Synthesis of Novel Dibenzylbutyrolactones as Dimethylmatairesinol Analogues

Article abstract of DOI:10.1002/jhet.2266

In this work, (R)-4-(3,4-dimethoxybenzyl)dihydrofuran-2(3H)-one was prepared though an efficient and novel method starting from (S)-5-((benzyloxy)methyl)dihydrofuran-2(3H)-one. Then, it was utilized as a versatile starting material for the synthesis of novel dimethylmatairesinol analogues; dibenzylbutyrolactone derivatives, via the reaction of the later compound and various aromatic aldehydes.

Full text of DOI:10.1002/jhet.2266

November 2015 Synthesis of Novel Dibenzylbutyrolactones as Dimethylmatairesinol
Analogues
1693
d
b
b
Babak Heidary Alizadeh,a Alireza Foroumadi,b,c Farzad Kobarfard, Mina Saeedi, and Abbas Shafiee
*
aIranian Research Institute of Plant Protection (IRIPP), Shahid Chamran Avenue, Yaman St. No 1; P.O. Box:1454, Tehran
bDepartment of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran
University of Medical Sciences, Tehran 14176, Iran
cDrug Design & Development Research Center, Tehran University of Medical Sciences, Tehran 14176, Iran
dDepartment of Medicinal Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
*
E-mail: shafieea@tums.ac.ir
Received February 10, 2014
DOI 10.1002/jhet.2266
Published online 23 October 2014 in Wiley Online Library (wileyonlinelibrary.com).
In this work, (R)-4-(3,4-dimethoxybenzyl)dihydrofuran-2(3H)-one was prepared though an efficient and
novel method starting from (S)-5-((benzyloxy)methyl)dihydrofuran-2(3H)-one. Then, it was utilized as a
versatile starting material for the synthesis of novel dimethylmatairesinol analogues; dibenzylbutyrolactone
derivatives, via the reaction of the later compound and various aromatic aldehydes.
J. Heterocyclic Chem., 52, 1693 (2015).
INTRODUCTION
hydroxymethyl]-dihydrofuran-2-one (Fig. 2a), collinusin
(Fig. 2b), and neoisostegane (Fig. 2c) [12].
Natural compounds, particularly lignans, have attracted
lots of attention owing to their valuable and numerous bio-
logical activities. At this juncture, compounds isolated from
woody plants have been the center of attention. For exam-
ple, taxol and podophyllotoxin derived from conifers are
well recognized for their remarkable antitumor activity [1].
Among a wide spectrum of natural compounds derived
from the heartwood of plants, compounds having dibenzyl-
butyrolactone framework absorbed our attention because
they have exhibited a variety of biological properties
including antibiotic, fungicidal, antiviral, anti-HIV, anti-
helmintic, anti-inflammatory, antiallergenic, and antitumor
activities [2–7].
(-)-Yatein (Fig. 1a), one of the famous naturally occur-
ring lignans isolated from Juniperus thurifera, depicted a
significant cytotoxic activity against different cancer cell
lines [8]. Lignans such as arctigenin (Fig. 1b) and
dimethylmatairesinol (Fig. 1c), isolated from Taiwania
cryptomerioides, are well known as important cytotoxic,
anti-proliferative, hepatoprotective, anti-inflammatory, and
analgestic agents [9–11].
Following our studies on the synthesis of dibenzyl-
butyrolactone derivatives [13], herein focusing on the im-
portance of these compounds, we describe an efficient
method for the preparation of novel dibenzylbutyrolactones
3 through the reaction of optically pure (R)-4-(3,4-
dimethoxybenzyl)dihydrofuran-2(3H)-one 1 and various aro-
matic aldehydes 2 (Scheme 1).
RESULTS AND DISCUSSION
To achieve our goal, initially, we prepared (R)-4-(3,4-
dimethoxybenzyl)dihydrofuran-2(3H)-one 1 through an
efficient procedure. Although different routes have been
reported for the synthesis of compound 1 [14], still more
effective synthesis is necessary. Our synthetic route for the
synthesis of (R)-4-(3,4-dimethoxybenzyl)dihydrofuran-2
(3H)-one 1 has been outlined in Scheme 2, which is based
on our previous report for the asymmetric synthesis of
isochahulactone [13]. It was prepared through six steps
starting from (S)-(+)-γ-benzyloxymethyl-γ-butyrolactone
(4) in 36% yield.
As can be seen in Scheme 2, two-step condensation
reaction of (S)-(+)-γ-benzyloxymethyl-γ-butyrolactone
(4) and 3,4-dimethoxybenzaldehyde led to the formation
of 5-((benzyloxy)methyl)-3-(3,4-dimethoxybenzylidene)
dihydrofuran-2(3H)-one (6). It should be noted that
the nucleophilic reaction of compound 4 and 3,4-
Apart from favorable biological activities of the afore-
mentioned compounds, their analogues can be considered
as a versatile starting material for the synthesis of various
natural compounds. Our literature review revealed that
dimethylmatairesinol (Fig. 2a) has been used as a key in-
termediate for the synthesis of other lignan lactones such
as 4-(3,4-Dimethoxybenzyl)-3-[(3,4-dimethoxyphenyl)-
© 2014 HeteroCorporation

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presence of p-TsOH in refluxing xylene and purified
using column chromatography to afford pure 6. Then,
the later compound underwent reduction to form the
corresponding
alcohol,
3-(3,4-dimethoxybenzyl)-5-
(hydroxymethyl)dihydrofuran-2(3H)-one 7, using Pd-C/
H2 hydrogenation (67% yield for three steps). Com-
pound 7 was treated with lithium aluminum hydride in
THF to give triol 8, which tolerated cyclization reaction
to give 4-(3,4-dimethoxybenzyl)tetrahydrofuran-2-ol (9)
using sodium periodate in high yield. Oxidation of 9
with Collin’s reagent gave (R)-4-(3,4-dimethoxybenzyl)
dihydrofuran-2(3H)-one 1 in good yield (53% yield for
three steps).
Figure 1. Structure of (-)-yatein (a), arctigenin (b), dimethylmatairesinol (c).
dimethoxybenzaldehyde was conducted in the presence
of LDA at À78°C in tetrahydrofuran (THF) to obtain
compound 5. Next, crude 5 was dehydrated in the
Figure 2. Structure of 4-(3,4-Dimethoxybenzyl)-3-[(3,4-dimethoxyphenyl)-hydroxymethyl]-dihydrofuran-2-one (a), collinusin (b), and neoisostegane (c).
Scheme 1. Synthesis of dibenzylbutyrolactones 3.
Scheme 2. Synthesis of (R)-4-(3,4-dimethoxybenzyl)dihydrofuran-2(3H)-one 1.
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Synthesis of Novel Dibenzylbutyrolactones as Dimethylmatairesinol Analogues
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Table 1
Then, we focused on the synthesis of products 3
according to Scheme 2. Treatment of lactone 1 and various
aromatic aldehydes 2 in the presence of LDA at À78°C
gave dibenzylbutyrolactones 3a–f bearing hydroxyl group
at benzylic position.
Calculated anti/syn products ratios.a
Entry
Product 3
anti/syn ratio
All products 3 were obtained as a mixture of two syn/anti
diastereomers based on the S-configuration or R-configuration
of C7 benzylic hydroxyl group (Fig. 3), which were distin-
guishable from their 1H-NMR spectra. It is worth to mention
that corresponding chemical shift of proton H7 in syn-isomer
was shifted downfield. Also H7-H3 coupling constant was
smaller in comparison to similar coupling in anti-isomer.
Because of the formation of hydrogen bond between
hydroxyl group at C7 and carbonyl group of lactone, the
H7-H3 relationship of the syn-isomer is axial-equatorial
and that of the anti-isomer is di-axial. Thus, the observed
coupling constant between H7 and H3 of syn-isomer was
lower than that of anti-isomer in accordance with the data
reported in the literature [15].
1
55/45
2
54/46
Our investigations revealed that diastereoselectivity
(anti/syn ratio) directly depends on the substitutions and
also their positions on the benzaldehyde derivatives. The
results are summarized in Table 1.
3
4
50/50
44/45
Compounds 3a and 3b bearing three and two methoxy
groups, respectively, showed larger anti/syn ratios compar-
ing with other derivatives (55/45 and 54/46, entries 1 and 2,
Table 1). In the case of compounds 3c possessing one
methoxy group located at meta position of benzaldehyde,
equal amounts of syn and anti isomers were generated
(50/50). Interestingly, anti/syn ratio was reduced to 44/55
when p-methoxy benzaldehyde used for the construction
of 3d. Also, similar result was observed in the absence of
an electron-donating group and compound 3e, which did
not have any substituents on the aromatic ring showed the
anti/syn ratio of 46/54. Finally, in the presence of electron
withdrawing group NO2, located at para position of benzal-
dehyde, anti/syn ratio of 33/67 was obtained. It can be
5
6
46/54
33/67
aDetermined by 1H-NMR on the crude mixture.
concluded that in syn configuration, the aromatic ring is in
the pseudoequatorial position in which a hydrogen bond
can be formed between oxygen of nitro and hydroxyl group
(Fig. 4). However, in the case of methoxy group, the forma-
tion of hydrogen bond is not possible or strong enough.
Figure 3. syn/anti diastereomers relationship.
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(lactone) cm–1. ESI-Mass m/z: 395 [M + Na]+. Anal. Calcd for
C21H24O6: C, 67.73; H, 6.50. Found: C, 67.82; H, 6.61.
5-((Benzyloxy)methyl)-3-(3,4-dimethoxybenzylidene)
dihydrofuran-2(3H)-one (6).
The crude oil obtained from
previous step 5, was heated at reflux in xylene (10 mL) in the
presence of catalytic amount of p-TsOH for 2 h. After cooling,
the solution was washed with sat. NaHCO3 aq. and brine. The
organic layer was dried over MgSO4 and concentrated to give a
yellow oil, which was purified by column chromatography silica
gel (EtOAc/Hexane 3:1).
Yellow oil; yield: 75% (0.75 g); [α]2D5+81° (c 0.009, CHCl3).
1H-NMR (500 MHz, CDCl3) δ: 3.09 (m, 1H, CH2), 3.27 (m,
1H, CH2), 3.69 (m, 2H, OCH2CH), 3.92 and 3.95 (s, 6H, CH3),
4.46 (d, 2H, J = 12.1 Hz, OCHPh), 4.80 (m, 1H, CHO), 6.94 (d,
1H, J = 8.4 Hz, CHAr), 7.01 (d, 1H, J = 1.9 Hz, CHAr), 7.13
(dd, 1H, J = 8.4, 1.9 Hz, CHAr), 7.28–7.32 (m, 5H, Ph), 7.51 (t,
1H, J = 2.8 Hz, H vinylic). IR (film) ν 3540 (OH), 1680 (lactone)
cm–1. ESI-Mass m/z: 377 [M + Na]+. Anal. Calcd for C21H22O5:
C, 71.17; H, 6.26. Found: C, 71.38; H, 6.20.
Figure 4. Pseudoequatorial position aromatic ring bearing nitro group in
Syn configuration.
CONCLUSION
In conclusion, we have established an efficient synthetic
approach for the synthesis of novel dibenzylbutyrolactone
derivatives as analogues of dimethylmatairesinol through
the reaction of optically pure (R)-4-(3,4-dimethoxybenzyl)
dihydrofuran-2(3H)-one and aromatic aldehydes. All prod-
ucts were obtained as a mixture of syn/anti diastereomers,
3-(3,4-Dimethoxybenzyl)-5-(hydroxymethyl)dihydrofuran-
2(3H)-one (7). Catalytic hydrogenation of compound 6 (3.0 g,
8.4 mmol) was carried out with 10% Pd-C (0.15 g), PdCl2 and small
amount of conc. HCl in EtOAc (90mL) under a H2 atmosphere
using a hydrogen balloon on the top of reaction vessel. After
completion of reaction (checked by TLC), the mixture was
filtered, and the filtrate was concentrated in vacuo and purified by
column chromatography on silica gel (EtOAc/Hexane 3:1).
1
which were demonstrated from their H-NMR spectra. It
should be noted that we also developed a new method for
the optically pure preparation of selected starting material,
(R)-4-(3,4-dimethoxybenzyl)dihydrofuran-2(3H)-one, starting
from (S)-5-((benzyloxy)methyl)dihydrofuran-2(3H)-one.
1
Yellow oil; yield: 89% (2.0 g); [α]2D5+75° (c …, CHCl3). H-
NMR (500 MHz, CDCl3) δ: 2.07 (s, 1H, OH), 3.09–3.20 (m,
2H, CH2), 3.69 (m, 1H, OCH2CH), 3.70 (m, 1H, CHCO), 3.85–
3.91 (m, 8H, CH3, OCH2Ph), 4.10 (m, 1H, CHO), 6.95 (d, 1H,
J = 8.4 Hz, CHAr), 7.01 (brs, 1H, CHAr), 6.95 (d, 1H,
J = 8.4 Hz, CH–Ar). IR (film) ν 3460 (OH), 1680 (lactone) cm–1.
ESI-Mass m/z: 289 [M + Na]+. Anal. Calcd for C14H18O5: C,
63.15; H, 6.81. Found: C, 63.29; H, 6.74.
EXPERIMENTAL
All chemicals and reagents were obtained from Merck and
1
Sigma-Aldrich. H-NMR spectra were measured using a Bruker
4-(3,4-Dimethoxybenzyl)pentane-1,2,5-triol (8). A solution
of compound 7 (2.0g, 7.5 mmol) in THF (10 mL) was added
dropwise to a suspension of lithium aluminum hydride (0.25 g,
2.5 mmol) in THF (60mL) under ice-cooling, and the mixture was
then stirred at room temperature for 1 h. After that water (0.3mL),
15% aq. NaOH (0.3mL), and water (1 mL) were added
successively, and the whole was filtered off. The filtrate was
concentrated in vacuo to give a pale yellow oil 8.
80 and 500 spectrometer (Brucker, Rheinstetten, Germany),
and chemical shifts were expressed as
δ (ppm) with
tetramethylsilane as internal standard. The infrared (IR) spec-
tra were obtained on a Shimadzu IR prestige-21. Mass spectra
were recorded on Agilent 6410 Triple Quad. LC/MS. The purity of
all compounds was confirmed by thin-layer chromatography (TLC)
using different mobile phases. The elemental analysis was
performed with an Elementar Analysensystem GmbH VarioEL
CHNS mode, which were within 0.4% of theoretical values for
C, H, and N.
Pale yellow oil; yield: 80% (1.60 g). [α]2D5+35° (c …, CHCl3).
1H-NMR (500 MHz, CDCl3) δ: 1.7–3.9 (m, 5H, CH2CH–CH2),
4.25 (m, 1H, CHO), 3.87 and 3.89 (s, 6H, OMe), 6.61 (s, 1H, ar-
omatic-H), 6.84 (s, 2H, aromatic-H). IR (film) ν 3400 (OH) cm–1.
ESI-Mass m/z: 293 [M + Na]+. Anal. Calcd for C14H22O5: C,
62.20; H, 8.20. Found: C, 62.31; H, 8.33.
5-((Benzyloxy)methyl)-3-((3,4-dimethoxyphenyl)(hydroxy)
methyl)dihydrofuran-2(3H)-one (5).
A solution of (S)-5-
((benzyloxy)methyl)dihydrofuran-2(3H)-one 4 (0.5 g, 2.4 mmol) in
THF (2 mL) was added to a solution of lithium diisopropylamide
(LDA) in THF (1.4 mL, 2.4 mmol) at À78°C and stirred for 1 h at
this temperature. After that 3,4-dimethoxybenzaldehyde (0.55 g,
2.4 mmol) was added dropwise over a period of 10 min, and the
resultant mixture was stirred at À78°C for 2 h, quenched with
concentrated HCl (1 mL), extracted with EtOAc, and washed with
water and brine. Evaporation of the solvent in vacuo gave a brown
oil 5 as mixture of isomers.
4-(3,4-Dimethoxybenzyl)tetrahydrofuran-2-ol (9).
A
solution of compound 8 (1.60 g, 6 mmol) in tert-BuOH (20 mL)
was added to a solution of NaIO4 (2.22 g, 10 mmol) in water
(20 mL)/tert-BuOH (20 mL). The reaction mixture was stirred at
room temperature for 2 h, and then extracted three times with
EtOAc. The combined extracts were washed successively with
10% aq. NaHSO3, satd. aq. NaHCO3, and aq. NaCl, then dried
over MgSO4. Concentration in vacuo afforded the objective
lactol as a pale yellow oil 9.
1
[α]2D5+100° (c 0.001, CHCl3). H-NMR (500 MHz, CDCl3) δ:
1.90–2.50 (m, 2H, CH2), 2.50 (m, 1H, CHCO), 3.15–3.66 (m,
2H, OCH2), 3.687 (s, 6H, CH3), 4.45–4.46 (m, 2H, OCH2Ph),
4.72 (m, 1H, CHO), 5.31 (d, J = 8.2 Hz, 1H, CH), 6.81–6.94 (m,
3H, Ar), 7.25–7.35 (m, 5H, Ph). IR (film) ν 3520 (OH), 1700
Pale yellow oil; yield: 85% (1.20g). [α]2D5-12° (c …, CHCl3). 1H-
NMR (500 MHz, CDCl3) δ: 1.78 (m, 2H, –CH–CH2–CH), 1.8–2.3
(m, 1H, Ar–CH2–CH), 2.86–2.86 (m, 2H, ArCH2), 2.93 and 2.96
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Synthesis of Novel Dibenzylbutyrolactones as Dimethylmatairesinol Analogues
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1
(c …, CHCl3). H-NMR (500 MHz, CDCl3) δ: 2.15 anti (dd, 1H,
J = 13.9, 5.1 Hz, H6), 2.22 anti (dd, 1H, J = 13.9, 9.7 Hz, H6), 2.31
syn (dd, 1H, J = 13.7, 7.3 Hz, H6), 2.44 syn (dd, 1H, J =13.7,
8.25 Hz, H6), 2.50 syn and 2.83 anti (m, –H4), 2.64–2.67 (m, 1H,
H3 syn and anti), 3.80 (s, 3H, OMe), 3.83 (s, 3H, OMe), 3.88 (s,
3H, OMe), 3.90 (s, 3H, OMe), 3.96 anti (dd, 1H, J =8.8Hz, H5),
4.14 (t, 2H, J =8.8 Hz, H5 syn and anti), 4.33 syn (t, 1H,
J = 8.3 Hz, H5), 4.84 anti (d, 1H, J =8.1Hz, H7), 5.29 syn (d, 1H,
J = 3.1 Hz, H7), 6.35 (dd, 1H, J =7.4, 1.8Hz, Ar), 6.40 (dd, 1H,
J = 9.8, 1.8 Hz, Ar), 6.44 (dd, 1H, J = 8.1, 1.8 Hz, Ar), 6.66 (d, 1H,
J = 8.1 Hz, Ar), 6.72 (d, 1H, J = 8.1 Hz, Ar), 6.81 (s, 1H, Ph),
6.88 (d, 1H, J = 8.15 Hz, Ph), 6.96 (dd, 1H, J = 8.1, 1.8 Hz,
Ph), 6.98 (dd, 1H, J = 6.8, 1.8 Hz, Ar). 13C-NMR (125 MHz,
CDCl3) δ: 29.6, 36.5, 38.1, 38.7, 39.2, 39.8, 51.5, 52.8, 55.7,
55.8, 55.9, 108.4, 109.5, 110.8, 111.1, 111.3, 111.7, 117.4,
119.1, 120.3, 120.4, 130.3, 132.6, 133.4, 147.7, 147.8, 148.4,
148.8, 148.9, 149.0, 149.3, 149.4, 178.3, 179.0. IR (film) ν
(two brs, total 1H, OH), 3.87 (m, 6H, OCH3), 4.55 (d, 1H, J = 12.7,
CHO), 4.74 (d, 1H, J = 12.7Hz, CHO), 5.75 (d, 1H, J = 4.9 Hz,
CHOH), 6.36 (s, 1H, CHAr), 6.83–6.86 (m, 2H, CHAr). IR (film)
ν 3500 (OH) cm–1. ESI-Mass m/z: 261 [M + Na]+. Anal. Calcd for
C13H18O4: C, 65.53; H, 7.61. Found: C, 65.68; H, 7.51.
4-(3,4-Dimethoxybenzyl)-dihydrofuran-2(3H)-one (1).
A
solution of lactol 9 (120 mg, 0.5 mmol) in CH2Cl2 (50 mL) was
added to a suspension of Collins reagent, prepared from CrO3
(770 mg, 7.7 mmol) and pyridine (1.25 mL) in CH2Cl2 (70 mL).
The reaction mixture was stirred at room temperature for
20 min, then diluted with ether-hexane (1:1) (150 mL), and the
whole was stirred for an additional 10 min. The mixture was
filtered through celite, and the filtrate was concentrated in
vacuo to give a pale yellow oil. The crude was purification by
column chromatography (silica gel, EtOAc/Hexane, 3:1) to
give compound 1.
Pale yellow oil; yield: 78% (100 mg). [α]2D5-25° (c …, CHCl3).
1H-NMR (500 MHz, CDCl3) δ: 2.30 (dd, 1H, J = 17.5, 6.8 Hz,
CHO), 2.63 (dd, 1H, J = 17.5, 8.2 Hz, CHO), 2.85 (m, 1H,
CHCH2), 2.73 (m, 2H, –CH2–Ar), 3.88 (s, 6H, CH3), 4.06 (dd,
1H, J = 8.8, 6.2 Hz, CHO), 4.35 (t, 1H, J = 8.0 Hz, CHO), 6.67
(s, 1H, CHAr), 6.71 (d, 1H, J = 8.0, CHAr), 6.82 (d, 1H,
J = 8.0, CHAr). IR (film) ν 1780 (lactone) cm–1. ESI-Mass m/z:
259 [M + Na]+. Anal. Calcd for C13H16O4: C, 66.09; H, 6.83.
Found: C, 66.22; H, 6.70.
3570 (OH), 1770 (lactone) cm–1
. ESI-Mass m/z: 425
[M + Na]+. Anal. Calcd for C22H26O7: C, 65.66; H, 6.51.
Found: C, 65.78; H, 6.69.
4-(3,4-Dimethoxybenzyl)-3-(hydroxy(3-methoxyphenyl)methyl)
dihydrofuran-2(3H)-one (3c). Brown viscous oil; yield: 65%
as
a
mixture of diasteromers (anti/syn: 50/50). 1H-NMR
(500 MHz, CDCl3) δ: 2.19 anti (s, H6), 2.21 anti (s, H6), 2.63
syn (dd, 1H, J = 9.4, 8.2 Hz, H6), 2.70 syn (dd, 1H, J = 9.4,
6.85 Hz, H6), 2.83 syn and 2.95 anti (m, 1H, H4), 2.68–2.74
(m, 1H, H3 syn and anti), 3.82 (m, 3H, OMe), 3.97 syn (dd,
1H, J = 14.3, 6.2 Hz, H5), 4.12 syn (dd, 1H, J = 14.3, 7.1 Hz,
H5), 4.16 anti (t, 1H, J = 8.4 Hz, H5), 4.32 anti (dd, 1H, J = 8.7,
8.0, Hz, H5), 4.86 anti (d, 1H, J = 8.3 Hz, H7), 5.35 syn (d, 1H,
J = 3.0 Hz, H7), 6.67 (d, 1H, J = 8.1 Hz, Ar), 6.72 (d, 1H,
J = 8.1 Hz, Ar), 6.85 (m, Ph) 6.94 (m, Ar), 7.35 (m, Ph). IR
(film) ν 3530 (OH), 1760 (lactone) cm–1. ESI-Mass m/z: 373
[M + Na]+. Anal. Calcd for C21H24O6: C, 67.73; H, 6.50.
Found: C, 67.64; H, 6.62.
General procedure for the synthesis of compounds 3
(3a–f). A solution of compound 1 (30 mg, 0.12 mmol) in dry
THF (0.5 mL) was added to a solution of LDA (0.4 mL,
0.6 mmol) in THF/Hexane (3 mL : 1 mL) at À78°C and
stirred for 30 min. Mixture of aromatic aldehyde
2
(0.13 mmol) and HMPA (0.1 mL) was added to this solution
and it was stirred for 2 h, then it was quenched with
saturated aq. NH4Cl (1 mL). The mixture was extracted with
EtOAc (3 × 20 mL), washed successively with water (1 mL),
10% HCl (1 mL), water, saturated aq. NaHCO3, and NaCl.
Organic phase was dried over Na2SO4, filtered, and
evaporated in vacuo to give a brown viscous oil. The residue
was purified by TLC chromatography (silica gel, hexane/
EtOAc, 5:1) to give 3.
4-(3,4-Dimethoxybenzyl)-3-(hydroxy(2,3,4-trimethoxyphenyl)
methyl)dihydrofuran-2(3H)-one (3a). Brown viscous oil; yield:
53 % (29.0 mg) as a mixture of diasteromers (anti/syn: 55/45). 1H-
NMR (500 MHz, CDCl3) δ: 2.18 anti (dd, 1H, J = 13.9,
4.8 Hz, H6), 2.28 anti (dd, 1H, J = 13.9, 2.9 Hz, H6), 2.30
syn (dd, 1H, J = 13.8, 7.2 Hz, H6), 2.48 syn (dd, 1H,
J = 13.8, 8.3 Hz, H6), 2.52 and 2.84 (m, H4), 2.63–2.68 (m,
1H, H3 syn and anti), 3.80 (s, 3H, OMe), 3.83 (s, 6H,
OMe), 3.87 and 3.82 (s, 3H, OMe), 3.98 syn (dd, 1H,
J = 8.8, 5.9 Hz, H5), 4.12 syn (dd, 1H, J = 14.3, 7.1 Hz, Hz,
H5), 4.16 anti (dd, 1H, J = 9.0, 8.15 Hz, H5), 4.37 anti (t,
1H, 1H, J = 8.5 Hz, H5), 4.83 anti (d, 1H, J = 7.8 Hz, H7),
5.28 syn (d, 1H, J = 2.9 Hz, H7), 6.35 (dd, J = 8.1 Hz, Ar),
6.37 (m, 1H, Ar), 6.44 (dd, 1H, J = 8.1, 1.9 Hz, Ph), 6.51
(s, 1H, Ar), 6.59 and 6.61 (s, 2H, Ph), 6.65 (d, 1H,
J = 8.1 Hz, Ar), 6.67 (s, 1H, Ph), 6.72 (d, 1H, J = 8.1 Hz,
Ar). IR (film) ν 3520 (OH), 1730 (lactone) cm–1. ESI-Mass
m/z: 455 [M + Na]+. Anal. Calcd for C23H28O8: C, 63.88;
H, 6.53. Found: C, 63.62; H, 6.71.
4-(3,4-Dimethoxybenzyl)-3-(hydroxy(4-methoxyphenyl)
methyl)dihydrofuran-2(3H)-one (3d). Brown viscous oil; yield:
70% as mixture of diasteromers (anti/syn: 44/55). [α]2D5+26° (c …,
CHCl3). 1H-NMR (500 MHz, CDCl3) δ: 2.12 anti (dd, 1H, J= 13.8,
4.5 Hz, H6), 2.19 anti (dd, 1H, J= 13.9, 9.9 Hz, H6), 2.30 syn (dd,
1H, J= 13.7, 6.8 Hz, H6), 2.42 syn (dd, 1H, J= 13.8, 8.4 Hz, H6),
2.47 anti and 2.81 syn (m, 1H, H4), 2.64–2.69 (m, 1H, H3 syn and
anti), 3.80 (s, 3H, OMe), 3.80 (s, 6H, OMe), 3.86 (s, 3H, OMe),
3.95 (m, 1H, H5 syn and anti), 4.14 syn (dd, 1H, J=8.2, 7.8Hz,
H5), 4.29 anti (t, 1H, J=8.2Hz, H5), 4.84 anti (d, 1H, J=8.4Hz,
H7), 5.31 syn (d, 1H, J=3.2Hz, H7), 6.34 (s, Ar), 6.46 (d, 1H,
J= 7.9 Hz, Ar), 6.70 (d, 1H, J= 8.2 Hz, Ar), 6.73 (d, 1H,
J= 8.05 Hz, Ar), 6.85 (d, 1H, J= 8.35 Hz, Ph), 6.94 (d, 1H,
J= 8.3 Hz, Ph), 7.20 (d, 1H, J= 8.3 Hz, Ph), 7.36 (d, 1H, J=8.3Hz,
Ar). 13C-NMR (125 MHz, CDCl3) δ: 36.5, 37.3, 39.1, 40.5, 51.4,
52.7, 55.2, 55.6, 55.7, 55.7, 55.8, 71.5, 71.9, 72.1, 72.5, 76.7, 77.0,
77.2, 111.0, 111.2, 111.5, 113.7, 113.9, 120.3, 120.5, 126.2, 127.9,
128.7, 130.3, 130.4, 132.1, 132.8, 147.2, 147.7, 148.8, 148.9,
158.9, 159.7, 178.4, 179.1. IR (film) ν 3560 (OH), 1760 (lactone)
cm–1. ESI-Mass m/z: 395 [M + Na]+. Anal. Calcd for C21H24O6: C,
67.73; H, 6.50. Found: C, 67.88; H, 6.58.
4-(3,4-Dimethoxybenzyl)-3-(hydroxy(phenyl)methyl)
4-(3,4-Dimethoxybenzyl)-3-((3,4-dimethoxyphenyl)(hydroxy)
dihydrofuran-2(3H)-one (3e). Brown viscous oil; yield: 50%
methyl)dihydrofuran-2(3H)-one (3b).
Brown viscous oil;
mixture of diasteromers (anti/syn: 46/54). 1H-NMR
yield: 60% as mixture of diasteromers (anti/syn: 54/46). [α]2D5+ 20°
as
a
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1698
B. H. Alizadeh, A. Foroumadi, F. Kobarfard, M. Saeedi, and A. Shafiee
Vol 52
(500 MHz, CDCl3) δ: 2.05 anti (s, 1H, J = 13.8, 3.9 Hz, H6), 2.21
anti (dd, 1H, J = 13.8, 4.8 Hz, H6), 2.24 syn (dd, 1H, J = 13.7,
6.75 Hz, H6), 2.40 syn (dd, 1H, J = 13.8, 8.2 Hz, H6), 2.53 syn
and 2.88 anti (m, H4), 2.67–2.74 (m, 1H, H3 syn and anti), 3.78
(s, 3H, OMe), 3.82 (s, 3H, OMe), 3.84 (s, 3H, OMe), 3.85
(s, 3H, OMe), 3.90 (s, 3H, OMe), 3.95 syn (dd, 1H, J = 8.9,
6.3 Hz, H5), 4.12 syn (dd, 1H, J = 14.4, 7.1 Hz, H5), 4.15 (m,
1H, H5 anti), 4.30 anti (t, 1H, J = 8.0 Hz, H5), 4.90 anti (d,
1H, J = 8.3 Hz, H7), 5.40 syn (d, 1H, J = 3.0 Hz, –H7), 6.31
(dd, J = 8.0, 1.9 Hz, Ar), 6.44 (m, Ph), 6.69 (d, 1H, J = 8.15,
Ar), 6.73 (d, 1H, J = 8.15, Hz, Ar), 7.36 (m, Ph). IR (film) ν
3530 (OH), 1760 (lactone) cm1. ESI-Mass m/z: 365
[M + Na]+. Anal. Calcd for C20H22O5: C, 70.16; H, 6.48.
Found: C, 70.30; H, 6.32.
Acknowledgments. The authors gratefully acknowledge the
research council of Tehran University of Medical Sciences
and Iran National Science Foundation (INSF).
REFERENCES AND NOTES
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4-(3,4-Dimethoxybenzyl)-3-(hydroxy(4-nitrophenyl)methyl)
dihydrofuran-2(3H)-one (3f). Brown viscous oil; yield 45% as
a mixture of diasteromers ((anti/syn: 33/67). 1H-NMR (500 MHz,
CDCl3) δ: 2.23–2.33 (m, H6), 2.50 anti and 2.87 syn (m, H4),
2.73 (m, 1H, H3 syn and anti), 3.76 (s, 3H, OMe), 3.83 (s, 3H,
OMe), 3.87 (s, 3H, OMe), 4.06 syn (m, H5), 4.21 syn (m, 1H,
H5), 4.35 anti (t, 1H, J = 8.0 Hz, H5), 4.42 anti (t, 1H,
J = 8.9 Hz, H5), 5.29 anti (dd, 1H, J = 7.8, 4.25 Hz, H7), 5.27
syn (d, 1H, J = 3.1 Hz, H7), 6.27 (s, 1H, Ar), 6.33 (d, 1H,
J = 7.1 Hz, Ar), 6.59 (d, 1H, J = 8.1 Hz, Ar), 6.72 (m, 1H, Ar),
6.82 (m, 1H, J = 8.2 Hz, Ar), 7.39 (d, 1H, J = 8.5 Hz, Ph), 7.55
(d, 1H, J = 8.6 Hz, Ph), 7.60 (m, Ph), 8.11 (d, 1H, J = 8.7 Hz,
Ph), 8.22 (d, 1H, J = 8.6 Hz, Ph), 8.28 (m, Ph), 8.41 (d, 1H,
J = 8.5 Hz, Ph). IR (film) ν 3520 (OH), 1760 (lactone) cm–1.
ESI-Mass m/z: 488 [M + Na]+. Anal. Calcd for C20H21NO7: C,
62.01; H, 5.46. Found: C, 62.15; H, 5.31.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet