Stereoselective synthesis of 2-aryltetrahydrofuran-3,4-dicarboxylate derivatives: Efficient approach to tetrahydrofuran lignans

Article abstract of DOI:10.1055/s-2000-8725

A convenient and stereoselective synthetic route to the precursor of natural products, lignans, containing tetrahydrofuran has been developed. A series of asymmetric 2-aryltetrahydrofuran-3,4-carboxylic acid derivatives were synthesized in high yields wit

Full text of DOI:10.1055/s-2000-8725

PAPER
2069
Stereoselective Synthesis of 2-Aryltetrahydrofuran-3,4-dicarboxylate
Derivatives: Efficient Approach to Tetrahydrofuran Lignans
Weiwei Pei,a* Jian Pei,a,b * Shaohui Li,a Xiulin Yea
aDepartment of Chemistry, Peking University, Beijing 100871, People’s Republic of China
bInstitute for Polymers and Organic Solids, University of California at Santa Barbara, CA 93106, U.S.A.
Fax +658727528; E-mail: j-pei@imre.org.sg
Received 27 September 1999; revised 10 August 2000
2-Aryltetrahydrofuran-3,4-dicarboxylates 2 are key start-
ing materials in the synthesis of these natural products
containing tetrahydrofuran rings. Compounds 2 could
also be the precursors for some natural products, such as
Abstract: A convenient and stereoselective synthetic route to the
precursor of natural products, lignans, containing tetrahydrofuran
has been developed. A series of asymmetric 2-aryltetrahydrofuran-
3,4-carboxylic acid derivatives were synthesized in high yields with
this route. The effect of substituents on the Diels-Alder reaction of lactones, substituted tetrahydrofurans, aryl substituted
aryl-substituted oxazoles with alkyne dienophile and on the catalyt-
3,7-dioxabicyclo[3.3.0]octanes 1, and so forth (Scheme
ic hydrogenation of dimethyl 2-arylfuran-3, 4-dicarboxylates has
1). In this contribution, a stereoselective and straightfor-
been investigated. The regioselective hydrolyses of the dimethyl es-
ward method for the preparation of 2-aryltetrahydrofuran-
ter group was also studied. All products were characterized by ele-
3,4-dicarboxylate derivatives 2 was developed. The syn-
thetic route to 2-arylfuran-3, 4-dicarboxylate esters
through the Diels-Alder reactions of 2-aryl-1,3,4-oxadia-
zoles, 2-alkyl (or aryl)-4,5-diphenyloxazoles or 2-aryl-4-
phenyloxazoles as the dienes with dimethyl acetylenedi-
carboxylate (DMAD) as the dienophile was studied. The
effect of substituted groups on the oxazole ring upon the
Diels-Alder reactions was also investigated. In addition,
the stereoselective catalytic hydrogenation of the furan
ring and regioselective hydrolysis of dimethyl ester
groups were demonstrated.
mental analysis, FT-IR, 1H NMR and MS.
Key words: stereoselectivity, Diels-Alder reactions, hydrogena-
tion, hydrolysis, furans
As a major group of natural products, lignans, which
widely exist in all parts of various plants, is still receiving
considerable interest due to their special biological prop-
erties. They present significant activities, such as anti-tu-
mor, antimitotic, antiviral activities and inhibition of
specific enzymes.1 Recently, some derivatives of podo-
phyllotoxin have been used in the clinic. Among the fam-
ily of lignans, 2-aryl, 2,5-diaryltetrahydrofuran and aryl-
substituted 3,7-dioxabicyclo[3.3.0]octane 1 (aryl = 3,4-
methenedioxyphenyl, 3,4-dimethoxyphenyl, 3,4,5-tri-
methoxyphenyl, etc.) are quite interesting and their syn-
thesis has attracted considerable attention.2-13
The Diels-Alder reaction is a very useful organic synthet-
ic method. The preparation of heterocyclic compounds
utilizing 1,3,4-oxadiazole and oxazole compounds
through a tandem Diels-Alder reaction and reverse Di-
els-Alder reaction has been investigated.14-20 Furan com-
pounds can be prepared in high yields through the reaction
Scheme 1
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2070
W. Pei et al.
PAPER
of oxadiazoles with alkenes or alkynes that contain angle The synthetic route to tetrahydrofuran derivatives is
strain or are electron-rich.21 Initially, substituted 1,3,4-ox- shown in Scheme 3. Aryl-substituted oxazoles were em-
adiazoles were selected as diene because they are easily ployed in place of 1,3,4-oxadizoles. The reaction of
prepared. Following known reaction conditions, the neat 2,4-diphenyloxazole 3a with DMAD afforded dimethyl
reaction between 2-phenyl-1,3,4-oxadiazole and dimethyl 2-phenylfuran 3,4-dicarboxylate 4a in a very high yield
acetylenedicarboxylate at 140-150 °C for 70 hours gave under the same conditions as used in the reaction of oxa-
dimethyl 2-phenylfuran-3,4-dicarboxylate in only 10% diazoles with DMAD. The results indicate that the reac-
yield (Scheme 2). However, no desired furan products tivity of the oxazoles towards DMAD is higher than that
were obtained under the same conditions using some of 1,3,4-oxadiazoles towards DMAD. In order to under-
1,3,4-oxadiazole derivatives with strong electron-donat- stand the effect of the substituents of the oxazole ring on
ing or strong electron-withdrawing groups attached onto the reaction, different substituted oxazoles were prepared
the phenyl ring. Even after increasing the reaction temper- as starting materials.22,23 All the results are shown in Table
ature to over 200 °C, no desired product was found. In- 2. When two phenyl groups were attached at the C-2 and
stead, dimethyl acetylenedicarboxylate was easily C-4 positions of the oxazole ring, compound 3a, the yield
polymerized under the high reaction temperatures to yield of 4a was 98%. However, when the two phenyl groups
an oil or a gum. This is probably due to the fact that the were at the C-4 and C-5 positions of the oxazole ring,
dienophilicity of dimethyl acetylenedicarboxylate to- compound 3e, the yield of 4e was decreased to 62%. The
wards the 1,3,4-oxadiazoles with aryl-substituted groups noticeable lower reaction yield of 4e compared with that
is low. All results are outlined in Table 1.
of compound 4a may be attributed to the steric hindrance
arising from the two close phenyl groups, which is larger
Reagents and conditions: i) DMAD, hydroquinone, Na2CO3, 150 °C; ii) -N2
Scheme 2
Table 1 Results of the Diels−Alder Reactions of 2-Aryl-Substituted 1,3,4-Oxadiazoles
R
H
p-MeO
o-HO
p-CH3
p-Br
p-Cl
o-I
o-Cl
o-F
m-N2O
Yield %
10
trace
trace
trace
trace
trace
0
0
0
0
Reagents and conditions: i) DMAD, hydroquinone, Na2CO3; ii) -PhCN; iii) -H2, Pd/C; iv) KOH, MeOH/H2O
Scheme 3
Synthesis 2000, No. 14, 2069–2077 ISSN 0039-7881 © Thieme Stuttgart · New York

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Stereoselective Synthesis of 2-Aryltetrahydrofuran-3,4-dicarboxylate Derivatives
2071
and high reaction temperature.24 However, under such
conditions, the phenyl ring may also be hydrogenated to
form cyclohexyl ring. After the investigation for different
reaction conditions, as shown in Scheme 4, dimethyl
2-aryltetrahydrofuran-3,4-dicarboxylates 5 were obtained
by using 4-5 mol% Pd-C catalyst under 100 MPa of hy-
drogen atmosphere at 100 °C for 4 hours without hydro-
genation of the phenyl ring. Since there are three
asymmetric carbons in the hydrogenated products, the re-
sulting stereoselectivity of the products are outlined in Ta-
ble 3. It can be seen that corresponding to the different
substituents on compounds 4, the 2,3-cis-3,4-cis com-
pounds are always the main products under our experi-
mental conditions, but the stereoselectivity does depend
on the substituents on compounds 4. When the substituent
in C-2 position of the furan ring was the benzene ring,
compound 4a, the product was pure 2,3-cis-3,4-cis com-
pound 5a¢. If the attached benzene group is substituted,
the isomer, 2,3-cis-3,4-trans compound appeared. The ra-
tios of these isomers, which were separated by flash col-
Table 2 Yields of Compounds 4a-g by the Diels-Alder Reactions
of Compounds 3a-g with or without Solvent
Compounds 4
Yieldsa Yieldsb
%
%
4a: R1 = H, R2 = Ph
98
94
88
88
62
32
21
98
98
98
96
65
37
23
4b: R1 = H, R2 = 3,4-methylenedioxyphenyl
4c: R1 = H, R2 = 3,4-dimethyoxyphenyl
4d: R1 = H, R2 = 3,4,5-trimethoxyphenyl
4e: R1 = Ph, R2 = H
4f: R1 = Ph, R2 = Me
4g: R1 = Ph, R2 = Ph
a Neat reaction.
b Xylene as solvent.
in compound 3e than that in compound 3a. In addition, umn chromatography, are shown in Table 3. The ratios of
since two phenyl groups on the C-2 and C-4 positions of the compounds 5¢b-d and 5¢¢b-d are approximately 2 to
the oxazole ring can rotate freely, while they cannot freely 1.
rotate on the C-4 and C-5 positions, the torsion angle be-
tween the phenyl and oxazole rings of 4,5-diphenylox-
azole will be larger than that of 2,4-diphenyloxazole.
When the third phenyl group was introduced onto the C-2
The relative configurations of the hydrogenation prod-
ucts, 5d¢ and 5d¢¢ were determined by X-ray diffraction
(Figure). The configurations of other compounds were
1
further confirmed through the comparison of H NMR
position of 4,5-diphenyloxazole 3g, the yield of the furan
spectra of compounds 5¢d and 5¢¢d. Comparison of the 1H
was further lowered. Thus, 2,4,5-triphenyloxazole 3g
NMR data of the furan ring of all the hydrogenation prod-
ucts is summarized in Table 4. The chemical shifts of pro-
gave the lowest yield of 21%, for compound 4g.
Most of the Diels-Alder reactions were exothermic, which tons on the tetrahydrofuran ring, especially the protons on
made the temperature of neat reactions difficult to control. the C-3 and C-4 positions of the tetrahydrofuran rings in
In our reactions, the temperature could reach over 220 °C 5b¢-d¢ are remarkably different from those in 5b¢¢-d¢¢.
even though heating was discontinued after the reaction The chemical shifts of the protons on the tetrahydrofuran
was irradiated. In order to investigate the effect of the sol- ring of compounds 5a¢-c¢ were in agreement with those of
vent on the Diels-Alder reactions and to prevent dimethyl compound 5d¢, and the chemical shifts of the protons on
acetylenedicarboxylate from polymerizing, xylene was the tetrahydrofuran ring of compounds 5b¢¢-c¢¢ were also
selected as the solvent because its boiling point is close to in agreement with those of compound 5d¢¢. It is evident
the reaction temperature. The results are outlined in Table that the compounds 5a¢-c¢ were all obtained in the 2,3-
2. The comparison of the yields with those obtained in cis-3,4-cis configuration, while compounds 5b¢¢ and 5c¢¢
neat reactions suggests that the utilization of this solvent were also obtained in the form of 2,3-cis-3,4-trans isomer.
is not important for these Diels-Alder reactions.
The results of the 1H NMR data and the X-ray diffraction
data suggest that the catalytic hydrogenation reaction is a
1,2-cis-addition mechanism of 2, 3 positions and 4, 5 po-
sitions at the furan ring, respectively, and not a 1,4-addi-
tion mechanism.
The furan ring of the above products can be readily satu-
rated to yield tetrahydrofuran without ring opening
through catalytic hydrogenation in methanol in the pres-
ence of 5% Pd-C catalyst under low hydrogen pressure
Scheme 4
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Table 3 Yields of Coumpounds 5a-d by Catalytic Hydrogenation of
Compounds 4a-d
KOH solution in methanol and water were used. Monom-
ethyl 2-aryltetrahydrofuran-3-carboxylate-4-carboxylic
acid 2 were obtained by selective hydrolysis of com-
pounds 5 with 2 equivalents of KOH-H2O-MeOH solu-
tion for 8 hours at room temperature. The results are
shown in Table 5. The configuration of the hydrolysis
products of compounds 5b¢¢-d¢¢¢¢, compounds 2b¢¢-d¢¢,
was 2,3-cis-3,4-trans, which was the same as of their
starting materials. It indicated that the configuration of
compounds 5 remained unchanged during the hydrolysis.
However, the hydrolysis products of dl-2,3-cis-3,4-cis
compounds 5b¢-d¢, compounds 2b¢-d¢, were mixtures of
2,3-cis-3,4-trans and 2,3-cis-3,4-cis compounds. The
Compounds 4
Yields Ratios of Compounds
%
5′ and 5′′
4a: R1 = R2 = R3 = H
91
76
71
83
100/0
4b: R1 = H, R2, R3 = OCH2O
4c: R1 = H, R2 = R3 = MeO
4d: R1 = R2 = R3 =MeO
72/28
67/33
67/33
The hydrolysis of compounds 5 was also investigated configurations of most of the dl-2,3-cis-3,4-cis com-
(Scheme 5). Because of the effect of the aryl group on the pounds were converted 2,3-cis-3,4-cis compounds. The
tetrahydrofuran ring, the two ester groups have different two isomers were easily separated by flash column chro-
1
reactivity. The H NMR chemical shifts of the methyl matography. The ratios were determined to be approxi-
group of the esters on the C-3 position of the tetrahydro- mately 3 to 1. This proved that 2,3-cis-3,4-trans
furan ring are about 3.1-3.3 ppm, while those of the other compounds are more stable than 2,3-cis-3,4-cis com-
methyl group on the C-4 position are about 3.70 ppm. pounds. A comparison of the 1H NMR chemical shifts of
Some different bases, such as metal hydroxides and car- the remaining methyl ester group of the hydrolysis prod-
bonate salts, were employed. When 6 equivalents of KOH ucts with those of compounds 5 are shown in Table 6. The
solution in methanol and water was employed, com- comparison indicated that only the ester group on the 4
pounds 5 were hydrolyzed to 2-aryltetrahydrofuran-3,4- position of the tetrahydrofuran ring was hydrolyzed under
dicarboxylic acid. Other bases did not give ideal results. these conditions. The chemical shifts of the methyl group
In order to obtain compounds 2, different equivalents of
Figure
Table 4 1H NMR Data (400 MHz, CDCl3) for Protons on the THF Ring of Compounds 5
Compounds
H-2 (d, ppm)
H-3 and H-4 (d, ppm)
H-5 (d, ppm)
H-5 (d, ppm)
5a′
5.25 (d, J = 1.2 Hz)
5.14 (d, J = 5.42 Hz)
5.15 (d, J = 8.04 Hz)
5.18 (d, J = 5.36 Hz)
5.16 (d, J = 8.40 Hz)
5.16 (d, J = 5.04 Hz)
5.12 (d, J = 7.84 Hz)
3.54-3.60 (m)
3.53-3.55 (m)
3.66-3.77 (m)
3.54-3.61 (m)
3.67-3.79 (m)
3.57-3.61 (m)
3.67-3.76 (m)
4.30-4.35 (m)
4.28-4.30 (m)
3.92-3.96 (m)
4.28-4.33 (m)
3.93-3.97 (m)
4.29-4.31 (m)
3.94-3.98 (m)
4.64-4.68 (m)
4.60-4.62 (m)
4.53-4.58 (m)
4.64-4.68 (m)
4.56-4.60 (m)
4.64-4.66 (m)
4.59-4.60 (m)
5b′
5b′′
5c′
5c′′
5d′
5d′′
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Stereoselective Synthesis of 2-Aryltetrahydrofuran-3,4-dicarboxylate Derivatives
2073
Reagents and conditions: i) KOH/MeOH/H2O
Scheme 5
Dimethyl 2-Substituted- and 2,5-Disubstituted Furan-3,4-di-
of the ester on the 3-position of the hydrolysis products
are similar to those of compounds 5.
carboxylates 4e-f: General Procedure
Method 1
A mixture of 2-substituted-4,5-diphenyloxazole (0.020 mol), dime-
thyl acetylene dicarboxylate (3.268 g, 0.023 mol), anhyd Na2CO3
(0.530 g, 0.005 mol) and p-hydroquinone (0.055 g, 0.0005 mol) was
degassed three times, and then was stirred and heated at 150-
160 °C for 8 h under N2 atm. After the mixture was cooled, a mix-
ture of Et2O (50 mL) and H2O (20 mL) was added. The organic lay-
er was separated and the aqueous layer was extracted thrice with
Et2O. The combined extracts were washed with H2O, sat. NaHCO3,
and brine, and then dried (Na2SO4). Evaporation of the solvent gave
the crude products, which were purified by column chromatography
(CH2Cl2) giving the title compounds (yields: 21-62%) as crystals.
In summary, a series of optical active 2-arylterahyfuran-
3,4-carboxylic acid derivatives have been synthesized in
high yields. They are important intermediates in the syn-
thesis of lignans natural products. It was found that the di-
enophilic activity of DMAD towards oxazole compounds
is higher than that towards1,3,4-oxadiazole compounds
and the steric-hindrance of oxazole compounds may af-
fect the yield of the Diels-Alder reactions. The hydroge-
nation of the furan derivatives gave two isomers, which
could be separated. Their configurations were confirmed
by X-ray diffraction and proton NMR spectroscopy. The
substituents on the tetrahydrofuran rings can affect the hy-
drolyses of the methyl ester groups.
Method 2
After a mixture of 2-substituted-4,5-diphenyloxazole (0.020 mol),
dimethyl acetylene dicarboxylate (3.126 g, 0.022 mol), anhyd
Na2CO3 (0.530 g, 0.005 mol) and p-hydroquinone (0.033 g,
0.0003 mol) was degassed three times, dry xylene (25 mL) was add-
ed through a syringe. The solution was stirred and heated to gentle
reflux for 8 h. The mixture was cooled and the work-up procedure
was as above. The yields were 23-65%.
Mps were measured using a Yanaco MP-500 melting point appara-
tus and are uncorrected. IR measurements were made on KBr
pressed pellets or neat on a 75 IR spectrophotometer. 1H NMR spec-
tra were obtained with a ARX-400 NMR instrument and all samples
were dissolved in CDCl3. Chemical shifts (d) were reported in ppm
downfield relative to TMS. Mass spectral analyses were carried out
on a VG-ZAB-HS mass spectrometer. Reagents and solvents were
purified in the usual ways.
Dimethyl 2-Phenylfuran-3,4-dicarboxylate [4e (=4a)]
White needles; mp: 71-73 °C.
IR (KBr): n = 2980, 1720, 1420, 1280, 1160, 770, 690 cm-1.
1H NMR (400 MHz, CDCl3): d = 3.85 (s, 3H, -OCH3), 3.90 (s, 3H,
-OCH3), 7.35-7.67 (m, 5H, Ar-H), 7.96 (s, 1H, Fur-H).
Table 5 Yields of Compounds 2 by the Hydrolysis Reaction of
Compounds 5
EIMS: m/z (%) = 260 (M+), 229 (M+-OCH3, 100%), 105 (PhCO+),
77 (Ph+).
Reactants Products
Yield (%) Ratios of Compounds
Anal. Calcd. for C14H12O5: C, 64.61; H, 4.65. Found: C, 64.67; H,
4.61.
2′′ and 2′
5b′
5b′′
5c′
5c′′
5d′
5d′′
2b′ and 2b′′
2b′′
2c′ and 2c′′
2c′′
2d′ and 2d′′
2d′′
80
95
85
94
80
97
74/26
100/0
76/24
100/0
77/23
100/0
Dimethyl 2-Methyl-5-phenylfuran-3,4-dicarboxylate (4f)
White needles; mp: 76-77 °C.
IR (KBr): n = 2960, 1720, 1460, 830, 765, 695 cm-1.
1H NMR (400 MHz, CDCl3): d = 2.62 (s, 3H, -CH3), 3.85 (s, 3H, -
OCH3), 3.90 (s, 3H, -OCH3), 7.25-7.75 (m, 5H, Ar-H).
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W. Pei et al.
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Table 6 Comparison of the 1H NMR shifts (400 MHz, CDCl3; d, ppm) of the Methyl Ester Groups of Compounds 5 and 2
5b¢
2b¢
5b¢¢
2b¢¢
5c¢
2c¢
5c¢¢
2c¢¢
5d¢
2d¢
5d¢¢
2d¢¢
3–OCH3
4–OCH3
3.33
3.69
3.33
–
3.31
3.75
3.33
–
3.28
3.70
3.28
–
3.25
3.75
3.27
–
3.29
3.70
3.29
–
3.27
3.75
3.29
–
EIMS: m/z (%) = 274 (M+), 242 [(M-32)+, 100%], 105 (PhCO+), 77
IR (KBr): n = 2960, 2880, 1720, 1480, 1440, 1210, 1030, 860, 815,
(Ph+).
760, 710 cm-1.
Anal. Calcd for C15H14O5: C, 65.69; H, 5.15. Found: C, 65.71; H,
5.10.
1H NMR (400 MHz, CDCl3): d = 3.85 (s, 3H, -OCH3), 3.90 (s, 3H,
-OCH3), 6.00 (s, 2H, -OCH2O-), 6.84-7.27 (m, 3H, Ar-H), 7.91 (s,
1H, Fur-H).
EIMS: m/z (%) = 304 (M+, 100), 289 (M-CH3)+, 273 (M-OCH3)+.
Dimethyl 2,5-Diphenylfuran-3,4-dicarboxylate (4g)
White needles; mp = 101-103 °C.
IR (KBr): n = 2940, 1710, 1460, 820, 760, 795 cm-1.
1H NMR (400 MHz, CDCl3): d = 3.85 (s, 6H, -OCH3), 7.40-7.88
(m, 10H, Ar-H).
Anal. calcd for C15H12O7: C, 59.21; H, 3.98. Found: C, 59.17; H,
4.03.
Dimethyl 2-(3,4-Dimethoxyphenyl)furan-3,4-dicarboxylate (4c)
White needles; mp: 102-103 °C.
EIMS: m/z (%) = 336 (M+), 305 (M-OCH3)+, 105 (100), 77.
IR (KBr): n = 2960, 1740, 1710, 1600, 1510, 1450, 1260, 1130, 840,
Anal. Calcd for C20H16O5: C, 71.42; H, 4.80. Found: C, 71.22; H,
4.75.
805, 760, 705 cm-1.
1H NMR (400 MHz, CDCl3): d = 3.86 (s, 3H, -OCH3), 3.90 (s, 3H,
-OCH3), 3.92 (s, 3H, -OCH3), 3.93 (s, 3H, -OCH3), 6.90-7.34 (m,
3H, Ar-H), 7.93 (s, 1H, Fur-H).
Dimethyl 2-arylfuran-3,4-dicarboxylates, 4a-d: General Proce-
dure
EIMS: m/z (%) = 320 (M+, 100), 305 (M-CH3)+, 289 (M-OCH3)+.
Method 1
Anal. Calcd for C16H16O7: C, 60.00; H, 5.04. Found: C, 59.98; H,
5.07.
A mixture of 2-aryl-4-phenyloxazole (0.020 mol), dimethyl acety-
lene dicarboxylate (3.268 g, 0.023 mol), anhyd Na2CO3 (0.530 g,
0.005 mol) and p-hydroquinone (0.055 g, 0.0005 mol) was degassed
three times, then stirred, and gently heated at 140-145 °C for 8 h
under N2 atm. After the mixture was cooled, a mixture of Et2O
(50 mL) and H2O (20 mL) was added, the organic layer was sepa-
rated and the aqueous layer was extracted thrice with Et2O. The
combined extracts were washed with H2O, sat. NaHCO3 and brine,
and then dried (Na2SO4). Evaporation of the solvent gave the crude
products that were purified by recrystallization from 95% EtOH to
give needle crystals (yields: 88-98%).
Dimethyl 2-(3,4,5-Trimethoxyphenyl)furan-3,4-dicarboxylate
(4d)
White plate crystals; mp: 150.5-152 °C.
IR (KBr): n = 1730, 1715, 1580, 1505, 1350, 1290, 1250,
1210,1130, 1070, 1005, 860, 815, 770, 710 cm-1.
1H NMR (400 MHz, CDCl3): d = 3.87-3.91 (m, 15H, -OCH3), 7.03
(s, 2H, Ar-H), 7.95 (s, 1H, Fur-H).
EIMS: m/z (%) = 350 (M+, 100), 335 (M-CH3)+, 319 (M-OCH3)+,
307 (M-CH3CO)+.
Method 2
After the mixture of 2-aryl-4-phenyloxazole (0.020 mol), dimethyl
acetylene dicarboxylate (3.126 g, 0.022 mol), anhyd Na2CO3
(0.530 g, 0.005 mol) and p-hydroquinone (0.033 g, 0.0003 mol) was
degassed for three times, dry xylene (25 mL) was added through a
syringe. The solution was stirred and heated to gently reflux for 8 h.
The mixture was cooled and the work-up procedure was as above.
The crude products were filtered and recrystallized from 95% EtOH
to give needle crystals (yields: 96-98%).
Anal. Calcd for C17H18O8: C, 58.28; H, 5.18. Found: C, 58.24, H,
5.29.
Dimethyl 2-Aryltetrahydrofuran-3,4-dicarboxylate 5: General
Procedure
Dimethyl 2-arylfuran-3,4-dicarboxylate (0.01 mol), 10% Pd-C cat-
alyst (0.5 g) and anhyd MeOH (60 mL) were added in an autoclave.
The autoclave was degassed three times, then filled with H2 to
100 MPa pressure. The mixture was stirred and heated to 100 °C
for 4 h. After cooling and releasing the pressure, the catalyst was fil-
tered, and the solvent was removed in vacuo. The products were pu-
rified by recrystallization from MeOH or separated by flash column
chromatography [(EtOAc/petroleum ether (60-90 °C), 1:2.5].
Dimethyl 2-Phenylfuran-3,4-dicarboxylate [4a (=4e)]
White needles; mp: 71-73 °C.
IR (KBr): n = 2980, 1720, 1420, 1280, 1160, 770, 690 cm-1.
1H NMR (400 MHz, CDCl3): d = 3.85 (s, 3H, -OCH3), 3.90 (s, 3H,
-OCH3), 7.35-7.67 (m, 5H, Ar-H), 7.96 (s, 1H, Fur-H).
Dimethyl 2-Phenyltetrahydrofuran-3,4-dicarboxylate (5a)
White needles; yield: 91.2%; mp: 91-93 °C.
IR (KBr): n = 2920, 1730, 1430, 1320, 1250, 1010, 750, 700 cm-1.
1H NMR (400 MHz, CDCl3): d = 3.17 (s, 3H, -OCH3), 3.54-3.60
(m, 2H, -C3H-, -C4H-), 3.69 (s, 3H, -OCH3), 4.30-4.35 (m, 1H,
-OC5H-), 4.64-4.68 (m, 1H, -OC5H-), 5.25-5.26 (d, 1H, J = 1.2
Hz, -OC2H-), 7.26-7.32 (m, 5H, Ph-H).
EIMS: m/z (%) = 264 (M+), 232 (M-CH3OH)+, 204, 145, 127, 99
(100).
EIMS: m/z (%) = 260 (M+), 229 [(M-OCH3)+, 100], 105 (PhCO+),
77 (Ph+).
Anal. Calcd. for C14H12O5: C, 64.61; H, 4.65. Found: C, 64.67; H,
4.61.
Dimethyl 2-(3,4-Methylenedioxyphenyl)furan-3,4-dicarboxy-
late (4b)
White needles; mp: 101-103 °C.
Synthesis 2000, No. 14, 2069–2077 ISSN 0039-7881 © Thieme Stuttgart · New York

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Stereoselective Synthesis of 2-Aryltetrahydrofuran-3,4-dicarboxylate Derivatives
2075
Anal. Calcd for C14H16O5: C, 63.62; H, 6.10. Found: C, 63.66; H,
6.05.
Anal. Calcd for C16H20O7: C, 59.25; H, 6.22. Found: C, 59.20, H,
6.28.
Dimethyl 2-(3,4-Methylenedioxyphenyl)tetrahydrofuran-3,4-
dicarboxylate (5b)
Dimethyl 2-(3,4,5-Trimethoxyphenyl)tetrahydrofuran-3,4-di-
carboxylate (5d)
White solid; yield: 76%.
White solid; yield: 83%.
EIMS: m/z (%) = 308 (M+), 278 (M-CH2O)+, 189, 149, 127, 99
(100).
EIMS: m/z (%) = 354 (M+, 100), 339 (M-CH3)+, 323 (M-OCH3)+,
236.
dl-2,3-cis-3,4-cis-Dimethyl 2-(3,4-Methylenedioxyphenyl)tet-
rahydrofuran-3,4-dicarboxylate (5b¢)
White needles; content: 72% of 76%; mp: 96-97 °C.
dl-2,3-cis-3,4-cis-Dimethyl 2-(3,4,5-Trimethoxyphenyl)tetrahy-
drofuran-3,4-dicarboxylate (5d¢)
White needles; content: 67% of 83%; mp: 96-97 °C.
IR (KBr): n = 2960, 1730, 1500, 1440, 1240, 1030, 930, 870, 810
IR (KBr): n = 2980, 1720, 1580, 1500, 1470, 1435, 1370, 1220,
cm-1.
1120, 1000 cm-1.
1H NMR (400 MHz, CDCl3): d = 3.33 (s, 3H, -OCH3), 3.53-3.55
(m, 2H, -C3H-, -C4H-), 3.69 (s, 3H, -OCH3), 4.28-4.30 (m, 1H, -
OC5H-), 4.60-4.62 (m, 1H, -OC5H-), 5.14-5.16 (d, 1H, J = 5.42
Hz, -C2H-), 5.94 (s, 2H, -OCH2O-), 6.77-6.80 (m, 3H, Ar-H).
1H NMR (400 MHz, CDCl3): d = 3.29 (s, 3H, -OCH3), 3.57-3.61
(m, 2H, -C3H-, -C4H-), 3.70 (s, 3H, -OCH3), 3.85 (s, 9H, Ar-OCH3),
4.29-4.31 (m, 1H, -OC5H-), 4.64-4.66 (m, 1H, -OC5H-), 5.16-
5.17 (d, 1H, J = 5.04 Hz, -C2H-), 6.55 (s, 2H, Ar-H).
Anal. Calcd for C15H16O7: C, 58.44; H, 5.23. Found: C, 58.42; H,
5.18.
Anal. Calcd for C17H22O8: C, 57.62; H, 6.26. Found: C, 57.47; H,
5.79.
dl-2,3-cis-3,4-trans-Dimethyl 2-(3,4-Methylenedioxyphenyl)tet-
rahydrofuran-3,4-dicarboxylate (5b¢¢)
White rhombohedron crystals; content: 28% of 76%; mp: 55-
56 °C.
dl-2,3-cis-3,4-trans-Dimethyl 2-(3,4,5-Trimethoxyphenyl)tet-
rahydrofuran-3,4-dicarboxylate (5d¢¢)
White plate crystals; content: 33% of 83%; mp: 83-85 °C.
IR (KBr): n = 2980, 1720, 1590, 1500, 1435, 1370, 1220, 1120,
IR (KBr): n = 2960, 2880, 1720, 1500, 1440, 1250, 1170, 1030, 930,
1000 cm-1.
865, 820 cm-1.
1H NMR (400 MHz, CDCl3): d = 3.27 (s, 3H, -OCH3), 3.67-3.76
(m, 2H, -C3H-, -C4H-), 3.75 (s, 3H, C4-CO2CH3), 3.82-3.85 (s, 9H,
3 (Ar-OCH3), 3.94-3.98 (m, 1H, -OC5H-), 4.59-4.60 (m, 1H, -
OC5H-), 5.13-5.15 (d, 1H, J = 7.84 Hz, -C2H-), 6.52 (s, 2H, Ar-H).
1H NMR (400 MHz, CDCl3): d = 3.31 (s, 3H, -OCH3), 3.66-3.77
(m, 2H, -C3H-, -C4H-), 3.75 (s, 3H, -OCH3), 3.92-3.96 (m, 1H, -
C5H-), 4.53-4.58 (m, 1H, -OC5H-), 5.15-5.17 (d, 1H, J = 8.04 Hz,
-C2H-), 5.94 (s, 2H, -OCH2O-), 6.75-6.77 (m, 3H, Ar-H).
Anal. Calcd for C17H22O8: C, 57.62; H, 6.26. Found: C, 57.47; H,
5.79.
Anal. Calcd for C15H16O7: C, 58.44; H, 5.23. Found: C, 58.40; H,
5.20.
Monomethyl 2-Aryltetrahydrofuran-3-carboxylate-4-carboxyl-
ic acid 2: General Procedure
Dimethyl 2-(3,4-Dimethoxyphenyl)tetrahydrofuran-3,4-dicar-
boxylate (5c)
White needles; yield: 71%.
EIMS: m/z (%) = 324 (M+, 100), 309 (M-CH3)+, 293 (M-OCH3)+,
261, 205, 165, 127, 97.
(1) Hydrolysis of dl-2,3-cis-3,4-trans-Dimethyl 2-Aryltetrahy-
drofuran-3,4-dicarboxylate 5¢¢
After KOH (1.122 g, 0.02 mol) was dissolved in a mixture of MeOH
(20 mL) and deionized H2O (10 mL), 2,3-cis-3, 4-trans-dimethyl
2-aryltetrahydrofuran-3,4-dicarboxylate (0.01 mol) was added to
this solution. The mixture was stirred at r.t. for 6-8 h, then acidified
with concd HCl. The organic layer was extracted with Et2O and the
combined extract was washed with H2O, sat. NaHCO3, and brine.
After drying (MgSO4), the solvent was removed in vacuo. The res-
idue was purified by recrystallization from 60% MeOH to give
white crystals.
dl-2,3-cis-3,4-cis-Dimethyl 2-(3,4-Dimethoxyphenyl)tetrahy-
drofuran-3,4-dicarboxylate (5c¢)
White needles; content: 67% of 71%; mp: 103-104 °C.
IR (KBr): n = 2980, 1730, 1600, 1520, 1440, 1240, 1030, 865, 820,
760 cm-1.
1H NMR (400 MHz, CDCl3): d = 3.28 (s, 3H, -OCH3), 3.54-3.61
(m, 2H, -C3H-, -C4H-), 3.70 (s, 3H, -OCH3), 3.87 (s, 6H, -OCH3),
4.28-4.33 (m, 1H, -OC5H-), 4.64-4.68 (1H, m, -OC5H-), 5.18-
5.19 (d, 1H, J = 5.36 Hz, -C2H-), 6.80-6.88 (m, 3H, Ar-H).
dl-2,3-cis-3,4-trans-Monomethyl 2-(3,4-methylenedioxyphe-
nyl)tetrahydrofuran-3-carboxylate-4-carboxylic Acid (2b¢¢)
White needles; yield: 95%; mp: 119-121 °C.
Anal. Calcd for C16H20O7: C, 59.25; H, 6.22. Found: C, 59.23; H,
6.20.
IR (KBr): n = 3600 (b), 1720, 1695, 1500, 1440, 1330, 1240, 1190,
1170, 1030, 930, 875, 800, 650 cm-1.
1H NMR (400 MHz, CDCl3): d = 3.33 (s, 3H, -OCH3), 3.67-3.82
(m, 2H, -C3H-, -C4H-), 3.98-4.02 (m, 1H, -OC5H-), 4.57-4.61 (m,
1H, -OC5H-), 5.17-5.19 (d, 1H, J = 8.00 Hz, -C2H-), 5.94 (s, 2H, -
OCH2O-), 6.73-6.77 (m, 3H, Ar-H), 11.00-11.25 (br, 1H, -
COOH).
dl-2,3-cis-3,4-trans-Dimethyl 2-(3,4-Dimethoxyphenyl)tetrahy-
drofuran-3,4-dicarboxylate (5c¢¢)
White granular solid; content: 33% of 71%; mp: 38-40 °C.
IR (KBr): n = 2980, 1730, 1600, 1520, 1440, 1240, 1030, 865, 820,
760 cm-1.
EIMS: m/z (%) = 294 (M+), 261, 233, 190, 149, 99 (100).
1H NMR (400 MHz, CDCl3): d = 3.25 (s, 3H, -OCH3), 3.67-3.79
(m, 2H, -C3H-, -C4H-), 3.75 (s, 3H, -OCH3), 3.87 (s, 6H, -OCH3),
3.93-3.97 (m, 1H, -OC5H-), 4.56-4.60 (m, 1H, -OC5H-), 5.16-
5.18 (d, 1H, J = 8.40 Hz, -C2H-), 6.80-6.83 (m, 3H, Ar-H).
Anal. Calcd for C14H14O7: C, 57.14; H, 4.80. Found: C, 57.21; H,
5.11.
Synthesis 2000, No. 14, 2069–2077 ISSN 0039-7881 © Thieme Stuttgart · New York

2076
W. Pei et al.
PAPER
dl-2,3-cis-3,4-cis-Monomethyl 2-(3,4-Dimethoxyphenyl)tet-
rahydrofuran-3-carboxylate-4-carboxylic Acid (2c¢)
White needles; content: 20% of 85% (yield); mp: 156-158 °C.
dl-2,3-cis-3,4-trans-Monomethyl 2-(3,4-Dimethoxyphenyl)tet-
rahydrofuran-3-carboxylate-4-carboxylic Acid (2c¢¢)
White needles; yield: 94%; mp: 125-126.5 °C.
IR (KBr): n = 3200, 1740, 1695, 1505, 1460, 1420, 1320, 1245,
IR (KBr): n = 3310, 1730, 1700, 1500, 1380, 1280, 1250, 1120,
1200, 1130, 1070, 1010, 930, 795 cm-1.
1115, 960, 760 cm-1.
1H NMR (400 MHz, CDCl3): d = 3.27 (s, 3H, C3-CO2CH3), 3.67-
3.86 (m, 2H, -C3H-, -C4H-), 3.87-3.88 (s, 6H, Ar-OCH3), 4.00-
4.04 (m, 1H, -OC5H-), 4.60-4.64 (m, 1H, -OC5H-), 5.18-5.20 (d,
1H, J = 8.00 Hz,-C2H-), 6.81-6.85 (m, 3H, Ar-H), 7.40-9.80 (br,
1H, -COOH).
1H NMR (400 MHz, CDCl3): d = 3.28 (s, 3H, -OCH3), 3.54-3.67
(m, 2H, -C3H-, -C4H-), 3.87 (s, 6H, Ar-OCH3), 4.27-4.32 (m, 1H, -
OC5H-), 4.64-4.68 (m, 1H, -OC5H-), 5.19-5.20 (d, 1H, J = 5.60
Hz, -C2H-), 5.40-6.70 (b, 1H, -COOH), 6.80-6.87 (m, 3H, Ar-H).
EIMS: m/z (%) = 310 (M+, 100), 295, 278, 206, 165, 99.
EIMS: m/z (%) = 310 (M+, 100), 295, 279, 247, 206, 165, 99.
Anal. Calcd for C15H18O7: C, 58.06; H, 5.85. Found: C, 57.89; H,
5.84.
Anal. Calcd for C15H18O7: C, 58.06; H, 5.85. Found: C, 57.82; H,
5.86.
dl-2,3-cis-3,4-trans-Monomethyl 2-(3,4,5-Trimethoxyphe-
nyl)tetrahydrofuran-3-carboxylate-4-carboxylic Acid (2d¢¢)
Content: 62% of 80% (yield).
dl-2,3-cis-3,4-trans-Monomethyl 2-(3,4,5-Trimethoxyphe-
nyl)tetrahydrofuran-3-carboxylate-4-carboxylic Acid (2d¢¢)
White needles; yield: 97%; mp: 115.5-117 °C.
dl-2,3-cis-3,4-cis-Monomethyl 2-(3,4,5-Trimethoxyphenyl)tet-
rahydrofuran-3-carboxylate-4-carboxylic Acid (2d¢)
White needles; content: 18% of 80% (yield); mp: 156-158 °C.
IR (KBr): n = 3200, 1730, 1600, 1470, 1430, 1235, 1180, 1130, 990,
810 cm-1.
1H NMR (400 MHz, CDCl3): d = 3.29 (s, 3H, -OCH3), 3.69-3.80
(m, 2H, -C3H-, -C4H-), 3.78 (s, 3H, Ar-OCH3), 3.85 (s, 6H, Ar-
OCH3), 4.01-4.05 (m, 1H, -OC5H-), 4.61-4.66 (m, 1H, -OC5H-),
5.15-5.17 (d, 1H, J = 7.90 Hz, -C2H-), 6.55 (s, 2H, Ar-H), 6.90-
8.00 (br, 1H, -COOH).
IR (KBr): n = 3210, 1720, 1670, 1575, 1500, 1440, 1370, 1225,
1180, 1105, 1070, 970, 750, 670 cm-1.
1H NMR (400 MHz, CDCl3): d = 3.29 (s, 3H, OCH3), 3.56-3.68 (m,
2H, -C3H-, -C4H-), 3.82 (s, 3H, Ar-OCH3), 3.85 (s, 6H, Ar-OCH3),
4.28-4.32 (m, 1H, -OC5H-), 4.64-4.68 (m, 1H, -OC5H-), 5.17-
5.18 (d, 1H, J = 5.60 Hz, -C2H-), 6.52 (s, 2H, Ar-H), 9.16 (br, 1H,
-COOH).
EIMS: m/z (%) = 340 (M+, 100), 309, 281, 236, 181, 99.
Anal. Calcd for C16H20O8: C, 56.46; H, 5.92. Found: C, 56.18; H,
5.86.
EIMS: m/z (%) = 340 (M+, 100), 308, 281, 236, 195, 181, 99.
(2) Hydrolysis of dl-2,3-cis-3,4-cis-Dimethyl 2-Aryltetrahydro-
furan-3,4-dicarboxylate 5¢
Anal. Calcd for C16H20O8: C, 56.46; H, 5.92. Found: C, 56.18; H,
5.86.
After KOH (1.122 g, 0.02 mol) was dissolved in a mixture of MeOH
(20 mL) and deionized H2O (10 mL), 2,3-cis-3,4-trans-dimethyl
2-aryltetrahydrofuran-3,4-dicarboxylate (0.01 mol) was added to
this solution. The mixture was stirred at r.t. for 6-8 h, then acidified
with concd HCl. The organic layer was extracted with Et2O and the
combined extract was washed with H2O, sat. NaHCO3, and brine.
After drying (MgSO4), the solvent was removed under vacuum. The
residue of dl-2, 3-cis-3, 4-trans products and dl-2,3-cis-3, 4-cis
products were separated by flash column chromatography [EtOAc/
petroleum ether (60-90 °C, 1:2.5] to give two sets of white crystals.
Acknowledgement
This project was supported by the National Natural Science Found-
ation of China. The authors would like to thank Professor Qiyi Xing
for helpful discussions and advice.
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dl-2,3-cis-3,4-trans-Monomethyl 2-(3,4-Methylenedioxyphe-
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Content: 59% of 80% (yield).
(3) Sawyer, D. A.; Beams, R. M.; Blackwell, G. J.; Brockwell, M.
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dl-2,3-cis-3,4-cis-Monomethyl 2-(3,4-Methylenedioxyphe-
nyl)tetrahydrofuran-3-carboxylate-4-carboxylic Acid (2b¢)
White needles; content: 21% of 80% (yield); mp: 161-162 °C.
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EIMS: m/z (%) = 294 (M+), 261, 233, 189, 149, 99 (100).
Anal. Calcd for C14H14O7: C, 57.14; H, 4.80. Found: C, 56.85; H,
4.94.
dl-2,3-cis-3,4-trans-Monomethyl 2-(3,4-Dimethoxyphenyl)tet-
rahydrofuran-3-carboxylate-4-carboxylic Acid (2c¢¢)
Content: 65% of 85% (yield).
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Synthesis 2000, No. 14, 2069–2077 ISSN 0039-7881 © Thieme Stuttgart · New York

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Stereoselective Synthesis of 2-Aryltetrahydrofuran-3,4-dicarboxylate Derivatives
2077
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1437-210X,E;2000,0,14,2069,2077,ftx,en;M02699SS.pdf
Synthesis 2000, No. 14, 2069–2077 ISSN 0039-7881 © Thieme Stuttgart · New York