Synthesis of optically active β-benzyl-γ-butyrolactone through lipase-catalyzed kinetic resolution

Article abstract of DOI:10.1016/S0957-4166(01)00317-2

The lipase-catalyzed kinetic resolution of the racemic γ-hydroxy ester 2, coupled with subsequent acid-mediated cyclization, is an effective method for the synthesis of both enantiomers of β-benzyl-γ-butyrolactone 1. This enzymatic process affords the pro

Full text of DOI:10.1016/S0957-4166(01)00317-2

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 1723–1726
Synthesis of optically active b-benzyl-g-butyrolactone through
lipase-catalyzed kinetic resolution
Yolanda Caro, Christian F. Masaguer and Enrique Ravin˜a*
Departamento de Qu´ımica Orga´nica, Laboratorio de Qu´ımica Farmace´utica, Facultad de Farmacia,
Universidad de Santiago de Compostela, E-15782 Santiago de Compostela, Spain
Received 21 May 2001; accepted 11 July 2001
Abstract—The lipase-catalyzed kinetic resolution of the racemic g-hydroxy ester 2, coupled with subsequent acid-mediated
cyclization, is an effective method for the synthesis of both enantiomers of b-benzyl-g-butyrolactone 1. This enzymatic process
affords the product with high enantiomeric excess under mild reaction conditions and does not require optically active starting
materials. © 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
asymmetric synthesis of a variety of compounds, enan-
tiomerically pure (R)- and (S)-b-benzyl-g-butyrolactone
are used as the most versatile intermediates.
b-Benzyl-g-butyrolactone 1 is the core framework of a
variety of the naturally occurring lignans which include
some medicinally important compounds.1,2 This com-
pound is a key intermediate not only for preparing
dibenzylbutyrolactone lignans, a class of natural com-
pounds that can be found in many plants, but also for
synthesizing other lignans which can be derived from
dibenzylbutyrolactones themselves.3
Although many synthetic methods to obtain both enan-
tiomers have been developed, in general, multi-step, low
yielding routes are reported.9 In the cases when short
synthetic routes are described, low enantiomeric excess
are obtained.10 Development of efficient synthetic meth-
ods producing optically pure benzylbutyrolactone is,
therefore, very important. Herein, we report the synthe-
sis of the optically active b-benzyl-g-butyrolactone
through the lipase-catalyzed kinetic resolution of the
g-hydroxy ester 2.
b-Benzyl-g-butyrolactone has also attracted attention
because of its versatility as synthetic intermediate for
other pharmacologically active compounds such as
O
OH
*
O
NRR
1
COOPr
2
3
O
platelet aggregation inhibitors,4 non-steroidal anti-
progestins,5 or central nervous system active com-
pounds.6,7 We are interested in these compounds as
starting materials in the synthesis of optically active
3-aminomethyltetralones 3, conformationally con-
strained butyrophenones, as potential antipsychotic
compounds.8 Therefore, in order to accomplish the
2. Results and discussion
Our search was initially directed towards the enantiose-
lective enzyme-catalyzed lactonization of the racemic
b-benzyl-g-hydroxy ester 2, which was prepared in 81%
yield from racemic b-benzyl-g-butyrolactone 111 by
nucleophilic substitution of bromopropane with the
potassium salt of the hydroxy acid in DMF solvent.
The g-hydroxy ester was subjected to enzyme screening
for the biocatalytic cyclization using several commer-
* Corresponding author. Tel.: +34 981 594 628; fax: +34 981 594 912;
e-mail: qofara@usc.es
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00317-2

1724
Y. Caro et al. / Tetrahedron: Asymmetry 12 (2001) 1723–1726
cially available lipases (Amano’s Pseudomonas lipases
AK, AH and PS, Candida lipase AYS, and Aspergillus
lipase AS; and Novo Nordisk’s Lipozime IM® and
Novozym® 435): lipases were checked in a tert-butyl
methyl ether solution of ( )-2, stirred for 24 h and then
analyzed by TLC. A low conversion, as judged visually,
had taken place with Amano AK, PS, AYS and AS
lipases, while a high-yielding transformation appeared
in the Lipozime IM® lipase (immobilized lipase from
Rhizomucor miehei ) and Novozym® 435 lipase (immo-
bilized lipase from Candida antarctica) reactions. These
reactions were repeated in tert-butyl methyl ether,
THF, dioxane, benzene or hexane as solvents at either
room temperature or 50°C, and reaction times of 12–24
h (Table 1). With Novozym® 435 lipase no enantiodif-
ferentiation was observed, and racemic lactone 1 was
always obtained. When the reaction was carried out in
the presence of Lipozime IM® enantiomeric excesses
(e.e.s) were obtained in all cases, the best result being
an e.e. of 64%12 for the (S)-(−)-1 lactone (entry 3) ([h]2D5
−5.0 (c 1, CHCl3)) after 14 h in hexane solvent at room
temperature, and 12% e.e.13 for the residual ester (R)-
(−)-2 ([h]2D0 −1.0 (c 1, CHCl3)).
were checked under acylating conditions. A solution of
( )-2 (10 mg) and the lipase (5 mg) in anhydrous vinyl
acetate (1 mL) used as solvent and acyl donor was
stirred at room temperature for 24 h. The acetylation
was analyzed by TLC and NMR, and the Amano
lipases from Pseudomonas cepacia (AH and PS) showed
the best results for the acetylation. These reactions were
repeated on a higher scale using ( )-2 (100 mg), the
lipase (50 mg) and vinyl acetate (5 mL). With lipase
AH, the acetate (+)-4 was obtained in 46% yield with
an e.e. of 38%,15 and the residual hydroxy ester (+)-2
was returned in 48% yield and 12% e.e. The enantiose-
lectivity of the reaction was rather poor (E=2.5). Thus,
the enantiodiscrimination in kinetic resolution of ( )-2
using lipase AH as catalyst was not satisfactory. How-
ever, when the lipase-catalyzed transesterification was
carried out using lipase PS, good kinetic resolution was
achieved, which furnished the hydroxy ester (+)-2 in
good yield with e.e. of 94%, and the acetate (+)-4 with
69% e.e., E=20 (Scheme 2).
Since acetate (+)-4 could not be obtained in satisfactory
e.e. in the transesterification, we carried out the enan-
tioselective lipase-catalyzed hydrolysis of the acetate
group. Good results were obtained when lipase PS was
added to a solution of acetate (+)-4 ([h]2D0 +5.5 (c 1,
MeOH), 69% e.e.) in tert-BuOH:phosphate buffer (1:6),
and stirred at room temperature for 8 h (Scheme 2).
Hydroxy ester (R)-(−)-2 was obtained in 71% yield
(39% from ( )-2) with 96% e.e., [h]2D0 −8.0 (c 1, MeOH).
Cyclization of the optically active hydroxy esters (+)-2
and (−)-2 with p-TsOH in benzene afforded the lac-
tones (S)-(−)-1 ([h]D24 −7.3 (c 1, CHCl3), 94% e.e.), and
Since the enzymatic lactonization of ( )-2 proved to be
ineffective for the preparation of enantiomerically pure
b-benzyl-g-butyrolactone, an alternative route was
explored. This consisted of the lipase-catalyzed kinetic
resolution of hydroxy ester ( )-2 (Scheme 1) and subse-
quent acid-mediated cyclization.
In the enzyme-catalyzed acetylation of the hydroxy
ester ( )-2, the seven above-mentioned tested enzymes
Table 1. Lipase-catalyzed lactonization of g-hydroxyester 2
Lipase
OH
OH
O
+
COOPr
COOPr
O
(R)-(-)-2
(–)-2
Solvent
(S)-(-)-1
Entry
Lipasea
Temp. (°C)
Time (h)
Lactone (S)-(−)-1
Alcohol (R)-(−)-2
E-valueb
Yield (%)
% e.e.
Yield (%)
% e.e.
1
2
3
4
5
6
7
8
N. 435
N. 435
L. IM
L. IM
L. IM
L. IM
L. IM
L. IM
tBuOMe
Hexane
Hexane
Benzene
Toluene
Cyclohexane
THF
rt
rt
rt
rt
rt
rt
50
50
30
13
14
50
50
50
60
60
61
37
17
11
11
28
0
5
64
45
22
38
20
45
62
70
65
55
0
ND
12
2
2
14
–
–
5
2
2
2
No reaction
No reaction
Dioxane
a N. 435, Novozym® 435; L. IM, Lipozime IM®
b Enantioselectivity was calculated from the formula E=ln[1−c(1−e.e.s)]/ln[1−c(1+e.e.s)].14
Lipase
OH
OAc
OH
+
COOPr
COOPr
(R)-(+)-4
COOPr
(±)-2
(S)-(+)-2
Scheme 1.

Y. Caro et al. / Tetrahedron: Asymmetry 12 (2001) 1723–1726
1725
Lipase PS
p-TsOH
OH
OAc
OH
O
+
Benzene
94%
COOPr
OAc
COOPr
COOPr
O
(R)-(+)-4
55%, 69%
e.e.
(+)-2
--
(S)-(+)-2
40%, 94% e.e.
(S)-(-)-1
Lipase PS
tBuOH/Phosphate
p-TsOH
buffer (1:6)
OH
COOPr
O
Benzene
94%
O
(R)-(-)-2
(R)-(+)-1
39% from (+)-2
--
96% e.e.
Scheme 2.
(R)-(+)-1 ([h]2D4 +7.5 (c 1, CHCl3), 96% e.e.), respec-
iodine vapor and/or UV light for detection. The com-
mercially available lipase samples were obtained as gifts
from Amano Pharmaceutical Co., Ltd. (Nagoya,
Japan) and Novo Nordisk Bioindustrial, S.A. (Madrid,
Spain), and used as received.
tively, in excellent yields.
The absolute configurations of the (+)-2 hydroxy ester
as (S) and the acetate (+)-4 as (R) were assigned based
on the literature values of (S)-(−)-1 lactone10a ([h]D23
−6.4 (c 2, CHCl3), 82% e.e.).
4.2. Preparation of propyl 3-benzyl-4-hydroxybutanoate
( )-2
3. Conclusion
Lactone ( )-1 (5 g, 28.4 mmol) was dissolved in a
solution of KOH in methanol (5%, 65 mL) and stirred
at rt for 8 h. The solvent was evaporated in vacuo and
the residue suspended in anhydrous DMF (15 mL).
1-Bromopropane (5.2 mL, 56.8 mmol) was added, the
mixture was stirred for 24 h, and more 1-bromo-
propane (5.2 mL, 56.8 mmol) was added and stirring
continued for a further 16 h at rt. Water (20 mL) was
added and the solution was extracted with Et2O (3×30
mL). The organic extracts were concentrated under
reduced pressure and the residue was purified by
column chromatography (silica gel, CH2Cl2) to give
propyl 3-benzyl-4-hydroxybutanoate ( )-2 as a yellow-
ish oil (5.4 g, 81%). IR (film): w 3446, 2966, 1732, 1496
cm−1; 1H NMR: l 0.93 (t, J=7.4 Hz, 3H, CH3),
1.57–1.71 (m, 2H, CH2-CH3), 2.32–2.44 (m, 3H, CH-
CH2COO), 2.61, 2.73 (ABX, JAB=13.6, JAX=6.8,
In conclusion, the lipase-catalyzed kinetic resolution of
racemic g-hydroxy ester ( )-2, coupled with subsequent
acid-mediated cyclization, is an effective method for the
synthesis of both enantiomers of b-benzyl-g-butyrolac-
tone 1. This enzymatic process affords high e.e.s under
mild reaction conditions and does not require optically
active starting materials. Utilization of optically active
butyrolactone 1 for the stereoselective synthesis of new
central nervous system agents is currently under
investigation.
4. Experimental
4.1. General
J
J
BX=6.5 Hz, 2H, CH2Ph), 3.51, 3.64 (ABX, JAB=10.8,
AX=5.3, JBX=3.8 Hz, 2H, CH2OH), 4.02 (t, J=6.7
Melting points were determined with a Kofler hot stage
instrument or a Gallenkamp capillary melting point
apparatus and are uncorrected. Infrared spectra were
recorded with a Perkin–Elmer 1600 FTIR spectropho-
Hz, OCH2), 7.17–7.32 (m, 5H, Ph); MS (EI) m/z 237
(M+H)+.
tometer; the main bands are given in cm−1. H NMR
1
spectra were recorded with a Bruker WM AMX (300
MHz); chemical shifts are recorded in parts per million
(l) downfield from tetramethylsilane (TMS). Mass
4.3. General procedure for the lipase-catalyzed
lactonization
spectra were performed on
a
Hewlett–Packard
The lipase (Lipozime IM® or Novozym® 435, 50 mg)
was added to a solution of ( )-2 (100 mg, 0.42 mmol) in
the solvent of choice (5 mL, Table 1), stirred at rt or
50°C (Table 1) for several hours (Table 1). After filtra-
tion through Celite, the filtrate was concentrated in
vacuo. Purification of the residue by column chro-
matography (silica gel, CH2Cl2) gave the lactone (S)-
(−)-1 and the hydroxyester (R)-(−)-2.
HP5988A mass spectrometer by electron impact (EI).
Optical rotations at the sodium D-line were determined
using a Perkin–Elmer 241 polarimeter. Flash column
chromatography was performed using Kieselgel 60 (60–
200 mesh, E. Merck AG, Darmstadt, Germany). Reac-
tions were monitored by thin-layer chromatography
(TLC) on Merck 60 GF254 chromatogram sheets using

1726
Y. Caro et al. / Tetrahedron: Asymmetry 12 (2001) 1723–1726
4.4. Procedure for the lipase-catalyzed acylation of the
hydroxy ester ( )-2
Grant SAF98-0148-C04-03. We would like to thank
Amano Pharmaceutical Co. Ltd (Nagoya, Japan) and
Novo Nordisk Bioindustrial, S.A. (Madrid, Spain) for
their generous gifts of lipases.
To a solution of the hydroxy ester ( )-2 (500 mg, 2.1
mmol) in vinyl acetate (20 mL), lipase PS (250 mg) was
added. The mixture was stirred for 12 h at rt, filtered
through Celite and concentrated in vacuo. The residue
was purified by flash column chromatography (silica
gel, CH2Cl2) to give propyl (R)-4-acetoxy-3-benzylbu-
tanoate (+)-4 (327 mg, 55%) and propyl (S)-3-benzyl-4-
hydroxybutanoate (+)-2 (200 mg, 40%).
References
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Propyl (S)-3-benzyl-4-hydroxybutanoate (+)-2: [h]D20
+7.80 (c 1.0, CH3OH), 94% e.e.
Propyl (R)-4-acetoxy-3-benzylbutanoate (+)-4: [h]D20
+5.50 (c 1.0, CH3OH), 69% e.e.; IR (film): w 2670, 1732,
1
1361 cm−1; H NMR: l 0.94 (t, J=7.4 Hz, 3H, CH3),
1.60–1.70 (m, 2H, CH2-CH3), 2.05 (s, 3H, CH3COO),
2.34 (d, J=3.6 Hz, 1H, CHCOO), 2.37 (d, J=3.0 Hz,
1H, CHCOO), 2.42–2.53 (m, 1H, CH(CH2)3), 2.67–
2.70 (m, 2H, CH2Ph), 3.91–4.09 (m, 2H, CH2OAc),
4.02 (t, J=6.7 Hz, 2H, O-CH2-), 7.15–7.32 (m, 5H, Ph);
MS (EI) m/z 278 M+.
4.5. Procedure for the lipase-catalyzed hydrolysis of the
acetate (+)-4
Lipase PS (60 mg) was added to a solution of acetate
(+)-4 (100 mg, 0.36 mmol) ([h]2D0 +5.5 (c 1, MeOH), 69%
e.e.) in tert-BuOH:phosphate buffer (1:6 v/v, 10 mL),
and stirred at rt for 8 h. After filtration through a Celite
pad, the filtrate was concentrated in vacuo. Purification
of the residue by column chromatography (CH2Cl2)
gave the hydroxy ester (R)-(−)-2 (60.5 mg, 71%, 96%
e.e.), [h]2D0 −8.0 (c 1, CH3OH).
8. Ravin˜a, E.; Masaguer, C. F. Curr. Med. Chem. CNSA
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van Oeveren, A.; Feringa, B. L. J. Chem. Soc., Perkin
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4.6. Procedure for the acid-catalyzed lactonization of
the hydroxy esters 2
A solution of the hydroxy ester 2 (100 mg, 0.42 mmol)
and p-TsOH (catalytic) in benzene (10 mL) was heated
under reflux under argon for 3 h. The mixture was
cooled to rt and then washed with saturated aqueous
NaHCO3 and water. The aqueous layers were extracted
with ethyl acetate, and the combined organic phases
dried (Na2SO4) and concentrated in vacuo. The residue
was purified by flash column chromatography (silica
gel, CH2Cl2) to afford the corresponding lactone (S)-
(−)-1 (70 mg, 94%). ([h]2D4 −7.3 (c 1, CHCl3), 94% e.e.),
or (R)-(+)-1 ([h]D24 +7.5 (c 1, CHCl3), 96% e.e.).
10. (a) Gagnon, R.; Grogan, G.; Groussain, E.; Pedragosa-
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Luong, T. K. K.; Schlingloff, G. Synlett 1997, 1151–1152.
11. Rothe, J.; Zimmer, H. J. Org. Chem. 1959, 24, 586–589.
12. The e.e. was determined from the ratio of the observed
and literature10a specific rotations.
13. Determined by comparison with literature9d values after
transformation into (R)-(+)-lactone.
14. Chen, C.-S.; Fujimoto, Y.; Girdaukas, G.; Sih, C. J. J.
Am. Chem. Soc. 1982, 104, 7294–7299.
15. The acetate (S)-(−)-4 ([h]2D0 −6.7 (c 1, MeOH), 84% e.e.),
which was required as reference sample, was synthesized
quantitatively by acetylation of the hydroxy ester (S)-(+)-
2 ([h]2D0 +7.0 (c 1, MeOH), 84% e.e.) with acetic anhydride
in pyridine.
Acknowledgements
This work was supported by Spanish Comisio´n Inter-
ministerial de Ciencia y Tecnolog´ıa (CICYT) under
.