and practical approach to enantiomerically
pure (S)-3-hydroxy-c-butyrolactone: synthesis of
(R)-4-cyano-3-hydroxybutyric acid ethyl ester
Pradeep Kumar,* Anis N. Deshmukh, Rajesh K. Upadhyay and Mukund K. Gurjar
Division of Organic Chemistry: Technology, National Chemical Laboratory, Pune 411 008, India
Received 1 June 2005; accepted 13 July 2005
Available online 15 August 2005
Abstract—The oxidation of a- or b-(1,4) linked disaccharides or oligosaccharides with cumene hydroperoxide in the presence of a
base gave (S)-3,4-dihydroxybutyric acid, which was cyclized under acidic conditions to furnish (S)-3-hydroxy-c-butyrolactone. This
was subsequently converted into (R)-cyano-3-hydroxybutyric acid ethyl ester, an intermediate for statin based drugs and other
related compounds.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
produce a low yield of the desired material along with
D,L-2,4-dihydroxybutyric acid, glycolic acid, isosac-
charinic acid, ketones, diketones, glycolic acid, and
a plethora of other degradation and condensation
products.8 Similarly, the alkaline oxidation of a carbo-
hydrate containing a glucose substituent at the 4-posi-
tion is known to give a dicarbonyl compound, which
is then oxidized to furnish (S)-3,4-dihydroxybutyric
acid.9 The yield reported for the desired compound is
very low due to the formation of a large number of
by-products.
(S)-3-Hydroxy-c-butyrolactone is an important syn-
thetic intermediate for a variety of chiral compounds.
It serves as key intermediate for the preparation of neuro-
mediator (R)-GABOB, L-carnitine,1 and HMG-CoA
reductase inhibitor, CI-981.2 (S)-3-Tetrahydrofuran
derived from 3-hydroxy-c-butyrolactone is an interme-
diate for an AIDS drug.3 (S)-3-Hydroxy-c-butyrolac-
tone has been reported as a satiety agent as well as a
potentiating agent to neuroleptic drugs.4 Its utility as a
synthetic intermediate for a variety of natural products
is well documented.5
Defunctionalization of a carbohydrate has been attract-
ing much attention as a useful synthetic tool for the
enantioselective synthesis of a variety of compounds.
The synthesis of a chiral compound with a desired num-
ber of stereogenic centers could be achieved by eliminat-
ing the unneeded stereogenic centers quickly from the
carbohydrate precursors. Though a large number of
small scale complex syntheses of (S)-3-hydroxy-c-
butyrolactone have been developed, the majority of
these methods suffer from drawbacks such as multi-step
synthesis, long reaction times, high temperature, enzy-
matic methods, and use of expensive metal catalysts
for the reduction of the prochiral center, side reactions,
low enantiomeric purity, and overall low yield of prod-
uct. Therefore, there is genuine need for a simple and
inexpensive method for the large-scale preparation of
(S)-3-hydroxy-c-butyrolactone and its derivatives.10
We, herein, report the synthesis of the title compound
The synthesis of (S)-3-hydroxy-c-butyrolactone has
been accomplished by employing various synthetic strat-
egies. A commonly used strategy for its synthesis and for
its intermediate (S)-3-hydroxybutyric acid derivatives is
from the enzymatic or catalytic b-keto ester reduction.6
It has also been prepared from the selective reduction of
L-malic acid ester.7 There have been reports of its syn-
thesis from carbohydrate sources as well, either using
just a base or a combination of a base and an oxidant.
The treatment of a carbohydrate containing glucose
substituent in the 4-position, such as cellobiose, amy-
lose, and cellulose with alkali, has been shown to
*
Corresponding author. Tel.: +91 20 25902050; fax: +91 20
25893614; e-mail: pk.tripathi@ncl.res.in
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.07.012

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P. Kumar et al. / Tetrahedron: Asymmetry 16 (2005) 2717–2721
by employing the oxidation of a 1,4-linked D-hexose
sugar under basic conditions.
in the presence of an acid to afford the desired butyro-
lactone 4 in reasonably good yield.
The advantages of the present method are that it is sim-
ple, practical, and economical. Initially, various D-hex-
ose sugars were screened in order to obtain the best
possible yield of the desired product. While the reaction
of maltodextrin with 80% cumene hydroperoxide in the
presence of sodium hydroxide gave 56% yield of the
butyrolactone 4, maltose under similar reaction condi-
tions afforded a slightly lower yield (54%). However,
other carbohydrate sources such as lactose gave only
moderate yields of the desired product. Similarly,
amongst the various oxidizing agents screened, cumene
hydroperoxide proved to be an ideal reagent. The use
of other oxidizing agents, such as hydrogen peroxide,
tert-butyl hydroperoxide, and Oxone, gave only poor
yields of product. Similarly, the use of solid bases such
as K-L, K-Y, Cs-KL, Na-MCM in place of sodium
hydroxide, afforded the desired lactone only in low yield.
2. Results and discussion
The synthesis of (S)-3-hydroxy-c-butyrolactone started
from the readily available carbohydrate source as
depicted in Scheme 1. Thus, a 1,4-linked D-hexose sugar,
such as maltose/maltodextrin/lactose, was treated with
cumene hydroperoxide under basic conditions at 70 ꢁC
to give 3,4-dihydroxybutyric acid 2, which was cyclized
O
OH
O
a
HO
+
Maltodextrin
HO
OH
OH
1
3
2
b
HO
The reaction mechanism for the formation of (S)-3-hy-
droxy-c-butyrolactone from a 1,4-linked hexose source,
such as maltodextrin, maltose, etc., is illustrated in
Scheme 2. Thus, treatment of 1,4-linked hexose source
with base leads to an isomerization to the 4-linked
ketose 5, which readily undergoes b-elimination to form
O
O
4
Scheme 1. Reagents and conditions: (a) NaOH, 40 ꢁC, 2 h, then 80%
cumene hydroperoxide, 70 ꢁC, 10 h; (b) concd H2SO4.
OH
OH
RO
RO
OH
HO
-
OH
OH
H
HO
OH
OH
OH
OH
O
O
HO
HO
OH
OH
O
H
5
O
1,4-linked hexose source
-
OH
OH
OH
OH
OH
OH
RO
HO
+
OH
OH
OH
-
O
HO
O
O
7
O
6
O O
H
O
OH
base
-
OH
O
8
+
HO
+
O
HO
OH
10
3
9
+
H
O
O
HO
4
Scheme 2. Proposed mechanism for the formation of (S)-3-hydroxy-c-butyrolactone from 1,4-linked hexose source with cumene hydroperoxide in
the presence of base.

P. Kumar et al. / Tetrahedron: Asymmetry 16 (2005) 2717–2721
2719
enone 6. Subsequent tautomerization leads to the for-
mation of diketone 7, which is readily cleaved with
cumene hydroperoxide 8 to give the salt of (S)-3,4-
dihydroxybutyric acid 9 and glycolic acid 3. Cumene
alcohol 10 is also formed as by-product. Acidification
and concentration gave the desired lactone 4.
In order to achieve the synthesis of 13 (Scheme 4),
butyrolactone 4 was first treated with 30–33% HBr in
AcOH/EtOH to afford the corresponding bromo ester
12 in 85% yield. The subsequent treatment with sodium
cyanide furnished the cyano compound 13 (by direct dis-
placement of bromo with cyano) in about 50% yield. In
our initial attempt for the preparation of cyano com-
pound 13 via an epoxide, it was observed that the con-
version of the bromo compound 12 to the epoxide was
not a clean reaction but led to the formation of an
unsaturated ester as a major side product, resulting in
the facile elimination of hydroxyl group.
It was observed that the downstream process and work-
up procedure played an important role in the isolation
and purification of product 4. In the case of cumene
hydroperoxide as an oxidizing agent, the acidic work-
up of reaction mixture showed the formation of a num-
ber of products by TLC. During column purification,
the faster moving by-products were separated and ana-
lyzed by GC/GC–MS/spectral data. The compounds
obtained were cumene alcohol 10, phenol, a-methylstyr-
ene 11, and polymerized product. The major compound
found was the dimer of a-methylstyrene and a polymeric
product of high molecular mass as shown by GC. The
cumene alcohol, which is one of the by-products of the
reaction, led to a-methylstyrene and the polymeric prod-
uct under acidic work-up as shown in Scheme 3. There-
fore, in order to avoid the formation of by-products, the
work-up procedure was modified. Cumene alcohol was
first recovered by the extraction of the reaction mixture
with diethyl ether, then the aqueous layer extract was
subjected to the acidic work-up (for details, see Section
4.3).
3. Conclusion
In conclusion, a method for preparing enantiomerically
pure (S)-3-hydroxy-c-butyrolactone by the oxidation of
a (1,4)-linked disaccharide or oligosaccharide with
cumene hydroperoxide has been developed. The process
uses an inexpensive and readily available carbohydrate
as the chiral pool material. The hydroxy butyrolactone
has further been converted into (R)-cyano-3-hydroxy-
butyric acid ethyl ester, which is a useful intermediate
for the statin based drugs and other related compounds.
4. Experimental
Our next aim was to convert the hydroxy butyrolactone
4 into useful chiral intermediate such as the cyano ester
13 of pharmaceutical importance. It was envisaged that
compound 13 could easily be derived from butyrolac-
tone 4. It should be mentioned that the utility of 13 as
a chiral intermediate in the preparation of statin based
drugs (cholesterol lowering drugs), such as mevacor,
atorvastatin, lipitor, etc., and other related compounds
has already been demonstrated.2
4.1. General information
The solvents were purified and dried by the standard
procedures prior to use; petroleum ether of boiling range
60–80 ꢁC was used. Optical rotation was measured using
sodium D line on a JASCO-P-1020-polarimeter. Infrared
spectra were recorded on a Perkin Elmer FT-IR spec-
1
trometer. H NMR spectra were recorded on a Bruker
AC-200 spectrometer. The mass spectra were recorded
O
H
OH
O
HO
NaOH
+
Maltodextrin
OH
+
acidification
O
O
10
4
+
OH
H
H
H
acidic work-up
Polymeric product
11
10
Scheme 3.
HO
OH
O
OH
O
a
b
Br
NC
O
O
O
O
12
13
4
Scheme 4. Reagents and conditions: (a) 30–33% HBr in AcOH/EtOH, reflux, 8 h, 85%; (b) NaCN, DMF, rt, overnight, 50%.

2720
P. Kumar et al. / Tetrahedron: Asymmetry 16 (2005) 2717–2721
either by GC–MS or with a Finnigan LC–MS mass
spectrometer. Enantiomeric excess was measured using
either chiral HPLC or by comparison of specific
rotations.
unreacted cumene hydroperoxide and cumune alcohol,
which were fully characterized by NMR and GC–MS.
4.4. Synthesis of (S)-4-bromo-3-hydroxybutyric acid
ethyl ester 12
4.2. Synthesis of (S)-3-hydroxy-c-butyrolactone 4
To a cooled solution of hydroxy butyrolactone 4 (1.02 g,
10 mmol) was added with stirring 30–33% HBr (3 mL,
15 mmol) in glacial acetic acid. The reaction mixture
was warmed to room temp and then heated to 60 ꢁC
under nitrogen for 5 h. Absolute ethanol was added to
the reaction mixture and then left stirring at the same
temp for 5 h. The solvent was evaporated and the resi-
due taken in ethyl acetate, washed with 10% NaHCO3,
and then with water until the aq layer becomes neutral.
The organic layer was dried over sodium sulfate and the
solvent distilled. The residue was purified by silica gel
column chromatography using ethyl acetate and pet
In a two-necked 100 mL round bottom flask with a
thermo well and reflux condenser was added maltodex-
trin (1.0 g, 2.77 mmol) dissolved in 0.16 M NaOH solu-
tion (0.32 g in 50 mL water, 7.93 mmol, 2.86 equiv). The
reaction mixture was heated at 40 ꢁC for 2 h. The color
of the reaction mixture became yellowish to dark red.
To this solution was added slowly 80% cumene hydro-
peroxide (0.7 mL, 3.66 mmol, 1.32 equiv). The reaction
temperature was increased slowly to 70 ꢁC and heated
for another 10 h. The reaction mixture was cooled to
25 ꢁC, and then to 0 ꢁC temperature. The cooled reac-
tion mixture was acidified with concd H2SO4 to pH 1.
The acidified solution was concentrated to dryness at
55 ꢁC, in order to remove glycolic acid and water. To
the yellow colored syrup formed, was added 10 g of
ice and then the mixture neutralized with solid sodium
bicarbonate, extracted with ethyl acetate, and dried over
sodium sulfate. The solvent was removed under reduced
pressure. The residue obtained was purified by silica gel
column chromatography using EtOAc/pet ether (4:6) as
eluent to give 4 (0.16 g) as a colorless oil in 56% yield,
ether (2:8) as eluent to give 12 (1.91 g) as a colorless
25
oil in 85% yield. ½aꢀD ¼ ꢁ10 (c 1.2, EtOH), lit.12
20
½aꢀD ¼ ꢁ11 (c 1, EtOH).
1
The physical and spectroscopic data (IR, H NMR) are
in accordance with those described in the literature.13
4.5. Synthesis of (R)-4-cyano-3-hydroxybutyric acid
ethyl ester 13
25
25
½aꢀD ¼ ꢁ84.6 (c 3.1, EtOH), lit.11 ½aꢀD ¼ ꢁ86.1 (c 3.1,
EtOH). The spectroscopic data (IR, 1H NMR) are
in accordance with those described in the literature.11
To a cooled solution of (S)-4-bromo-3-hydroxybutyric
acid ethyl ester 12 (1.13 g, 5 mmol) dissolved in 5 mL
of dry DMF was added with stirring NaCN (0.98 g,
20 mmol). The reaction mixture was stirred at room
temperature overnight. DMF was evaporated under
reduced pressure, the residue left was extracted with
4.3. Modified work-up procedure for the recovery of
cumene alcohol
diethyl ether. The solvent was evaporated to afford 13
25
4.3.1. Synthesis of (S)-3-hydroxy-c-butyrolactone 4. In
a 500 mL two-necked round-bottom flask, was placed
maltodextrin (5 g) dissolved in 0.16 M NaOH solution
(1.6 g in 250 mL water). The reaction mixture was
heated at 40 ꢁC for 2 h. To the reaction mixture was
added 80% cumene hydroperoxide (3.5 mL, 1.32 equiv).
After addition, the reaction temperature was increased
to 70 ꢁC and heated for 10 h. After the reaction was
over, it was brought back to room temperature and
the reaction mixture extracted with ether (2 · 50 mL).
The organic layer was separated and the aqueous layer
cooled to 0 ꢁC. The pH of the solution was 8.16, and
the aqueous layer acidified with concd H2SO4 (2.8 mL)
to pH 1. The solution was concentrated to dryness at
60 ꢁC and to the residue crushed ice was added and neu-
tralized with sodium bicarbonate and then extracted
with ethyl acetate (3 · 200 mL). The organic layer was
washed with water and brine and dried over Na2SO4.
The evaporation of the solvent and purification by silica
gel column chromatography using pet ether/ethyl ace-
tate (4:6) gave 4 (0.8 g) as a colorless oil in 56% yield.
(0.43 g) as a light yellow liquid in 50% yield. ½aꢀD
¼
ꢁ32.5 (c 1, CHCl3), lit.2 [a]D = ꢁ33.1 (c 1.2, CHCl3).
1
The physical and spectroscopic data (IR, H NMR) are
in accord with those described in the literature.13
Acknowledgements
Financial support to this work under NMITLI pro-
gramme (Grant No. 5/258/2/2000-NMITLI) is grate-
fully acknowledged. This is NCL Communication No.
6684.
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