New chemo and chemo-enzymatic synthesis of β-benzyl-γ-butyrolactones

Article abstract of DOI:10.1016/S0040-4020(03)00476-9

β-Benzyl-γ-butyrolactones, important intermediates for the synthesis of butyrolactone lignans, have been synthesized by a new route involving preparation of α-β-unsaturated formyl esters. The formyl esters can easily be converted into the desired butyrolactones either through chemical transformations or by enzymatic methods.

Full text of DOI:10.1016/S0040-4020(03)00476-9

Tetrahedron 59 (2003) 3487–3491
New chemo and chemo-enzymatic synthesis of
b-benzyl-g-butyrolactonesq
*
S. Koul, B. Singh, S. C. Taneja and G. N. Qazi
Bio-organic Chemistry Section, Regional Research Laboratory, Canal Road, Jammu Tawi 180001, India
Received 2 January 2003; revised 28 February 2003; accepted 21 March 2003
Abstract—b-Benzyl-g-butyrolactones, important intermediates for the synthesis of butyrolactone lignans, have been synthesized by a new
route involving preparation of a-b-unsaturated formyl esters. The formyl esters can easily be converted into the desired butyrolactones either
through chemical transformations or by enzymatic methods. q 2003 Published by Elsevier Science Ltd.
1. Introduction
fully reduced alcohol undergoes facile cyclisation to
produce the desired butyrolactones in moderate yields.
Substituted b-benzyl-g-butyrolactones are key inter-
mediates in the synthesis of butyrolactone lignans as well
as other natural products.1 Due to various pharmacological
and medicinal properties associated with butyrolactone and
related lignans, chemical synthesis of the intermediate
butyrolactones has been the major target of several synthetic
schemes.2 One of the more common synthetic strategies
utilizes Stobbe’s condensation of an aromatic aldehyde with
alkyl succinates followed by selective reduction.3 Besides
this approach several new methodologies have also been
reported for the asymmetric synthesis of the butyrolactones
and the lignans.4 In recent years, asymmetric syntheses of
optically active butyrolactones and the corresponding
lignans have also been achieved using chemo-enzymatic
methods.5 In this paper a new and facile chemo- and chemo-
enzymatic strategy for the synthesis of b-benzyl-g-butyro-
lactones is delineated.
The preparation of substituted 4-oxo-4-arylbutanoic acids
was achieved through Friedel–Crafts reaction of substituted
benzenes 1 with succinic anhydride in the presence of
anhydrous aluminum chloride. The 4-oxoarylbutanoic acids
thus obtained were protected through ester formation to give
2, followed by catalytic reduction using 5% Pd/C and
hydrogen gas at 50 psi to furnish the hydroxy esters 3 in
quantitative yield. Sodium borohydride reduction of 2
however gave a mixture of 3 and a cyclised product
(butanolide). The butanolide may easily be converted into
hydroxy butyrate 3 with triethylamine in methanol. The
hydroxyester 3 was then subjected to a formylation reaction
with Vilsmeier’s reagent freshly prepared from phosphoryl
chloride and dimethyl formamide. The product, mainly the
(E)-a,b-unsaturated aldehydes 4 are isolated in 51–60%
yield. The reduction of the prochiral aldehydes with
borohydride generated primary alcohols 5 which were
hydrolyzed with dilute acid to butenolides 6 which were
then converted into the desired racemic b-benzyl-g-
butyrolactones 8 through hydrogenation over 5% Pd/C
(over all yield of approximately 25% based on starting
material). Alternatively, prochiral alcohol 5 can be hydro-
genated to furnish racemic hydroxymethyl esters 7 which
undergo facile cyclisation in dilute acid to furnish 8
(Scheme 1).
2. Results and discussion
The strategy outlined here utilizes Vilsmeier’s reaction6 of
substituted 4-hydroxy-4-arylbutanoates in the key step.
Thus, the synthetic pathway to b-benzyl-g-butyrolactones
utilizes 4-oxo-4-arylbutanoates which through their
reduction followed by formylation leads to the formation
of an a,b-unsaturated aldehyde (3-formyl-4-arylbut-3-
enoate). The unsaturated aldehyde thus obtained is an
ideal prochiral precursor that may easily be reduced
chemically as well as bio-catalytically. The partially or
To prepare optically active butyrolactones using a chemo-
enzymatic approach, intermediate a,b-unsaturated alde-
hyde 4a was subjected to Baker’s yeast mediated reduction
at 308C. The intermediate chiral alcohol 7a isolated in
56.9% yield was converted into optically enriched R-(þ)-
butyrolactone 8a (ee 47%, chiral HPLC) through acid
catalyzed hydrolysis and concomitant cyclisation
(Scheme 2). R-(þ)-Butyrolactone 8a has also been obtained
by asymmetric synthesis (ee ,97%).3b
q R.R.L. contribution no. 2362.
Keywords: b-benzyl-g-butyrolactones; chemo-enzymatic synthesis; a-b-
unsaturated formyl esters; Baker’s yeast; bioreduction.
*
Corresponding author. Tel.: þ91-191-2580329; fax: þ91-191-2548607;
e-mail: sc_taneja@yahoo.co.in
0040–4020/03/$ - see front matter q 2003 Published by Elsevier Science Ltd.
doi:10.1016/S0040-4020(03)00476-9

3488
S. Koul et al. / Tetrahedron 59 (2003) 3487–3491
Scheme 1. (a) R¼3,4-dimethoxy; (b) R¼4-methoxy. (i) (a) Succinic anhydride/AlCl3 (anhydrous), (b) diazomethane/diethyl ether; (ii) H2, 5% Pd/C;
(iii) DMF/POCl3; (iv) NaBH4/CH3OH; (v) dil. HCl; (vi) H2, 5% Pd/C.
Scheme 2. (i) Baker’s yeast/D-glucose/50 h/308C; (ii) dil. HCl.
It was observed that when 4-methoxyphenyl precursor 4b
was subjected to bio-reduction, the intermediate chiral
primary alcohol could not be detected among the products.
Instead Baker’s yeast produced the desired optically
enriched butyrolactone 8b (op, 46% based on specific
rotation value) directly (Scheme 3). Thus, in this case
reduction, hydrolysis and cyclisation are all performed in a
single step. The overall yield of the butyrolactone 8b was
comparable to 8a, however its enantiopurity could not be
accurately determined by chiral HPLC. Preparation of
butyrolactone 8b has earlier been reported through a kinetic
resolution pathway (ee ,98%) using meso-diol ester as the
substrate,5d present methodology however has a wider scope
and applicability in terms of synthesis of 8 through
asymmetric reduction or using other biocatalysts.
In conclusion the present new synthetic strategy provides
access to both racemic as well as optically enriched
b-benzyl-g-butyrolactones. Although moderate enantio-
purity of the final products have been achieved by the
present chemoenzymatic approach compared to some
reported kinetic resolution methodology and asymmetric
synthesis, however for any further improvements in ees, use
of other oxido-reductases as well as chiral catalysts using
prochiral formyl esters 4 as the substrates would make an
interesting study.
Scheme 3. (i) Baker’s yeast/D-glucose/45 h/308C.

S. Koul et al. / Tetrahedron 59 (2003) 3487–3491
3489
3. Experimental
226 mmol) by the same method as described for 2a to
furnish 4-(4-methoxyphenyl)-4-oxo-butanoic acid (17.9 g,
84.6%), which on purification and crystallization from
methanol/ethyl acetate (1:9) produced colorless crystals
(16.3 g, 77%), mp 142–438C [found C, 64.21; H, 5.86%
C11H12O4 requires C, 63.45; H, 5.80%]; nmax (KBr) 1670,
1600, 1426, 1358, 1246, 1026, 830 cm21; dH (200 MHz,
CDCl3þDMSO-d6) 2.70 (2H, t, J¼6.5 Hz, CH2COOMe),
3.26 (2H, t, J¼6.5 Hz, CH2CO), 3.93 (3H, s, OMe), 7.04
(2H, d, J¼8.5 Hz, Ar-H), 8.05 (2H, d, J¼8.5 Hz, Ar-H); dC
(50 MHz, CDCl3þDMSO-d6) 28.1, 32.9, 55.4, 114.2,
129.7, 130.1, 162.7, 174.6, 196.7; Mþ at m/z, 208 (40),
135 (83), 120 (12), 106 (69), 91 (100), 77 (100).
3.1. General
Melting points were determined on a Buchi 510 melting
point apparatus. 1H NMR spectra were recorded as d values
at 60, 90 and 200 MHz and 13C NMR at 50 MHz using
CDCl3 as a solvent (or as mentioned) and TMS as internal
standard. Infrared spectra were recorded as KBr pellets in
cm21 on a Hitachi 270-30 model spectrophotometer. Mass
spectra were obtained on JEOL MSD-300 mass-
spectrometer. Optical rotations were measured on Perkin–
Elmer-241 polarimeter. Chiral HPLC was carried out on a
Shimadzu LC-10 AT model. Reagents used were AR grade
and all solvents for synthesis, extraction and column
chromatography were distilled and dried before use.
(b) The butanoic acid (10.16 g,48.8 mmol) was esterified in
diethyl ether using freshly prepared diazomethane in
quantitative yield to furnish 2b (10.8 g, 99%),which is
crystallized from ethyl acetate/hexane (1:4) as colorless
solid mp 468C [found C, 65.46; H, 6.42% C12H14O4 requires
C, 64.85; H, 6.34%]; nmax (KBr) 1670, 1600, 1516, 1426,
1358, 1310, 1240, 1174, 1120, 1022, 944, 830 cm21; dH
(200 MHz, CDCl3) 2.75 (2H, t, J¼6.5 Hz, CH2COOMe),
3.28 (2H, t, J¼6.5 Hz, CH2CO), 3.75 (2H, s, COOMe), 3.90
(3H, s, OMe), 7.00 (2H, d, J¼8.5 Hz, Ar-H), 8.05 (2H, d,
J¼8.5 Hz, Ar-H); dC (50 MHz, CDCl3) 28.1, 33.0, 51.8,
55.4, 113.8, 129.6, 130.3, 163.6, 173.5, 196.6; Mþ at m/z, 222
(13), 191 (19), 135 (100), 107 (18), 97 (27), 92 (27), 77 (37).
3.1.1. Methyl 4-(3,4-dimethoxyphenyl)-4-oxobutanoate
2a. (a) In a three necked flask fitted with a guard tube, a
mixture of veratrole (3,4-dimethoxy benzene, 1) (7.0 g,
50 mmol) and anhydrous aluminum chloride (16 g,
120 mmol) in nitrobenzene (50 mL) stirred at 0–58C and
to the mixture was added dropwise a solution of succinic
anhydride (6 g, 60 mmol) in nitrobenzene (60 mL). After
the addition was over, the stirring mixture was allowed to
attain room temperature and heated up to 608C for a further
3 h till the evolution of hydrochloric acid subsides. The
reaction mixture was cooled, poured into ice-cold water
(200 mL) and the resulting precipitate was filtered, washed
with water. The dried crude acid (10.6 g, 89%) was
crystallized from methanol/ethyl acetate (1:9) to give a
white powder (9.7 g, 81.4%) mp 162–638C, [found C,
60.43; H, 5.90% C12H14O5 requires C, 60.49; H, 5.92%];
nmax (KBr) 3332, 1730, 1660, 1592, 1504, 1444, 1414,
1332, 1264, 1240, 1140, 1018 cm21; dH (200 MHz,
CD3OD) 2.67 (2H, t, J¼6.6 Hz, CH2COOMe), 3.27 (2H,
t, J¼6.6 Hz, COCH2), 3.86, 3.89 (6H, 2£s, 2£OMe), 7.02
(1H, d, J¼8.5 Hz, Ar-H), 7.65 (1H, d, J¼2.0 Hz, Ar-H),
7.68 (1H, dd, J¼8.5, 2.0 Hz, Ar-H); dC (50 MHz, CD3OD)
33.6, 33.7, 56.1, 56.2, 111.2, 111.4, 123.8, 130.8, 150.1,
154.7, 175.0, 198.9.
3.1.3. Methyl 4-(3,4-dimethoxyphenyl)-4-hydroxy-
butanoate 3a. The oxoester 2a (3.3 g, 13 mmol) was
reduced in presence of Pd/C (5%) and hydrogen gas at
50 psi in ethanol (30 mL) to quantitatively produce racemic
alcohol 3a (3.3 g, ,99%) [found C, 61.66; H, 7.20%
C13H18O5 requires C, 61.40; H, 7.13%]; nmax (KBr) 3256,
1718, 1594, 1332, 1250, 1236, 1144, 1030, 940, 858 cm21
;
dH (200 MHz, CDCl3) 2.01–2.12 (2H, m, CH2), 2.53 (2H, t,
J¼7.4 Hz, CH2COO), 3.65 (3H, s, OMe), 3.89 (6H, s,
2£OMe), 4.69 (1H, t, J¼6.6 Hz, CHOH), 6.82–6.89 (3H,
m, Ar-H); dC (50 MHz, CDCl3) 30.4, 33.8, 51.9, 55.8, 55.9,
73.2, 108.9, 111.0, 118.0, 136.8, 148.4, 149.1, 174.3; Mþ at
m/z 254 (6), 236 (1), 234 (5), 218 (7), 216 (4), 204 (5), 188
(6), 182 (8), 174 (10), 164 (22), 162 (17), 137 (22), 136
(100), 121 (17), 105 (18), 90 (27).
(b) 4-(3,4-Dimethoxyphenyl)-4-oxobutanoic acid (5 g,
21 mmol) in diethyl ether (150 mL) is esterified with a
freshly prepared ethereal solution of diazomethane to
furnish the corresponding ester in quantitative yield
(5.25 g, ,99%), which on crystallization from ethyl
acetate/n-hexane gave colorless needles of 2a (5 g) mp
878C [found C, 62.14; H, 6.41% C13H16O5 requires C,
61.89; H, 6.39%]; nmax (KBr) 2876, 1714, 1666, 1592, 1446,
1412, 1380, 1244, 1210, 1178, 1148, 1088, 1020, 988, 914,
872 cm21; dH (200 MHz, CDCl3) 2.76 (2H, t, J¼7.0 Hz,
CH2COOMe), 3.22 (2H, t, J¼7.0 Hz, COCH2), 3.56 (3H, s,
OMe), 3.96 (6H, s, 2£OMe), 6.94 (1H, d, J¼8.5 Hz, Ar-H),
7.60–7.73 (2H, m, Ar-H); dC (50 MHz, CDCl3) 27.7, 32.2,
51.6, 55.3, 55.4, 109.7, 109.8, 122.1, 129.3, 148.3, 152.7,
174.2, 196.3; Mþ at m/z 252 (16), 221 (7), 206 (8), 179 (5),
165 (61), 132 (49), 119 (100), 91 (36), 89 (79), 74 (91).
3.1.4. Methyl 4-(4-methoxyphenyl)-4-hydroxybutanoate
3b. Reduction of 2b (7.0 g, 31 mmol) was carried out by a
similar process as described for 2a, the reduced product
purified by column chromatography over silica gel using
dichloromethane/ethyl acetate (19:1) as eluant to give a
semi-solid (6.4 g, 92.7%) [found C, 64.93; H, 7.23%
C12H16O4 requires C, 64.27, H, 7.19%]; nmax (KBr) 1678,
1604, 1512, 1362, 1240, 1172, 1114, 1026, 944 cm21; dH
(200 MHz, CDCl3) 1.98–2.10 (2H, m, CH2), 2.40 (2H, t,
J¼7 Hz, CH2COOMe), 3.65 (3H, s, COOMe), 3.83 (3H, s,
OMe), 4.66 (1H, t, J¼6.5 Hz, CHOH), 6.94 (2H, d,
J¼8.5 Hz, Ar-H), 7.33 (2H, d, J¼8.5 Hz, Ar-H); dC
(50 MHz, CDCl3) 30.3, 33.7, 51.5, 55.07, 72.6, 113.6,
126.9, 131.0, 158.8, 174.2; Mþ at m/z 224 (2), 223 (6), 206
(3), 205 (7), 191 (15), 149 (21), 136 (100), 134 (21), 108
(28), 93 (12), 76 (29).
3.1.2. Methyl 4-(4-methoxyphenyl) methyl-4-oxobutano-
ate 2b. (a) The title compound was prepared from anisole
(11 g, 102 mmol) and succinic anhydride (12 g, 120 mmol)
in presence of anhydrous aluminum chloride (30 g,
3.1.5. Methyl 4-(3,4-dimethoxyphenyl)-3-formyl-3(E)-
butenoate 4a. To a stirring solution of hydroxy ester 3a

3490
S. Koul et al. / Tetrahedron 59 (2003) 3487–3491
(2.3 g, 9 mmol) in dimethyl formamide (9 mL) at 0–58C is
added phosphoryl chloride (5 mL) slowly for 30 min. The
contents further stirred for one hour maintaining the
temperature. The temperature is then raised to 35–408C
and stirring continued for 36 h till the completion of the
reaction. The contents were poured in cold water (200 mL)
and the resulting precipitate filtered. The aqueous layer was
extracted with ethyl acetate (3£20 mL). The combined solid
and organic layer were washed with water, dried, concen-
trated and chromatographed over silica gel using ethyl
acetate/dichloromethane (1:4) as eluant to give a light
yellow compound 4a (1.4 g, 59.5%). mp 618C [found C,
64.11; H, 6.09% C14H16O5 requires C, 63.62; H, 6.10%];
nmax (KBr) 1752, 1590, 1512, 1456, 1424, 1352, 1266,
1240, 1152, 1022, 864 cm21; dH (200 MHz, CDCl3) 3.56
(2H, s, CH2COOMe), 3.64 (3H, s, OMe), 3.86 (6H, 2£s,
2£OMe), 6.88 (1H, d, J¼8.5 Hz, Ar-H), 7.00 (1H, m, Ar-H),
7.05 (1H, s, Ar-H), 7.37 (1H, s, vCH), 9.56 (1H, s, CHO);
dC (50 MHz, CDCl3) 30.7, 52.2, 55.9, 55.9, 111.2, 112.3,
124.1, 126.9, 133.2, 149.1, 150.9, 152.2, 172.2, 193.2; Mþ
at m/z: 264 (26), 263 (91), 248 (11), 235 (41), 232 (25), 204
(39), 176 (100), 160 (92), 145 (60), 131 (25), 115 (25), 103
(24), 91 (28), 89 (28).
dilute hydrochloric acid (10%, 10 mL) was heated at 60–
808C with TLC monitoring. After the completion of the
reaction, the contents of the reaction were cooled and
extracted with chloroform (5£10 mL). The organic layer
washed free of acid, dried, concentrated and chromato-
graphed over silica gel with chloroform/ethylacetate (9:1) to
produce colorless gummy mass 6a (67 mg, 77%) [found C,
66.89; H, 6.04% C13H14O4 requires C, 66.66; H, 6.02%];
nmax (KBr) 1728, 1636, 1514, 1448, 1304, 1250, 1126,
1028, 886 cm21; dH (200 MHz, CDCl3) 3.66 (2H, s, CH2),
3.83, 3.85 (6H, 2£s, 2£OMe), 4.68 (2H, s, CH2O), 5.77 (1H,
s, vCH), 6.66 (1H, s, Ar-H), 6.70 (1H, d, J¼8.4 Hz, Ar-H),
6.81 (1H, d, J¼8.4 Hz, Ar-H); Mþ at m/z 234 (5), 221 (13),
207 (100), 191 (16), 133 (11), 121 (12), 111 (18), 107 (8).
3.1.9. 3-(4-Methoxyphenyl) methyl-2-butenolide 6b.
Sodium borohydride (70 mg) was added in small pro-
portions to a methanolic solution of 4b (0.6 g, 2.5 mmol) at
0–58C. After the completion of the reaction (TLC
monitored), the contents worked-up as described for the
preparation of 5a to give directly 6b which was purified on
silica column with chloroform/methanol (9:1) as eluant to
furnished pure product as a gum (0.45 g, 86.2%) [found C,
71.33; H, 5.99% C12H12O3 requires C, 70.57; H, 5.92%];
nmax (KBr) 1728, 1636, 1514, 1352, 1304, 1250, 1174,
1126, 1028, 886, 832 cm21; dH (200 MHz, CDCl3) 3.68
(2H, s, CH2), 3.80 (3H, s, OMe), 4.70 (2H, s, CH2O), 5.78
(1H, bs, vCH), 6.87 (2H, d, J¼8.5 Hz, Ar-H), 7.13 (2H, d,
J¼8.5 Hz, Ar-H); dC (50 MHz, CDCl3) 34.4, 55.3, 72.7,
114.2, 116.2, 127.6, 129.2, 158.9, 169.7, 173.8; Mþ at m/z:
204 (68), 189 (10), 175 (5), 160 (22), 159 (31), 147 (13), 145
(38), 135 (14), 121 (100), 107 (98), 90 (51), 78 (87).
3.1.6. Methyl 3-(4-methoxyphenyl)-3-formyl-3(E)-
butenoate 4b. Formylation of 3b (4.5 g, 20 mmol) was
carried out with Vilsmeier’s reagent as described for 3a. The
product purified by column chromatography with pet. ether/
ethyl acetate (9:1) to furnish 4b as a light yellow solid
(2.38 g, 51%), mp 54–568C [found C, 67.13; H, 6.09%
C13H14O4 requires C, 66.65; H, 6.02%]; nmax (KBr) 1722,
1666, 1632, 1602, 1494, 1438, 1416, 1380, 1254, 1200,
1018, 1004, 942, 912, 878, 834 cm21; dH (200 MHz,
CDCl3) 3.59 (2H, s, CH2), 3.72 (3H, s, COOMe), 3.89
(3H, s, OMe), 7.03 (2H, d, J¼8.5 Hz, Ar-H), 7.53 (1H, s,
vCH), 7.56 (2H, d, J¼8.5 Hz, Ar-H), 9.66 (1H, s, CHO);
dC (50 MHz, CDCl3) 30.7, 52.3, 55.5, 114.6, 126.8, 131.3,
133.3, 148.3, 161.4, 171.0, 194.3; Mþ at m/z: 234 (6), 233
(42), 205 (96), 202 (31), 174 (31), 159 (24), 146 (100), 134
(14), 107 (17).
3.1.10. Racemic methyl 4-(3,4-dimethoxyphenyl)-3-
hydroxymethylbutanoate 7a. The compound 5a (200 mg,
0.75 mmol) was hydrogenated in presence of Pd/C (5%,
60 mg) at 40 psi in ethanol (20 mL) to give racemic semi-
solid (178 mg, 88.5%) 7a after usual workup [found, C,
63.03; H, 7.58% C14H20O5 requires C, 62.67, H, 7.51%];
nmax (KBr) 1710, 1598, 1442, 1322, 1262, 1242, 1152,
1024, 804 cm21; dH (200 MHz, CDCl3) 2.37–2.48 (3H, m,
CH2, CH), 2.64 (2H, bs, Ar–CH2), 3.28 (3H, s, COOMe),
3.27–3.30 (2H, m, OCH2), 3.87 (6H, s, 2£OMe), 6.74–6.84
(3H, m, Ar-H); dC (50 MHz, CDCl3) 36.0, 36.1, 37.5, 55.8,
55.9, 58.9, 74.3, 111.3, 112.6, 121.4, 132.1, 147.6, 148.9,
178.6.
3.1.7. Methyl 4-(3,4-dimethoxyphenyl)-3-hydroxy-
methyl-3(E)-butenoate 5a. A methanolic solution of 4a
(0.4 g, 1.5 mmol) at 0–58C was reduced by slow addition of
sodium borohydride (40 mg). After the completion of the
reaction the contents poured into cold water and extracted
with chloroform (4£40 mL). The water washed organic
layer was concentrated and passed through a silica gel
column using chloroform/ethyl acetate (9:1) as eluant to
furnish a semi-solid 5a (0.34 g, 85.2%) [found C, 63.98; H,
6.86% C14H18O5 requires C, 63.14; H, 6.81%]; nmax (KBr)
3348, 1698, 1597, 1446, 1358, 1260, 1198, 1156, 1074,
866 cm21; dH (200 MHz, CDCl3) 3.70 (3H, s, OMe), 3.90,
3.93 (6H, 2£s, 2£OMe), 4.71 (2H, s, CH2OH), 5.86 (1H, s,
vCH), 6.72 (1H, s, Ar-H), 6.77 (1H, d, J¼8.5 Hz, Ar-H),
6.89 (1H, d, J¼8.5 Hz, Ar-H); dC (50 MHz, CDCl3) 34.9,
55.8, 55.9, 56.0, 72.7, 111.5, 111.6, 116.4, 121.0, 127.9,
133.7, 148.4, 149.4, 169.4; Mþ at m/z 266 (3), 205 (10), 204
(29), 178 (3), 173 (10), 159 (23), 147 (13), 145 (11), 134
(19), 121 (100), 108 (37), 91 (17).
3.1.11. Racemic 3-(3,4-dimethoxyphenyl) methylbutyro-
lactone 8a. Method A. A suspension of 7a (100 mg,
0.37 mmol) and dilute hydrochloric acid (10%, 5 mL)
heated at 708C for 20 min with stirring. The cooled solution
was diluted with water (10 mL) and extracted with chloro-
form (4£10 mL). The organic layer washed with water,
dried and concentrated under vacuo to furnish a crude solid
which was purified by column chromatography over silica
gel with chloroform/ethylacetate (9:1) as eluant to give a
white powder 8a (62 mg, 70.5%) mp 110–1118C [found C,
66.14; H, 6.87% C13H16O4 requires C, 66.08; H, 6.82%];
nmax (KBr) 1762, 1584, 1510, 1448, 1408, 1388, 1362,
1260, 1144, 1034, 841 cm21; dH (200 MHz, CDCl3) 2.33
(1H, dd, J¼6.6, 17.4 Hz, –CH), 2.55–2.84 (4H, m,
2£CH2), 3.89 (6H, s, 2£OMe), 4.06, 4.30 (2H, dd, J¼5.7,
9.2 Hz, OCH2), 6.66 (1H, s, Ar-H), 6.70 (1H, dd, J¼8.5,
3.1.8. 3-(3,4-Dimethoxyphenyl) methyl-2-butenolide 6a.
A solution of 5a (100 mg, 0.37 mmol) in ethanol (1 mL) and

S. Koul et al. / Tetrahedron 59 (2003) 3487–3491
3491
2.4 Hz, Ar-H), 6.84 (1H, d, J¼8.5 Hz, Ar-H); dC (50 MHz,
CDCl3) 34.3, 37.4, 38.7, 56.0, 56.1, 72.7, 111.6, 112.0,
120.9, 130.9, 148.1, 149.3, 176.9; Mþ at m/z 236 (22), 181
(7), 152 (15), 151 (100), 137 (6), 121 (8), 106 (12), 90 (130,
78 (11).
3.1.15. Optically enriched R-(1)-3-(4-methoxyphenyl)
methylbutyrolactone 8b. An ethanolic solution (3 mL) of
4b (160 mg, 0.68 mmol) is added to a stirring mixture of
Baker’s yeast (dry powder, 2.5 g) and D-glucose (2.1 g) in
distilled water (80 mL, pH 6.8) and the contents stirred at
308C using a bubbler. The reaction is monitored by TLC and
after the consumption of the starting material (45 h) the
contents worked up by the method as described for 8a to
furnish crude bio-product (0.13 g) which on chromato-
graphic purification on silica gel column and elution with
pet. ether/ethyl acetate (9:1) gave (þ)-8b (80 mg, 57%)
[found C, 70.13; H, 6.81% C12H14O3 requires C, 69.89; H,
6.84%]; [a]2D5¼þ2.5 (CHCl3, c, 1.6), reported [a]2D5¼þ5.4
(op, 98%) (CHCl3, c, 6.8).5d
3.1.12. Racemic 3-(4-methoxyphenyl) methylbutyrolac-
tone 8b. A solution of 6b (250 mg, 1.22 mmol) in ethanol
(10 mL) was hydrogenated in presence of Pd/C (5%, 50 mg)
at 45–50 psi and the product obtained after filtration,
removal of the solvent and column chromatography over
silica gel with hexane/ethyl acetate (9:1) as a semi solid
(215 mg, 85.6%) 8b [found C, 70.05; H, 6.99% C12H14O3
requires C, 69.89; H, 6.84%]; nmax (KBr) 1732, 1614, 1510,
1460, 1302, 1248, 1176, 1030, 834 cm21; dH (200 MHz,
CDCl3) 2.27 (1H, dd, J¼6.65, 17.45 Hz, –CH), 2.52–2.72
(4H, m, 2£CH2), 3.80 (3H, s, OMe), 4.04 (1H, dd, J¼5.90,
8.17 Hz, OCH2a), 4.31 (1H, dd, J¼6.65, 9.03 Hz, –OCH2b),
6.81 (2H, d, J¼8.5 Hz, Ar-H), 7.08 (2H, d, J¼8.5 Hz, Ar-
H); dC (50 MHz, CDCl3) 34.3, 37.3, 38.0, 55.2, 72.7, 113.8,
130.0, 130.3, 158.5, 177.0; Mþat m/z 206 (8), 192 (3), 147
(6), 121 (100), 103 (8), 91 (20), 78 (35).
References
1. (a) Ward, R. S. Nat. Prod. Rep. 1997, 14, 43. (b) Whiting, D. A.
Nat. Prod. Rep. 1990, 7, 349.
2. Ward, R. S. Tetrahedron 1990, 46, 5029. and references cited
therein.
Method B. Alternatively, 6a could easily be hydrogenated
catalytically to furnish racemic butyrolactone 8a in 90%
yield by the same method as described above for the
conversion of 5a to 7a.
3. (a) Banerji, J.; Biswanath, D. Heterocycles 1985, 23(3),
661–665. (b) Shao, L.; Miyato, S.; Muramatsui, H.; Kawano,
H.; Ishi, Y.; Soburi, M.; Uchida, Y. J. Chem. Soc. Perkin Trans.
1 1990, 5, 1441–1445. (c) Marimoto, T.; Chiba, M.; Achiwa, K.
Tetrahedron 1993, 49(9), 1793–1806.
3.1.13. Optically enriched methyl 4-(3,4-dimethoxy-
phenyl) 3-hydroxymethylbutanoate 7a. A mixture of
Baker’s yeast (3 g, dry powder) and D-glucose (3 g) in
distilled water (60 mL, pH 6.8) was stirred at 308C in a
fermentation flask with a bubbler for 10 min after which an
ethanolic solution (3 mL) of formyl ester 4a (173 mg,
0.65 mmol) was added to it. The mixture stirred at 308C for
50 h with TLC monitoring and after the consumption of 4a,
filtered through a pad of celite (2 g) and extracted with
chloroform (5£20 mL). The combined chloroform layer
was washed and dried (sod. sulfate), concentrated under
reduced pressure. The concentrated material was purified
over silica gel using chloroform/ethyl acetate (9:1). The
purified product 7a (100 mg, 56.9%) a semi-solid [found C,
62.92; H, 7.55% C14H20O5 requires C, 62.67; H, 7.50%];
[a]2D5¼23.4 (CHCl3, c, 1.4).
4. (a) Vanderlei, J. M. de. L.; Coelho, F.; Almeida, W. P. Synth.
Commun. 1998, 28(16), 3047–3055. (b) Carlton, J. L. Can.
J. Chem. 1997, 75(8), 1076–1083. (c) Filho, H. C. A.; Filho,
U. F. L.; Pinheiro, S.; Vasconcells, M. L. L. A.; Costa, P. R. R.
Tetrahedron: Asymmetry 1994, 5(7), 1219–1220. (d) Costo
Paulo, R. R. V.; Ferreiro, J. Braz. Chem Soc. 1996, 7(1), 67–73,
Chem. Abstr., 124, 260681y.
5. (a) Chenvert, R.; Mohammadi, Z. G.; Caron, D.; Dasser, M.
Can. J. Chem. 1999, 77(2), 223–226. (b) Brinksma, J.; Vander
Deen, H.; van Oeveren, A.; Feringa, B. L. J. Chem. Soc. Perkin
Trans. 1 1998, 1(24), 4159–4164. (c) Alphand, V.; Mazzini, C.;
Lebreton, J.; Furstoss, K. J. Mol. Catal. B. Enzym. 1998, 5(1–
4), 219–221. (d) Shiotani, S.; Okada, H.; Yamamoto, T.;
Nakamata, K.; Adachi, J.; Nakamoto, H. Heterocycles 1996,
43(1), 113–126. (e) Mazzini, C.; Lebreton, J.; Furstoss, R.
J. Org. Chem. 1996, 91(1), 8–9. (f) Lemoult, S. C.; Richardson,
P. F.; Roberts, S. M. J. Chem. Soc. Perkin Trans. 1 1995, 2,
89–91. (g) Gagnon, R.; Grogan, G.; Groussain, G. E.;
Pedragosa, M.; Sandrine, R.; Paul, F.; Roberts, S. M.; Willets,
A. J.; Alphand, V.; Lebreton, J.; Furstoss, R. J. Chem. Soc.
Perkin Trans. 1 1995, 2, 2527–2528. (h) Itoh, T.; Chicka, J. C.;
Takagi, Y. J. Org. Chem. 1993, 58(21), 5117–5123. (i) Kong,
S.-K.; Eon, J.-H.; Yamaguchi, T.; Hong, R. K.; Ko, B.-S.
Tetrahedron: Asymmetry. 1995, 6(1), 97–100. (j) Sime, J. T.;
Barnes, R. D.; Elson, S. W.; Jarvest, R. L.; OToole, K. J.
J. Chem. Soc. Perkin Trans. 1 1992, 13, 1653–1658. (k) Yang,
L. M.; Lin, S. J.; Yang, T. H.; Lee, K. H. Bioorg. Med. Chem.
Lett. 1996, 6(8), 941–944.
3.1.14. Optically enriched (R)-(1)-3-(3,4-dimethoxy-
phenyl) methyl butyrolactone 8a. A suspension of 7a
(60 mg,0.22 mmol) and dilute hydrochloric acid (10%,
5 mL) heated at 708C for 20 min with stirring. The product
processed as described for the preparation of racemic
lactone above to furnish optically enriched 8a (39 mg, 74%)
[ee, 47% on a Chiradex chiral column (b-cyclodextrin)
using methanol/water (9:1) as the mobile phase, oven
temperature 228C, detection at 256 nm, flow rate 0.5 mL/
min, retention time 13.8 and 18.4 min, respectively], mp
108–1098C [found C, 66.12; H, 6.87% C13H16O4 requires
C, 66.08; H, 6.82]; [a]2D5¼þ10.5 (CHCl3, c, 0.24); reported
[a]2D5¼þ23.8 (op, 97%).3b
6. Reddy, M. P.; Krishna Rao, G. S. Synthesis 1980, 815.