Asymmetric synthesis of γ-butyrolactones by enantioselective hydrogenation of butenolides

Article abstract of DOI:10.1016/j.tetasy.2003.08.031

Some optically active γ-butyrolactones derivatives, useful building blocks for the synthesis of several natural products, have been obtained by a convenient procedure using catalytic asymmetric hydrogenation. 3, 4-Disubstituted γ-butyrolactones were obtai

Full text of DOI:10.1016/j.tetasy.2003.08.031

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 3253–3256
Asymmetric synthesis of g-butyrolactones by enantioselective
hydrogenation of butenolides
Paulo Marcos Donate,a,* Daniel Frederico,a Rosangela da Silva,a,b Mauricio Gomes Constantino,a
Gino Del Ponteb and Pierina Sueli Bonattob
aUniversidade de Sa˜o Paulo, Departamento de Qu´ımica, Faculdade de Filosofia, Cieˆncias e Letras de Ribeira˜o Preto,
Avenida Bandeirantes 3900, 14040-901 Ribeira˜o Preto, SP, Brazil
bUniversidade de Sa˜o Paulo, Faculdade de Cieˆncias Farmaceˆuticas de Ribeira˜o Preto, Via do Cafe´ s/n,
14040-903 Ribeira˜o Preto, SP, Brazil
Received 18 August 2003; accepted 20 August 2003
Abstract—Some optically active g-butyrolactones derivatives, useful building blocks for the synthesis of several natural products,
have been obtained by a convenient procedure using catalytic asymmetric hydrogenation. 3,4-Disubstituted g-butyrolactones were
obtained in good yields and in high enantiomeric excess through the enantioselective hydrogenation of the corresponding
butenolides catalyzed by BINAP-Rh or Ru complexes.
© 2003 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Functionalized chiral g-butyrolactones are important
subunits present in a large variety of natural products
and biologically active compounds, such as alkaloids,
lignan lactones and sex attractant insect pheromones.1
The very attractive biological properties of these com-
pounds prompted us to develop a program for the
synthesis of several versatile compounds containing the
g-butyrolactone unit and for their utilization as thera-
peutic agents. Recently, we described a new synthetic
method which could be generally applicable to the
preparation of racemic hydroxy-lactones, as well as
a,a-disubstituted b-methylene-g-butyrolactones and
butenolides.2 Enantioselective hydrogenation of various
olefinic substrates catalyzed by BINAP-Rh or Ru com-
plexes has been shown to be one of the most efficient
methods for preparing several kinds of chiral biologi-
cally active molecules.3 We decided to extend this asym-
metric reduction process to the preparation of the
optically active g-butyrolactones derivatives and herein
we describe a convenient procedure to prepare chiral
non-racemic g-butyrolactones, from the corresponding
butenolides, using catalytic enantioselective hydrogena-
tion as a key reaction.
Racemic
4-(hydroxymethyl)-3-phenyldihydrofuran-
2(3H)-one 2, an important intermediate for the antibac-
terial penicillanic acid derivatives,4 can be easily
prepared from commercial a-bromophenyl acetic acid 1
in three steps with 70% overall yield.2 Protection of the
hydroxyl group of 2 with chloromethyl methyl ether5
afforded compound 3 in 91% yield, which on treatment
with LDA, phenylselenenyl chloride6 and H2O2 pro-
duced butenolide 4, in 82% yield (Scheme 1).
The asymmetric catalytic hydrogenation of the buteno-
lide 4 to form g-butyrolactone 5, was carried out in the
presence of the chiral complexes BINAP-Rh or Ru
(molar ratio substrate:catalyst=100:1) in methanol by
treatment with H2 (50 atm) at room temperature. The
substrate conversion reached a fairly good value (64–
75%) with the BINAP-Rh complexes but did not exceed
46% when the Ru catalyst was used (see Table 1). Since
a tetra-substituted olefin is usually reluctant to undergo
catalytic hydrogenation,7 these results can be consid-
ered satisfactory. The yield (see note on Table 1) of the
desired g-butyrolactone 5 was very high (96–98%) in all
cases. Hydrogenolysis products in varying ratio have
been observed in the hydrogenation reactions of
butenolides containing an unprotected allylic hydroxyl
group.8 No hydrogenolysis product, however, was
detected in the hydrogenation of 4. The hydrogenation
* Corresponding authors. Tel.: +55-16-602-3696; fax: +55-16-633-
8151; e-mail: pmdonate@usp.br
0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2003.08.031

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P. M. Donate et al. / Tetrahedron: Asymmetry 14 (2003) 3253–3256
Scheme 1. Enantioselective synthesis of g-butyrolactone 5. Reagents and reaction conditions: (a) MOMCl, DPEA, CH2Cl2, rt, 12
h, 91%; (b) LDA, PhSeCl, THF, −78°C, 4 h, then H2O2, rt, 82%; (c) H2 (50 atm), chiral catalyst, MeOH, rt, 72–80 h (see Table
1).
Table 1. Enantioselective hydrogenation of butenolide 4 to g-butyrolactone 5 using ruthenium and rhodium chiral catalyst
Entry
Catalysta
Reaction
time (h)
Conversionb Yieldc of 5
of butenolide (%)
4 (%)
g-Butyrolactone 5
5a (%)
5b (%)
5 (c or d)
(%)
5 (d or c)
(%)
% Eed [h]2D5
(MeOH)
1
2
3
A
B
C
80
72
72
46
64
75
97
96
98
5.4
0.9
90.8
75.0
92.0
0.7
1.6
1.4
6.3
18.0
5.7
2.2
87
98
98.5
+5.3 (c 0.5)
+5.8 (c 0.5)
−7.3 (c 0.5)
a A=[(R)-(+)-2,2%-Bis(diphenylphosphino)-1,1%-binaphthyl]chloro(p-cymene)ruthenium chloride. B=[(R)-(+)-2,2%-Bis(diphenylphosphino)-1,1%-
binaphthyl](1,5-cyclooctadiene)rhodium(I) perchlorate:THF complex (1:1). C=[(S)-(−)-2,2%-Bis(diphenylphosphino)-1,1%-binaphthyl](1,5-cyclo-
octadiene)rhodium(I) perchlorate: THF complex (1:1).
b Conversion determined by gas chromatography (GLC) of the crude reaction mixture.
c Isolated yield calculated based on the amount of butenolide actually transformed.
d Enantiomeric excess (% ee) were evaluated by HPLC analysis using a Chiralcel OJ® column.
For comparative purposes the itaconic acid 6 was sub-
mitted to the asymmetric hydrogenation (Scheme 2)
with the same types of catalysts, under the conditions
shown in Table 2. Comparison of the specific rotation
of the products with data reported in the literature,9
demonstrated that the asymmetric Rh catalysts show
higher enantioselectivity than the Ru catalyst, even
when a di-substituted olefin such as the itaconic acid
Scheme 2. Enantioselective hydrogenation of itaconic acid 6.
was used as a substrate.
of butenolide 4 produces a higher proportion of the
cis-g-butyrolactones
5 (5a+5b). In fact, a (91.5–
92.9):(7.1–8.5) ratio of cis (5a+5b) to trans (5c+5d)
isomers was produced with Rh catalysts, while a
80.4:19.6 ratio of cis to trans isomers was obtained with
the Ru catalyst. Moreover, the enantiomeric excess is
higher (ꢀ98% ee) for the Rh catalysts than for Ru
(87% ee).
3. Experimental
Melting points were determined on a Reichert Kofler
block melting point apparatus and are uncorrected.
NMR spectra were measured using a Bruker DPX-300

P. M. Donate et al. / Tetrahedron: Asymmetry 14 (2003) 3253–3256
3255
Table 2. Enantioselective hydrogenationa of itaconic acid 6 using ruthenium and rhodium chiral catalyst
Entry
Catalystb
Reaction time (h)
Conversionc of 6 (%)
Yieldd of 7 (%)
% Eee [h]2D5 (EtOH)
Config.
1
2
3
4
B
C
D
E
2
2
2
2
100
100
98
95
95
92
88
97
94
85
96
+16.4 (c 15.2)
−15.9 (c 14.5)
−14.4 (c 15.7)
+16.2 (c 12.8)
R
S
S
R
95
a All these hydrogenations were carried out under 18 atm of H2.
b Catalysts: B=[(R)-(+)-2,2%-Bis(diphenylphosphino)-1,1%-binaphthyl](1,5-cyclooctadiene)rhodium(I) perchlorate: THF complex (1:1). C=[(S)-(−)-
2,2%-Bis(diphenylphosphino)-1,1%-binaphthyl](1,5-cyclooctadiene)rhodium(I) perchlorate: THF complex (1:1). D=[(S)-(−)-2,2%-Bis(diphenylphos-
phino)-1,1%-binaphthyl]chloro(p-cymene)ruthenium chloride. E=(+)-1,2-Bis[(2S, 5S)-2,5-diethylphospholano]benzene (cyclooctadiene)rhodium
(I) trifluoromethanesulfonate.
c Conversion determined by 1H NMR analysis of the crude reaction mixture.
d Isolated yield calculated based on the amount of substrate actually transformed.
e Based on the values for enantiomerically pure (R)-(+)-7, [h]2D0=+16.9 (c 2.2, EtOH).9
(300 MHz H NMR and 75 MHz 13C NMR) instru-
ment. GC-MS spectra were obtained by EI ionization
at 70 eV on a HP-5988-A spectrometer. IR spectra were
measured with a Perkin–Elmer 1600 FT spectrometer.
Analytical gas chromatography (GLC) separations
were performed on a Varian GC 3400 instrument with
a fused silica capillary column (30 m length×0.25 mm
i.d.) coated with DB-1701 (phase thickness 0.25 mm)
operating at temperatures in the range 50–200°C.
HPLC analysis was performed with a Shimadzu instru-
ment consisting of a model LC-10AS solvent pump, a
model 7125 Rheodyne injector with a 20 mL loop, a
model SPD-10A UV detector (254 nm), and a model
CR6-A integrator. The enantiomers were separated
using a 10 mm Chiralcel OJ® column (4.6×250 mm) and
a mobile phase consisting of n-hexane:isopropyl alcohol
(9:1, v/v), at a flow rate of 1 mL/min. Optical rotation
was measured with a Schmidt+Haensch model Polar-
tronic HH8 polarimeter. TLC was performed on pre-
coated silica gel 60 F254 (0.25 mm thick, Merck), and
for column chromatography silica gel 60 70–230 mesh
(Merck) was used. Given yields correspond to materials
with the same purity as the samples used in the subse-
quent steps.
brine, dried over Na2SO4, and concentrated under
reduced pressure. The residue was purified by column
chromatography through silica gel, eluting with ethyl
acetate/hexane (1:1) to give compound 3. Yield 1.10 g
1
1
(4.73 mmol, 91%). H NMR (CDCl3, 300 MHz) l 7.30
(m, 5H), 4.65 (s, 2H), 4.55 (dd, J1=9.04 Hz, J2=7.91
Hz, 1H), 4.20 (t, J=9.0 Hz, 1H), 3.70 (d, J=10.2 Hz,
1H), 3.64 (dd, J1=10.18 Hz, J2=4.14 Hz, 1H), 3.58
(dd, J1=10.17 Hz, J2=6.03 Hz, 1H), 3.35 (s, 3H), 2.80
(m, 1H); 13C NMR (CDCl3, 75 MHz) l 176.95 (C=O),
135.86–127.84 (aromatics C), 96.68 (OCH2O), 68.96
(CH2 ring), 65.81 (CH2), 55.54 (benzyl C), 48.26 (CH3),
45.06 (CH); MS m/z (rel. intensity) 191 (12) (M+−45),
161 (20), 117 (98), 91 (59), 77 (22), 32 (100).
3.2. 4-[(Methoxymethoxy)methyl]-3-phenylfuran-2(5H)-
one 4
To a solution of N,N-diisopropylamine (0.68 mL, 4.86
mmol) in anhydrous THF (5 mL), maintained at 0°C
under a nitrogen atmosphere, was added a solution of
n-butyllithium in n-hexane (4.65 mmol). After stirring
for 20 min at 0°C, the solution was cooled to −78°C
and a solution of compound 3 (1.00 g, 4.23 mmol) in
anhydrous THF (2 mL) was added. Stirring was contin-
ued for 30 min, and then a solution of phenylselenenyl
chloride (0.81 g, 4.23 mmol) in THF (2 mL) was added.
After stirring for 4 h at −78°C, the reaction mixture was
quenched by addition of water and extracted with
ether. The ethereal solution was washed with water,
dried over MgSO4 and evaporated.
(R)-(+)- and [(S)-(−)-2,2%-Bis(diphenylphosphino)-1,1%-
binaphthyl](1,5-cyclooctadiene)rhodium(I) perchlorate:
tetrahydrofuran complex (1:1), and [(R)-(+)-2,2%-bis-
(diphenylphosphino)-1,1%-binaphthyl]chloro(p-cymene)-
ruthenium chloride were purchased from Aldrich. (+)-
1,2-Bis[(2S,5S)-2,5-diethylphospholano]benzene (cyclo-
octadiene)rhodium(I) trifluoromethanesulfonate was
purchased from Strem Chemicals.
The crude residue obtained (1.48 g) was diluted with
dichloromethane (10 mL), and stirred at 0°C with 30%
aqueous H2O2 (2 mL) for 2 h. After separation, the
aqueous solution was extracted with dichloromethane.
The organic solution was washed with saturated brine
and dried over MgSO4. The solvent was evaporated
and the residue was purified by column chromatogra-
phy through silica gel, eluting with ethyl acetate/hexane
(1:1) to give compound 4 as a white crystalline solid:
3.1. 4-[(Methoxymethoxy)methyl]-3-phenyldihydrofuran-
2(3H)-one 3
To a solution of compound 2 (1.00 g, 5.20 mmol) in
anhydrous dichloromethane (10 mL), maintained under
a nitrogen atmosphere and cooled to 0°C, was added
chloromethylmethylether (0.44 mL, 5.40 mmol) and
N,N,N-diisopropylethylamine (0.73 g, 5.70 mmol). The
reaction mixture was stirred at 0°C for 1 h and at room
temperature for 12 h. The organic solution was washed
with saturated sodium bicarbonate solution, saturated
1
mp 45–48°C. Yield 0.81 g (3.47 mmol, 82%). H NMR
(CDCl3, 300 MHz) l 7.30 (m, 5H), 5.00 (s, 2H), 4.70 (s,
4H), 3.40 (s, 3H); 13C NMR (CDCl3, 75 MHz) l 172.83
(CꢀO), 157.59 (benzyl C), 126.81 (C olefinic), 129.34–
129.01 (aromatics C), 96.05 (OCH2O), 70.34 (CH2

3256
P. M. Donate et al. / Tetrahedron: Asymmetry 14 (2003) 3253–3256
(100). Anal. calcd for C13H16O4: C, 66.09; H, 6.83.
Found: C, 65.96; H, 6.74.
ring), 62.88 (CH2), 55.68 (CH3); MS m/z (rel. intensity)
172 (54) (M+−62), 144 (7), 117 (10), 77 (6), 45 (100).
Anal. calcd for C13H14O4: C, 66.66; H, 6.02. Found: C,
66.84; H, 6.13.
Acknowledgements
3.3. General procedure for the enantioselective hydro-
genation reaction
The authors wish to thank the Fundac¸a˜o de Amparo a`
Pesquisa do Estado de Sa˜o Paulo (FAPESP), the Con-
selho Nacional de Desenvolvimento Cient´ıfico e Tecno-
In a stainless steel 150 mL pressure reactor were placed
100 mg (ꢀ0.4 mmol) of solid butenolide 4 (or ꢀ2.0
mmol of the itaconic acid) and 1 mol% of the catalytic
complex. The reactor was purged with argon, evacuated
to 30 mmHg and 5 mL of anhydrous methanol (previ-
ously distilled under argon atmosphere) was introduced
by suction.
lo´gico
(CNPq)
and
the
Coordenadoria
de
Aperfeic¸oamento de Pessoal do Ensino Superior
(CAPES) for financial support. Useful discussions with
Professor Dr. Carlo Botteghi of University of Venice,
Italy, are also acknowledged.
References
The vessel was purged with hydrogen, pressurized with
hydrogen (at 50 atm for butenolide 4 and at 18 atm for
itaconic acid) and stirred at room temperature. After
the reaction was completed, the reaction mixture was
filtered through a short-path column (8 cm) containing
silica gel (230–400 mesh) to remove the catalyst. The
solvent was evaporated and the residue was analyzed by
gas chromatography or 1H NMR to determine the
conversion, and by HPLC to determine the enan-
tiomeric excess. The 1H and 13C NMR spectra and
mass spectra were consistent with the structure of
desired products. For analytical purposes a small sam-
ple compound 5 was purified by column chromatogra-
phy through silica gel, eluting with hexane/ethyl ether
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1
mer 5b: H NMR (CDCl3, 300 MHz) l 7.40 (m, 5H),
4.60 (s, 2H), 4.49 (dd, J1=9.04 Hz, J2=6.50 Hz, 1H),
4.45 (dd, J1=6.78 Hz, J2=6.03 Hz, 1H), 4.43 (dd,
J1=6.78 Hz, J2=6.03 Hz, 1H), 4.32 (dd, J1=9.05 Hz,
J2=6.50 Hz, 1H), 4.05 (d, J=8.67 Hz, 1H), 3.3 (s, 3H),
3.0 (m, 1H); 13C NMR (CDCl3, 75 MHz) l 176.95
(CꢀO), 135.86–127.84 (aromatics C), 96.68 (OCH2O),
68.96 (CH2 ring), 65.81 (OCH3), 55.54 (CH2OR), 48.26
(benzyl C), 45.06 (CH ring); MS m/z (rel. intensity) 236
(11) (M+), 205 (7), 175 (17), 117 (21), 91 (20), 75 (5), 45
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