Synthesis of vulpinic and pulvinic acids from tetronic acid

Article abstract of DOI:10.1016/j.tet.2008.06.058

A common precursor, tetronic acid, was used in the synthesis of several vulpinic acids and pulvinic acids, which are pigments found in several lichens and mushrooms. The key features of this method are a two-step alkylidenation of benzyl tetronate and a Suzuki-Miyaura cross-coupling. The synthesis of several natural products, vulpinic acid, pinastric acid, xerocomic acid is described.

Full text of DOI:10.1016/j.tet.2008.06.058

Tetrahedron 64 (2008) 8930–8937
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of vulpinic and pulvinic acids from tetronic acid
1
*
´
Yann Bourdreux, Ewen Bodio, Catherine Willis, Celia Billaud, Thierry Le Gall , Charles Mioskowski
ˆ
CEA, iBiTecS, Service de Chimie Bioorganique et de Marquage, Bat. 547, 91191, Gif-sur-Yvette, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 22 April 2008
Received in revised form 11 June 2008
Accepted 16 June 2008
Available online 20 June 2008
A common precursor, tetronic acid, was used in the synthesis of several vulpinic acids and pulvinic acids,
which are pigments found in several lichens and mushrooms. The key features of this method are a two-
step alkylidenation of benzyl tetronate and a Suzuki–Miyaura cross-coupling. The synthesis of several
natural products, vulpinic acid, pinastric acid, xerocomic acid is described.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Natural products
Pulvinic acid
Vulpinic acid
Tetronic acid
Suzuki–Miyaura cross-coupling
1. Introduction
a cyclization to a bis(lactone), and by the selective opening of one
lactone ring that affords the pulvinic acid. The bis(lactone) can also
Pulvinic acids (1) and vulpinic acids (2, methyl esters of pulvinic
acids) are yellow and orange pigments found in lichens and in
mushrooms, which display various biological activities.1 Vulpinic
acid has been reported to display antimicrobial activity against
Gram-positive organisms.2 It displayed anti-inflammatory activity
in rats,3 but also caused hyperventilation in rats,3 cats, and guinea
pigs.4 Lichens containing vulpinic acid were employed in northern
Europe to poison wolves. The antiviral, antimicrobial, and antitu-
mor activities of pinastric acid were recently reported.5 Xerocomic
acid was reported as an inhibitor of HIV-1 integrase.6
be prepared by oxidation of a terphenylquinone.10 We recently
reported another process that makes use of the reaction of at least
2 equiv of silyl ketene acetal with oxalyl chloride,11 followed by
a base-mediated cyclization to the corresponding pulvinic acid
methyl ester. The access to non-symmetrical pulvinic acids cannot
be performed under such straightforward ways. The hydrolytic
cleavage of a non-symmetrical bis(lactone) leads to a mixture of
regioisomers.12 Various regioselective approaches have then been
reported.13 The key reactions in these approaches are Dieckmann
cyclizations of enol esters,13a alkylidenations of methyl 4-arylte-
tronates,13b Reformatsky-type reactions with arylmethoxymaleic
anhydrides,13c,d reactions of lithium enolates of arylacetic esters
with 4-alkylidene-1,3-dioxolan-4-ones,13e Wadsworth–Emmons
olefinations involving 2-aryl-4-methoxy-2(5H)-furanone phos-
Studies in our laboratory have shown that several pulvinic de-
rivatives have interesting antioxidant properties,7,8 and we thus
became interested in the synthesis of these compounds or their
analogs in a convergent, efficient fashion. Structurally, a pulvinic
acid is constituted by a
b-hydroxylated
a
,b
-unsaturated butyr-
phonates, and a
-oxoarylacetates.13f
olactone, which is substituted by an
methylidene bonded to a hydroxycarbonyl group and to an aryl
group.
Efficient processes have been reported for the access to sym-
metrical pulvinic acids (in which the two aryl groups are identical).
A classical example involves the reaction of 2 equiv of arylaceto-
nitrile anion with dialkyl oxalate,9,3 which is followed by
a
-aryl group, and by a
g
-
A palladium-mediated cross-coupling is particularly useful to
create a linkage between an aryl group and a double bond, it was
thus quite appropriate for the introduction of the aryl group
bonded on the lactone ring. This strategy, which made use of a tri-
flate such as 3, has been employed by us14 as well as by Langer
et al.15 for the preparation of several pulvinic acids (Scheme 1). It
was recently applied to the synthesis of norbadione A, a mushroom
pigment related to the pulvinic acids.16 The access to this triflate
relied on the Langer cyclocondensation of a bis(trimethylsilyloxy)-
diene on oxalyl chloride.17 We have then devised another approach,
which makes also use of a Suzuki–Miyaura cross-coupling18 as key
reaction, but which involves an iodide such as 4, which would
* Corresponding author. Tel.: þ39 1 6908 7105; fax: þ39 1 6908 7991.
E-mail address: thierry.legall@cea.fr (T. Le Gall).
1
Deceased on June 2007.
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.06.058

Y. Bourdreux et al. / Tetrahedron 64 (2008) 8930–8937
8931
OR'
Me3Si
R'O
SiMe3
OR
O
O
Cl
Cl
O
O
TfO
O
CO2R
Ar2
+
O
Ar2
OH
3
Ar1
O
CO2R
Ar2
O
OR'
OR'
O
CO2R
Ar2
1 (R = H)
2 (R = Me)
I
CO2R
Ar2
O
+
O
O
O
4
Scheme 1.
Table 1
Synthesis of compounds 7a–c, 8a–c, and 9a–c
be prepared via a two-step alkylidenation and an halogenation
from a protected form of tetronic acid.19
Herein, we report in detail the preparation of vulpinic and
pulvinic acids from tetronic acid following this general approach.20
Three iodides in which the exocyclic double bond is substituted by
a phenyl, a p-methoxyphenyl or a p-benzyloxyphenyl group have
been prepared and employed as intermediates. Several final com-
pounds are natural products. Hence, a formal synthesis of pulvinic
acid and the total synthesis of vulpinic acid, pinastric acid, and
xerocomic acid are described.
Entry
R
R0
Yield (%)
1
2
3
Me
Me
Bn
H
OBn
OBn
7a (67)
7b (62)
7c (36)
8a (88)
8b (91)
8c (100)
9a (78)
9b (73)
9c (65)
since the deshydratation conditions employed were efficient from
both isomers. Thus, using trifluoroacetic anhydride in the presence
of triethylamine and a catalytic amount of DMAP in methylene
chloride,22 alcohols 7a–c were converted efficiently to alkenes 8a–
c. These compounds were obtained mainly as E-stereomers, con-
taining 5–10% of the Z-stereomers, which proved to be difficult to
separate. The E-configuration of the major isomers was eventually
established by comparison of the spectroscopic properties of the
final products synthesized from them with known compounds.
Alkenes 8a–c were converted to the corresponding iodides 9a–c
in 65–78% yield by treatment with iodine and ammonium cer-
ium(IV) nitrate in acetonitrile.23 The reaction leading to 9a was
performed at 40 ꢁC. Preparation of compounds 9b and 9c at this
temperature led to some degradation of the products. These com-
pounds were eventually prepared at room temperature. Iodides
9a–c were thus obtained in four steps from tetronic acid.
The Suzuki–Miyaura cross-coupling of iodides 9a–c with several
arylboronates 11a–e was then performed in a THF/2 M aqueous
Na2CO3 refluxing mixture, using Pd(PPh3)2Cl2 as catalyst,24 as de-
scribed in the Scheme 3. These conditions were previously used for
the couplings involving triflates14 and were also found satisfactory
in the present case.
The results of the couplings are summarized in Table 2. The
expected adducts 12a–j were obtained in 55–93% yield after
chromatographic purification. In two cases, compounds 13 result-
ing from a cleavage of the benzyl enol ether function were also
obtained (entries 1 and 4). The debenzylation probably occurred
after the cross-coupling reaction. We had also observed such
debenzylation on some occasions in couplings involving triflates.14b
In compounds 12, the Z-isomer occurred in 6–12%.
2. Results and discussion
The preparation of the three iodides 9a–c started with the
conversion of tetronic acid to 4-benzyloxy-2(5H)-furanone
6
(Scheme 2, Table 1). Two methods were used for this purpose. Ei-
ther a Mitsunobu reaction with benzyl alcohol21 or an alkylation
with benzyl bromide in the presence of potassium carbonate led to
the expected compound, the latter method being more convenient
for large scale preparations. The reaction of the anion generated by
the treatment of 6 with butyllithium at ꢀ78 ꢁC in THF with
a-
oxoarylacetates 10a–c then led to alcohols 7a–c, which were
obtained as mixtures of diastereomers. The yield of alcohol 7c was
notably lower, perhaps because of the increased steric crowding in
that case. The diastereomers could be partially separated by silica
gel column chromatography. However, this was not necessary,
OBn
OH
OH
OBn
b
a
CO2R
O
O
O
O
O
O
R'
6
5
7a-c
OBn
OBn
I
CO2R
CO2R
c
d
The hydrogenolysis of the benzyl protecting groups of several
adducts 12a–c,i,j obtained by the cross-coupling reactions was then
performed by treatment under hydrogen (1 atm) over palladium on
charcoal (Scheme 4, Table 3).
O
O
O
O
R'
R'
8a-c
9a-c
The reaction of compound 12a in methylene chloride led to the
corresponding adduct, vulpinic acid 13a (entry 1). After 48 h, the
reaction was still incomplete. Chromatographic separation afforded
13a, isolated in 44% yield as pure E-isomer, and starting material
12a, recovered in 16% yield. The remaining minor Z-isomer was
easily removed by chromatography. The spectroscopic data of 13a
are in good agreement with those reported for vulpinic acid in the
literature.10b,c,13e,15a This also constitutes a formal synthesis of
pulvinic acid, which can be obtained by saponification of the ester
function of vulpinic acid.11 For the hydrogenolysis of compounds
O
7a, 8a, 9a, 10a: R = Me, R' = H
CO2R
7b, 8b, 9b, 10b: R = Me, R' = OBn
7c, 8c, 9c, 10c: R = Bn, R' = OBn
R'
10a-c
Scheme 2. Synthesis of iodides 9a–c. Reagents and conditions: (a) K2CO3, BnBr, DMF,
room temp, 12 h, 75% or BnOH, Ph3P, DEAD, room temp, 12 h, 85%; (b) (i) n-BuLi, THF,
ꢀ78 ꢁC, 20 min, (ii) Ketoester 10, ꢀ78 ꢁC to room temp, 12 h; (c) (CF3CO)2O, DMAP
(cat.), Et3N, CH2Cl2, 4 h, 0 ꢁC; (d) I2, CAN, CH3CN, 40 ꢁC, 4.5 h.

8932
Y. Bourdreux et al. / Tetrahedron 64 (2008) 8930–8937
R2
R2
R2
R1
R1
R1
OBn
OBn
OH
PdCl2(PPh3)2
I
CO2R
CO2R
CO2R
THF, 2 M aq. Na2CO3
O
+
+
B
O
80 °C, 2 h
O
O
O
O
O
O
R'
R'
R'
9
11
12
13
Scheme 3. Synthesis of compounds 12.
Table 2
Suzuki–Miyaura cross-couplings of iodides 9 with boronates 11
Entry
Iodide
Boronate
R
R0
R1
R2
Product
E/Z ratio in 12a
Yield of 12 (%)
Yield of 13 (%)
1
2
3
4
5
6
7
8
9
10
9a
9a
9a
9a
9b
9b
9b
9c
9c
9c
11a
11b
11c
11d
11a
11b
11d
11a
11b
11e
Me
Me
Me
Me
Me
Me
Me
Bn
H
H
H
H
OBn
OBn
OBn
OBn
OBn
OBn
H
OMe
H
Cl
H
OMe
Cl
H
OMe
OBn
H
H
OH
H
H
H
H
H
H
12a
12b
12c
12d
12e
12f
12g
12h
12i
94/6
91/9
91/9
88/12
89/11
95/5
90/10
95/5
95/5
93/7
55
77
93
62
79
69
60
71
71
70
16
d
d
31
d
d
d
d
d
d
Bn
Bn
OBn
12j
a
Determined by integration of characteristic signals in the 1H NMR spectra.
3. Conclusion
R2
R2
R1
R1
In summary, we have reported a flexible approach for the
synthesis of vulpinic acids and pulvinic acids, in a few steps from
tetronic acid. The key feature is a Suzuki–Miyaura cross-coupling
involving iodides 9a–c. The total syntheses of three natural prod-
ucts, vulpinic acid, pinastric acid, and xerocomic acid and a formal
synthesis of pulvinic acid were accomplished using this method.
OH
OBn
CO2R
CO2R
H2
O
O
10% Pd / C
O
O
13
12
R'
R'
12a, 13a: R = Me, R' = R1 = R2 = H
12b, 13b: R = Me, R1 = OMe, R' = R2 = H
12c, 13c: R = Me, R' = R1 = H, R2 = OH
12j: R = Bn, R' = R1 = R2 = OBn
4. Experimental section
4.1. General information
13j: R = H, R' = R1 = R2 = OH
THF was freshly distilled from sodium benzophenone ketyl.
Dichloromethane was freshly distilled over P2O5. Reactions were
performed under an argon atmosphere. TLC: Silica Gel 60F254 plates
with detection by UV light and by an ethanol solution of phos-
Scheme 4. Hydrogenolysis of compounds 12.
phomolybdic acid. Column chromatography: 40–63 mm silica gel.
Table 3
Melting points were uncorrected. NMR: 400.133 and 100.624 MHz
for 1H and 13C, respectively, or 300.13 and 75.47 MHz for 1H and 13C,
respectively. Except when noted otherwise, for mixtures of ster-
eomers, only the NMR chemical shifts values pertaining to the
Hydrogenolysis of compounds 12a–c,i,j
Entry
Compound 12
Product 13
Yield (%)
1
2
3
4
5
12aa
12bc
12cc
12ic
12jc
13a
13b
13c
13i
13j
44b
71
68
82
68
major (E)-stereomer are indicated. Chemical shifts (d) are in parts
per million (s¼singlet, d¼doublet, t¼triplet, m¼multiplet, and
br¼broad), coupling constants (J) are in hertz.
a
Reaction in CH2Cl2, 48 h.
The starting material was recovered in 16% yield.
Reaction in DMF, containing concentrated HCl, 2.5 h.
b
c
4.2. 4-Benzyloxy-5H-furan-2-one (6)
Potassium carbonate (13.8 g, 100 mmol) was added to a solution
of tetronic acid (5 g, 50 mmol) in DMF (100 mL). After stirring for
45 min at room temperature, benzyl bromide (6.54 mL, 50 mmol)
was added. After stirring for 15 h at room temperature, DMF was
removed under vacuum; ethyl acetate was added to the residue
obtained. The organic phase was extracted with water, and then
with saturated aqueous NH4Cl solution. The combined aqueous
phases were extracted with ethyl acetate. The combined organic
phases were dried over MgSO4, filtered, and concentrated under
vacuum. Ethyl acetate and diethyl ether were successively added to
12a,b,i,j, the conditions previously described by Ramage et al.13e for
the deprotection of benzylated pulvinic esters were applied. The
reactions, performed in DMF in the presence of hydrochloric acid,
were completed after 2.5 h. After chromatographic purification, the
products 13b,c,i,j were obtained as pure E-isomers in 68–82% yield.
The spectroscopic data of 13b are in good agreement with those
reported for pinastric acid.10c,15b The spectroscopic data of 13j are in
good agreement with those reported for xerocomic acid.13e,15b

Y. Bourdreux et al. / Tetrahedron 64 (2008) 8930–8937
8933
the viscous oil obtained, leading to the formation of a precipitate.
Filtration of the suspension afforded compound 6 as a white solid
(7.1 g, 75%).
layer was extracted with diethyl ether (3ꢂ100 mL). The combined
organic layers were washed successively with water and brine, dried
over MgSO4, filtered, and concentrated under vacuum. Silica gel
chromatography (7:3, then 6:4 pentane/AcOEt) afforded alcohol 7a.
Mp¼88–90 ꢁC (lit.25 90 ꢁC, lit.26 103–104 ꢁC); TLC: Rf¼0.70 (7:3
pentane/AcOEt); IR (KBr pellet) nmax¼3113, 2945, 2885, 1746, 1668,
1621, 1319, 1236, 1149, 1043, 956, 880, 817, 755, 702 cmꢀ1; 1H NMR
4.5.1. Methyl (3-benzyloxy-5-oxo-2,5-dihydrofuran-2-
yl)hydroxyphenylacetate (7a)
(400 MHz, CDCl3):
5.07 (s, 2H, OCH2Ph), 4.67 (s, 2H, CH2OCO); 13C NMR (100 MHz,
CDCl3):
d¼7.44–7.25 (m, 5H, Ar–H), 5.19 (s,1H, ]CHCO2),
Less polar diastereomer. White solid. Mp¼140–144 ꢁC; TLC:
Rf¼0.35 (6:4 pentane/AcOEt); IR (KBr pellet) nmax¼3309, 3130, 2957,
d
¼179.0, 173.4, 133.8, 129.1, 128.9, 128.3, 89.8, 74.6, 67.9;
Anal. Calcd for C11H10O3: C, 69.46; H, 5.30. Found: C, 69.52; H, 5.18.
1769, 1724, 1636, 1452, 1352, 1261, 1060, 996 cmꢀ1 1H NMR
;
(300 MHz, CDCl3):
d
¼7.72 (m, 2H, Ar–H), 7.46–7.28 (m, 4H, Ar–H),
4.3. Methyl (4-benzyloxyphenyl)oxoacetate (10b)27
7.20 (d, 2H, J¼7.3 Hz, Ar–H), 6.71 (d, 2H, J¼7.3 Hz, Ar–H), 5.66 (s, 1H,
OH), 5.16 (s, 1H, ]CHCOO), 4.82 (d, 1H, J¼11.6 Hz, OCH2Ph), 4.75 (d,
1H, J¼11.6 Hz, OCH2Ph), 4.18 (s, 1H, CHOCO), 3.84 (s, 3H, CH3); 13C
A
solution of n-butyllithium (10.3 mL, 1.6 M in hexanes,
16.4 mmol, 1.2 equiv) was added dropwise to a solution of 4-ben-
zyloxy-1-bromobenzene (3.7 g, 13.7 mmol, 1 equiv) in THF (75 mL)
cooled at ꢀ78 ꢁC. The white slurry obtained was stirred for 1 h at
ꢀ78 ꢁC, then it was transferred via cannula to a solution of dimethyl
oxalate (4.85 g, 41.1 mmol, 3 equiv) in THF (75 mL) cooled at
ꢀ78 ꢁC. The solution obtained was stirred for 1.5 h at ꢀ78 ꢁC, and
then allowed to warm to room temperature. A saturated aqueous
NH4Cl solution (150 mL) was added. The aqueous layer was
extracted with ethyl acetate (3ꢂ150 mL). The combined organic
layers were washed successively with water (50 mL) and brine
(50 mL), dried over MgSO4, filtered, and concentrated under vac-
uum. Silica gel chromatography (pentane/Et2O, 95:5 to 80:20 gra-
dient) afforded ketoester 10b as a clear oil (950 mg, 30%).
NMR(75 MHz, CDCl3):
d
¼177.2,171.9,135.6,133.4,128.3,128.1,128.0,
126.4, 125.9, 91.2, 81.7, 77.5, 73.5, 53.9 (several aromatic CH signals
overlap); MS (ESI-TOF) m/z 355 (100, [MþH]þ), 377 (20, [MþNa]þ).
More polar diastereomer. Slightly yellow solid. Mp¼137–138 ꢁC;
TLC: Rf¼0.25 (6:4 pentane/AcOEt); IR (KBr pellet) nmax¼3467, 3100,
2954, 1754, 1633, 1496, 1451, 1347, 1263, 1145 cmꢀ1 1H NMR
;
(300 MHz, CDCl3):
d¼7.63 (m, 2H, Ar–H), 7.39–7.26 (m, 8H, Ar–H),
5.67 (s, 1H, OH), 5.20 (s, 1H, ]CHCOO), 4.96 (d, 1H, J¼11.0 Hz,
OCH2Ph), 4.91 (d, 1H, J¼11.0 Hz, OCH2Ph), 4.24 (s, 1H, CHOCO), 3.45
(s, 3H, CH3); 13C NMR (75 MHz, CDCl3):
d
¼177.1, 172.0, 171.6, 137.4,
133.5, 128.9, 128.5, 128.3, 125.8, 91.5, 81.5, 77.1, 74.8, 53.1 (several
aromatic CH signals overlap); MS (ESI-TOF) m/z 355 (100, [MþH]þ),
377 (11, [MþNa]þ).
TLC: Rf¼0.65 (8:2 pentane/AcOEt); 1H NMR (300 MHz, CDCl3):
d
¼7.78 (d, 2H, J¼8.0 Hz, Ar–H), 7.46–7.33 (m, 5H, Ar–H), 7.02 (d, 2H,
4.5.2. Methyl (3-benzyloxy-5-oxo-2,5-dihydrofuran-2-yl)(4-
benzyloxyphenyl)hydroxyacetate (7b)
J¼8.0 Hz, Ar–H), 5.16 (s, 2H, ArOCH2Ph), 3.96 (s, 3H, CH3).
White solid (mixture of two diastereomers; isomer ratio: 60/40).
Mp¼153–154 ꢁC; TLC: Rf¼0.3 (6:4 pentane/AcOEt). Major di-
4.4. Benzyl (4-benzyloxyphenyl)oxoacetate (10c)28
astereomer. 1H NMR (400 MHz, CDCl3):
d
¼7.55 (d, J¼8.8 Hz, 2H, Ar–
A
solution of n-butyllithium (0.75 mL, 1.6 M in hexanes,
H), 7.50–6.90 (m,10H, Ar–H), 6.94 (d, 2H, J¼8.8 Hz, Ar–H), 5.61 (s,1H,
CHOCO), 5.26 (s, 1H, ]CHCO2), 5.06 (s, 4H, OCH2Ph), 5.01 (s, 2H,
OCH2Ph), 3.78 (s, 1H, OH), 3.54 (s, 3H, CH3); 13C NMR (100 MHz,
1.2 mmol, 1.2 equiv) was added dropwise to a solution of 4-benzyl-
oxy-1-bromobenzene (263 mg, 1 mmol, 1 equiv) in THF (5 mL)
cooled at ꢀ78 ꢁC. The white slurry obtained was stirred for 30 min at
ꢀ78 ꢁC, then it was transferred via cannula to a solution of dibenzyl
oxalate (324 mg,1.2 mmol,1.2 equiv) inTHF (5 mL) cooled at ꢀ78 ꢁC.
The solution obtainedwas stirredfor 2 h at ꢀ78 ꢁC, then 2 h at 0 ꢁC. A
saturated aqueous NH4Cl solution (20 mL) was added. The aqueous
layer was extracted with ethyl acetate (3ꢂ40 mL). The combined
organic layers were washed successively with water (20 mL) and
brine (20 mL), dried over MgSO4, filtered, and concentrated under
vacuum. Silica gel chromatography (pentane/Et2O, 95:5 to 90:10
gradient) afforded ketoester 10c as a white solid (105 mg, 30%).
Mp¼73–74 ꢁC (lit.28 75.0–76.5 ꢁC); TLC: Rf¼0.50 (9:1 pentane/
Et2O); IR (KBr pellet) nmax¼3061, 2910, 2868, 1729, 1687, 1600, 1508,
1455, 1379, 1302, 1261, 1208, 1171, 988, 840, 748, 697 cmꢀ1; 1H NMR
CDCl3):
128.6,128.2,128.0,127.4,127.3,114.7, 91.6, 81.5, 76.8, 74.9, 69.9, 53.3.
Minor diastereomer. 1H NMR (400 MHz, CDCl3):
d¼177.0, 172.0, 171.8, 158.9, 136.7, 135.6, 133.5, 129.2, 128.8,
d
¼7.62 (d, J¼8.4 Hz,
2H, Ar–H), 7.50–6.90 (m, 10H, Ar–H), 6.81 (d, 2H, J¼8.4 Hz, Ar–H),
5.62 (s,1H, CHOCO), 5.17 (s,1H, ]CHCO2), 5.03 (s, 2H, OCH2Ph), 4.86
(d, 1H, J¼11.8 Hz, OCH2Ph), 4.80 (d, 1H, J¼11.8 Hz, OCH2Ph), 4.02 (s,
1H, OH), 3.87 (s, 3H, CH3); 13C NMR (100 MHz, CDCl3):
d
¼177.3,172.2,
172.0,159.0,136.7,135.6,133.6,129.6,128.6,128.4,128.3,128.0,127.4,
126.7, 114.5, 91.3, 81.7, 77.4, 73.7, 69.9, 54.0.
4.5.3. Benzyl (3-benzyloxy-5-oxo-2,5-dihydrofuran-2-yl)(4-
benzyloxyphenyl)hydroxyacetate (7c)
Less polar diastereomer. White solid. Mp¼142–144 ꢁC. TLC:
Rf¼0.65 (6:4 pentane/AcOEt); IR (KBr pellet) nmax¼3463, 3097,
(300 MHz, CDCl3):
10H, Ar–H), 7.03 (d, 2H, J¼8.8 Hz, Ar–H), 5.43 (s, 2H, CO2CH2Ph),
5.16 (s, 2H, ArOCH2Ph); 13C NMR (100 MHz, CDCl3):
d
¼8.00 (d, 2H, J¼8.8 Hz, Ar–H), 7.50–7.35 (m,
3035, 1759, 1721, 1635, 1510, 1347, 1247, 1158, 695 cmꢀ1 1H NMR
;
d
¼184.4, 164.1,
(400 MHz, CDCl3):
d
¼7.60 (d, 2H, J¼8.5 Hz, Ar–H), 7.50–7.20 (m,
164.0,135.7, 134.6,132.4,128.6,128.4,128.2,127.4, 125.6, 115.0, 70.2,
13H, Ar–H), 6.92 (d, 2H, J¼8.5 Hz, Ar–H), 6.81 (m, 2H, Ar–H), 5.62 (s,
1H, CHOCO), 5.30 (d, 1H, J¼12.2 Hz, OCH2Ph), 5.23 (d, 1H, J¼12.2 Hz,
OCH2Ph), 5.17 (s, 1H, ]CHCO2), 5.02 (s, 2H, OCH2Ph), 4.83 (d, 1H,
J¼12.2 Hz, OCH2Ph), 4.76 (d, 1H, J¼12.2 Hz, OCH2Ph), 4.12 (s, 1H,
67.5; MS (ESI-TOF) m/z 347 (100, [MþH]þ); Anal. Calcd for
C
11H10O3: C, 69.46; H, 5.30. Found: C, 69.52; H, 5.18.
4.5. Typical procedure for the preparation of alcohols 7a–c
OH); 13C NMR (100 MHz, CDCl3):
d¼177.3, 172.0, 171.6, 159.0, 136.7,
134.4, 133.7, 128.6, 128.3, 128.2, 128.1, 128.0, 127.9, 127.4, 127.4,
126.7, 144.4, 91.4, 81.7, 77.4, 73.7, 69.9, 69.0 (several aromatic CH
signals overlap); MS (ESI-TOF) m/z 559 (100, [MþNa]þ). More polar
diastereomer. White solid. Mp¼122–123 ꢁC. TLC: Rf¼0.4 (6:4 pen-
tane/AcOEt); IR (KBr pellet) nmax¼3507, 3036, 2887, 1779, 1758,
1727,1633,1509,1348,1295,1237,1142, 948, 799, 764, 698 cmꢀ1; 1H
A solution of benzyl tetronate 6 (2.5 g, 13.2 mmol) in THF (60 mL)
was added dropwise to a solution of n-butyllithium (9 mL, 1.6 M in
hexanes, 14.55 mmol) in THF (30 mL) cooled at ꢀ78 ꢁC. The yellow
solution obtained was stirred at ꢀ78 ꢁC for 20 min, and then a solu-
tion of methyl benzoylformate (1.9 mL, 13.5 mmol) in THF (20 mL)
was added dropwise. The reaction mixture was maintained at ꢀ78 ꢁC
for 25 min, and then allowed to warm to room temperature. A satu-
rated aqueous NH4Cl solution (45 mL) was added and the aqueous
NMR (CDCl3, 300 MHz):
d¼7.55 (m, 2H, Ar–H), 7.46–7.24 (m, 13H,
Ar–H), 7.05 (m, 2H, Ar–H), 6.95 (m, 2H, Ar–H), 5.62 (s, 1H, CHOCO),
5.22 (s, 1H, ]CHCO2), 5.05 (s, 2H, OCH2Ph), 4.97 (d, 2H, J¼11.0 Hz,

8934
Y. Bourdreux et al. / Tetrahedron 64 (2008) 8930–8937
OCH2Ph), 4.91 (d, 1H, J¼11.0 Hz, OCH2Ph), 4.84 (d, 1H, J¼12.2 Hz,
OCH2Ph), 3.96 (s, 1H, OH); 13C NMR (100 MHz, CDCl3):
171.7, 171.5, 158.9, 136.7, 134.2, 133.6, 129.6, 129.3, 128.8, 128.7,
128.6, 128.5, 128.4, 128.3, 128.0, 127.4, 127.3, 114.7, 91.7, 81.4, 76.8,
74.8, 69.9, 68.5 (several aromatic CH signals overlap); MS (ESI-TOF)
m/z 559 (100, [MþNa]þ).
mixture was heated at 40 ꢁC for 4.5 h. After cooling to room tem-
perature, a saturated aqueous Na2S2O3 solution (40 mL) was added.
The aqueous layer was extracted with ethyl acetate (3ꢂ100 mL).
The combined organic layers were washed successively with a
saturated aqueous Na2S2O3 solution (35 mL), brine (35 mL), dried
over MgSO4, filtered, and concentrated under vacuum. Silica gel
chromatography (pentane/AcOEt, 95:5 to 8:2 gradient) afforded
iodide 9a as a slightly yellow solid (858 mg, 78%).
d¼176.9,
4.6. Typical procedure for the preparation of alkenes 8a–c
Triethylamine (5.19 mL, 37.29 mmol, 6 equiv) and DMAP (a
spatula tip) were added to a solution of alcohol 7a (2.2 g,
6.215 mmol, 1 equiv) in methylene chloride (45 mL) cooled at 0 ꢁC.
A solution of trifluoroacetic anhydride (2.64 mL, 18.64 mmol,
3 equiv) in methylene chloride (30 mL) was then added dropwise
over 90 min. The solution was allowed to warm to room tempera-
ture under stirring for 14 h. A saturated aqueous NaHCO3 solution
(50 mL) and water (50 mL) were successively added. The aqueous
layer was extracted with ether (3ꢂ75 mL). The combined organic
layers were washed with brine (100 mL), dried over MgSO4, fil-
tered, and concentrated under vacuum. Addition of diethyl ether to
the residue obtained led to the formation of a precipitate. Filtration
afforded alkene 8a as a white solid (1.84 g, 88%).
4.7.1. Methyl (3-benzyloxy-4-iodo-5-oxo-5H-furan-2-
ylidene)phenylacetate (9a)
Yellow solid (E/Z isomer ratio: 93/7). Mp¼137 ꢁC; TLC: Rf¼0.70
(7:3 pentane/AcOEt); IR (KBr pellet) nmax¼3035, 2944, 1775, 1729,
1590, 1299, 1271, 1215, 1132, 1044, 947 cmꢀ1 1H NMR (400 MHz,
;
CDCl3):
d
¼7.58 (m, 2H, Ar–H), 7.48–7.32 (m, 8H, Ar–H), 5.75 (s, 2H,
OCH2Ph), 3.17 (s, 3H, CO2CH3); 13C NMR (100 MHz, CDCl3):
d
¼166.8–166.0–165.9, 142.2, 133.5, 130.2, 129.5–129.3–129.0–
128.9–128.6, 116.5, 75.1, 50.2, 51.9; MS (ESI-TOF) m/z 463 (100,
[MþH]þ); Anal. Calcd for C11H10O3: C, 51.97; H, 3.27; I, 27.45. Found:
C, 51.83; H, 3.31; I, 27.15.
4.7.2. Methyl (3-benzyloxy-4-iodo-5-oxo-5H-furan-2-ylidene)(4-
benzyloxyphenyl)acetate (9b)
4.6.1. Methyl (3-benzyloxy-5-oxo-5H-furan-2-
ylidene)phenylacetate (8a)
Yellow solid (E/Z isomer ratio: 89/11). Mp¼158–159 ꢁC; TLC:
Rf¼0.50 (7:3 pentane/AcOEt); IR (KBr pellet) nmax¼3066, 3033,
2924, 2853, 1765, 1719, 1589, 1508, 1453, 1382, 1310, 1282, 1245,
1217, 1177, 1128, 1046, 946, 911, 835, 743, 696, 674, 640, 609,
White solid (E/Z isomer ratio: 95/5). Mp¼122–124 ꢁC; TLC:
Rf¼0.65 (7:3 pentane/AcOEt); IR (KBr pellet) nmax¼3109, 2953,1758,
1731, 1601, 1350, 1302, 1206, 1087, 1036, 959, 880 cmꢀ1
;
1H NMR
523 cmꢀ1; 1H NMR (400 MHz, CDCl3):
d¼7.51 (d, 2H, J¼8.9 Hz, Ar–
(400 MHz, CDCl3):
(m, 8H, Ar–H), 5.43 (s, 1H, ]CHCOO), 5.09 (s, 2H, OCH2Ph), 3.44 (s,
3H, CO2CH3); 13C NMR (100 MHz, CDCl3):
d
¼7.63 (dd, 2H, J¼8.0, 1.8 Hz, Ar–H), 7.44–7.33
H), 7.45–7.25 (m, 10H, Ar–H), 6.97 (d, 2H, J¼8.9 Hz, Ar–H), 5.76 (s,
2H, OCH2Ph), 5.42 (s, 2H, OCH2Ph), 3.19 (s, 3H, CO2CH3); HRMS (ESI-
TOF) (m/z): calcd for C27H21INaO6 [MþNa]þ 591.0281, found:
591.0267.
d
¼168.5, 167.3, 166.4,
141.0, 133.3, 130.7, 129.4, 129.3, 129.1, 128.9, 128.7, 128.5, 116.5, 90.8,
75.1, 52.4; MS (ESI-TOF) m/z 337 (100, [MþH]þ); Anal. Calcd for
C
11H10O3: C, 71.42; H, 4.79. Found: C, 71.01; H, 4.88.
4.7.3. Benzyl (3-benzyloxy-4-iodo-5-oxo-5H-furan-2-ylidene)(4-
benzyloxyphenyl)acetate (9c)
4.6.2. Methyl (3-benzyloxy-5-oxo-5H-furan-2-ylidene)(4-
benzyloxyphenyl)acetate (8b)
Yellow solid (E/Z isomer ratio: 80/20). Mp¼130–131 ꢁC; TLC:
Rf¼0.60 (7:3 pentane/AcOEt); IR (KBr pellet) nmax¼3054, 3033, 2932,
2871,1772,1738,1511,1500,1453,1382,1304,1280,1254,1213,1182,
White solid (E/Z isomer ratio: 95/5). Mp¼159 ꢁC; TLC: Rf¼0.6
(6:4 pentane/AcOEt); IR (KBr pellet) nmax¼3109, 1776, 1723, 1604,
1512, 1455, 1432, 1404, 1381, 1353, 1316, 1259, 1205, 1183, 1149,
1049, 949, 913, 831, 755, 741, 696, 610 cmꢀ1 1H NMR (CDCl3,
;
300 MHz):
d
¼7.52 (d, 2H, J¼9.2 Hz, Ar–H), 7.47–7.33 (m, 11H, Ar–H),
1090, 1043, 971, 880, 739, 696, 673, 632 cmꢀ1
;
1H NMR (400 MHz,
7.27 (m, 2H, Ar–H), 7.08 (m, 2H, Ar–H), 6.92 (d, 2H, J¼9.2 Hz, Ar–H),
CDCl3):
d
¼7.59 (dd, 2H, J¼8.0, 1.8 Hz, Ar–H), 7.45–7.25 (m, 10H, Ar–
5.71 (s, 2H, C4–OCH2Ph), 5.07 (s, 2H, OCH2Ph), 4.57 (s, 2H, OCH2Ph);
H), 6.98 (dd, 2H, J¼8.0, 1.8 Hz, Ar–H), 5.40 (s. 1H, OCH2Ph), 5.09 (s,
4H, OCH2Ph), 3.45 (s, 3H, CO2CH3); HRMS (ESI-TOF) (m/z): calcd for
C27H22NaO6 [MþNa]þ 465.1314, found: 465.1310.
13C NMR (100 MHz, CDCl3):
d¼167.1, 166.2, 165.6, 159.8, 141.1, 136.3,
134.7, 133.9, 130.9, 129.4, 129.0, 128.8, 128.6, 128.4, 128.32, 128.27,
128.1, 127.4, 123.0, 116.6, 115.1, 74.9, 70.0, 67.3, 51.5 (two non-iden-
tified aromatic CH signals overlap); HRMS (ESI-TOF) (m/z): calcd for
4.6.3. Benzyl (3-benzyloxy-5-oxo-5H-furan-2-ylidene)(4-
benzyloxyphenyl)acetate (7c)
C
33H25INaO6 [MþNa]þ 667.0594, found: 667.0597.
Slightly yellow solid (E/Z isomer ratio: 80/20). Mp¼142–143 ꢁC;
TLC: Rf¼0.75 (7:3 pentane/AcOEt); IR (KBr pellet) nmax¼3034, 1764,
1724, 1598, 1510, 1457, 1349, 1308, 1280, 1257, 1223, 1202, 1182,
4.8. Typical procedure for the Suzuki–Miyaura reaction
All the solvents were degassed. To a solution of iodide 9a (50 mg,
0.108 mmol) in THF (5.5 mL) were added Pd(PPh3)2Cl2 (4 mg,
5.4 mmol, 5 mol %), a solution of 4-methoxyphenylboronic acid
1040, 954, 891 cmꢀ1
;
1H NMR (CDCl3, 300 MHz):
d
¼7.59 (m,
2H, Ar–H), 7.43–7.24 (m,13H, Ar–H), 7.13 (m, 2H, Ar–H), 6.93 (m, 2H,
Ar–H), 5.33 (s, 1H, CHCO2), 5.04 (s, 2H, OCH2Ph), 4.96 (s, 2H,
pinacol ester (37.9 mg, 0.162 mmol,1.5 equiv) inTHF (2 mL), and 2 M
aqueous Na2CO3 (2.4 mL). The reaction mixture was refluxed for 2 h
under argon. After cooling to room temperature, water (5.5 mL) and
saturated aqueous NH4Cl (2 mL) were added. The aqueous layer was
extracted with CH2Cl2 (3ꢂ5 mL), the combined organic layers were
dried (MgSO4), filtered, and concentrated under vacuum. Silica gel
chromatography (9:1 to 6:4 pentane/AcOEt) afforded 12b (E/Z
isomer ratio: 91/9) as a yellow solid (37 mg, 77%).
OCH2Ph), 4.86 (s, 2H, OCH2Ph); 13C NMR (CDCl3, 75 MHz):
d
¼168.6,
167.6, 166.0, 159.6, 139.6, 136.4, 134.7, 133.5, 130.8, 128.8, 128.5,
128.4, 128.3, 128.0, 127.4, 123.5, 116.3, 115.1, 90.3, 74.8, 70.0, 67.6
(several aromatic CH signals overlap); MS (ESI-TOF) m/z 519 (100,
[MþH]þ); HRMS (ESI-TOF) (m/z): calcd for C33H26NaO6 [MþNa]þ
541.1614, found: 541.1627.
4.7. Typical procedure for the preparation of iodides 9a–c
4.8.1. Methyl (3-benzyloxy-5-oxo-4-phenyl-5H-furan-2-
ylidene)phenylacetate (12a)
Iodine (1.81 g, 7.14 mmol, 3 equiv) and cerium(IV) ammonium
nitrate (3.92 g, 7.14 mmol, 3 equiv) were added to a solution of 8a
(800 mg, 2.38 mmol, 1 equiv) in acetonitrile (70 mL). The reaction
Yellow solid (E/Z isomer ratio: 94/6). Mp¼151 ꢁC; TLC: Rf¼0.7
(8:2 pentane/AcOEt); 1H NMR (400 MHz, CDCl3):
d
¼7.67 (dd, 2H,

Y. Bourdreux et al. / Tetrahedron 64 (2008) 8930–8937
8935
J¼8.0, 1.8 Hz, Ar–H), 7.56–7.31 (m, 11H, Ar–H), 7.23 (m, 2H, Ar–H),
4.97 (s, 2H, OCH2Ph), 3.36 (s, 3H, CO2CH3); 13C NMR (100 MHz,
CDCl3):
753, 698, 834, 777, 753, 698, 662, 613, 550 cmꢀ1
(400 MHz, CDCl3):
2H, Ar–H), 7.45–7.32 (m, 10H, Ar–H), 7.01 (d, J¼9.1 Hz, 2H, Ar–H),
6.98 (d, J¼9.0 Hz, 2H, Ar–H), 5.11 (s, 2H, OCH2Ph), 4.96 (s, 2H,
OCH2Ph), 3.86 (s, 3H, ArOCH3), 3.38 (s, 3H, CO2CH3); 13C NMR
;
1H NMR
d
¼7.64 (d, J¼9.0 Hz, 2H, Ar–H), 7.50 (d, J¼8.9 Hz,
d
¼166.6 (2C), 161.3, 141.3 (s, C5), 134.1, 131.1, 130.2, 129.9,
129.2, 129.0, 128.7, 128.5, 128.4, 116.5, 108.3, 75.4, 52.3; MS (ESI-
TOF) m/z 435 (100, [MþNa]þ).
(100 MHz, CDCl3):
d
¼168.2, 167.1, 160.9, 160.1, 159.5, 140.3, 136.4,
4.8.2. Methyl [3-benzyloxy-4-(4-methoxyphenyl)-5-oxo-5H-furan-
2-ylidene]phenylacetate (12b)
Yellow solid (E/Z isomer ratio: 91/9). Mp¼138–139 ꢁC; TLC:
Rf¼0.6 (7:3 pentane/AcOEt); IR (KBr pellet) nmax¼3031, 2953, 2843,
1776, 1726, 1630, 1602, 1514, 1433, 1292, 1258, 1163, 1045, 941, 833,
134.4, 131.3, 130.8, 129.0, 128.7, 128.62, 128.57, 128.56, 128.1, 127.4,
123.8, 120.8, 116.1, 115.1, 114.0, 108.1, 75.0, 70.0, 55.3, 52.4; MS (ESI-
TOF) m/z 549 (100, [MþH]þ); HRMS (ESI-TOF) (m/z): calcd for
C
34H28NaO7 [MþNa]þ 571.1733, found: 571.1736.
759, 698 cmꢀ1; 1H NMR (400 MHz, CDCl3):
d
¼7.67 (d, J¼8.7 Hz, 2H,
4.8.7. Methyl [3-benzyloxy-4-(4-chlorophenyl)-5-oxo-5H-furan-2-
ylidene](4-benzyloxyphenyl)acetate (12g)
Ar–H), 7.49 (d, J¼8.7 Hz, 2H, Ar–H), 7.42–7.24 (m, 8H, Ar–H), 6.98 (d,
J¼8.7 Hz, 2H, Ar–H), 4.97 (s, 2H, OCH2Ph), 3.85 (s, 3H, ArOCH3), 3.39
Yellow solid (E/Z isomer ratio: 90/10). IR (NaCl, film) nmax¼3033,
2920, 1754, 1729, 1589, 1511, 1491, 1454, 1433, 1384, 1343, 1304,
1280, 1254, 1228, 1189, 1156, 1093, 1046, 1014, 999, 982, 942, 904,
(s, 3H, CO2CH3); 13C NMR (100 MHz, CDCl3):
d¼168.1, 166.8, 160.7,
160.2,141.6,134.4,131.4,131.2,129.2,129.0,128.7,128.7,128.6,120.7,
116.2, 114.1, 108.7, 75.1, 55.4, 52.4 (two non-identified aromatic CH
signals overlap); HRMS (ESI-TOF) (m/z): calcd for C27H22NaO6
[MþNa]þ 465.1314, found: 465.1323.
865, 833, 776, 755, 735, 697, 613, 574, 547, 514 cmꢀ1 1H NMR
;
(400 MHz, CDCl3):
d
¼7.63 (d, J¼9.0 Hz, 2H, Ar–H), 7.48 (d, J¼8.5 Hz,
2H, Ar–H), 7.45–7.33 (m, 10H, Ar–H), 7.24 (m, 2H, Ar–H), 7.01 (d,
J¼9.0 Hz, 2H, Ar–H), 5.11 (s, 2H, OCH2Ph), 4.95 (s, 2H, OCH2Ph), 3.38
4.8.3. Methyl [3-benzyloxy-4-(3-hydroxyphenyl)-5-oxo-5H-furan-
2-ylidene]phenylacetate (12c)
(s, 3H, CO2CH3); 13C NMR (100 MHz, CDCl3):
d¼167.7, 166.9, 161.8,
159.7, 139.8, 136.4, 135.1, 134.0, 131.3, 130.9, 129.2, 128.8, 128.7,
128.6, 128.1, 127.5, 127.3, 123.6, 117.0, 115.2, 106.9, 75.6, 70.0, 52.4;
HRMS (ESI-TOF) (m/z): calcd for C33H25ClNaO6 [MþNa]þ 575.1237,
found: 575.1233.
Yellow solid (E/Z isomer ratio: 91/9). IR (KBr pellet) nmax¼3389,
2951, 1763, 1727, 1707, 1633, 1594, 1496, 1441, 1346, 1328, 1304,
1245, 1217, 1048, 988, 868, 763, 693, 676, 609 cmꢀ1. Major (E)-iso-
mer. 1H NMR (400 MHz, CDCl3):
7.50–7.20 (m, 9H, Ar–H), 7.08 (d, 1H, J¼7.6 Hz, Ar–H), 6.96 (br s, 1H,
Ar–H), 6.89 (dd, 1H, J¼8.0, 2.5 Hz, Ar–H), 5.30 (br s, 1H, OH), 4.99 (s,
2H, OCH2Ph), 3.37 (s, 3H, CO2CH3); 13C NMR (100 MHz, CDCl3):
d
¼7.67 (d, 2H, J¼8.0 Hz, Ar–H),
4.8.8. Benzyl (3-benzyloxy-5-oxo-4-phenyl-5H-furan-2-ylidene)(4-
benzyloxyphenyl)acetate (12h)
Yellow solid (E/Z isomer ratio: 95/5). Mp¼129 ꢁC; IR (NaCl, film)
nmax¼3033, 2918, 2860, 1768, 1726, 1632, 1598, 1468, 1510, 1494,
1455, 1422, 1408, 1382, 1347, 1307, 1283, 1249, 1219, 1184, 1158,
1074, 1038, 939, 920, 785, 771, 752, 723, 696, 678, 612, 594, 546,
d
¼168.9, 166.9, 161.4, 156.9, 141.3, 134.1, 131.1, 130.2–129.2–129–
128.7–128.5–128.4, 129.9, 116.5, 108.3, 75.6, 52.3; HRMS (ESI-TOF)
(m/z): calcd for C26H20NaO6 [MþNa]þ 451.1158, found: 451.1155.
518 cmꢀ1; 1H NMR (400 MHz, CDCl3):
d
¼7.61 (d, J¼8.8 Hz, 2H, Ar–
4.8.4. Methyl [3-benzyloxy-4-(4-chlorophenyl)-5-oxo-5H-furan-2-
ylidene]phenylacetate (12d)
Yellow solid (E/Z isomer ratio: 88/12). Mp¼154–156 ꢁC; IR (KBr
pellet) nmax¼2953, 1772, 1720, 1629, 1591, 1493, 1437, 1346, 1328,
1302, 1234, 1161, 1126, 1046, 969, 941, 905, 845, 768, 690, 635,
H), 7.52–7.28 (m, 16H, Ar–H), 7.23–7.14 (m, 4H, Ar–H), 6.97 (d,
J¼9.2 Hz, 2H, Ar–H), 5.10 (s, 2H, OCH2Ph), 4.91 (s, 2H, OCH2Ph), 4.78
(s, 2H, OCH2Ph); 13C NMR (100 MHz, CDCl3):
d
¼168.0, 166.3, 161.5,
159.5, 140.1, 136.4, 134.9, 134.3, 130.8, 130.2, 129.0, 128.92, 128.85,
128.61, 128.57, 128.41, 128.35, 128.1, 127.5, 123.8, 116.4, 115.1, 107.8,
75.1, 70.0, 67.4; MS (ESI-TOF) m/z 595 (100, [MþH]þ); HRMS (ESI-
595 cmꢀ1; 1H NMR (400 MHz, CDCl3):
d
¼7.67 (dd, 2H, J¼8.0, 1.8 Hz,
Ar–H), 7.56–7.31 (m, 8H, Ar–H), 7.23 (m, 2H, Ar–H), 7.12 (d, 2H,
J¼8.0 Hz, Ar–H), 4.96 (s, 2H, OCH2Ph), 3.37 (s, 3H, CO2CH3); 13C
TOF) (m/z): calcd for
619.1967.
C
39H30NaO6 [MþNa]þ 617.1940, found:
NMR (100 MHz, CDCl3):
131.4, 131.0, 129.5, 129.2, 129.1, 128.82, 128.77, 128.70, 128.67, 127.1,
d
¼167.5, 166.6, 161.6, 141.2, 135.3, 133.9,
4.8.9. Benzyl [3-benzyloxy-4-(4-methoxyphenyl)-5-oxo-5H-furan-
2-ylidene](4-benzyloxy-phenyl)acetate (12i)
Yellow solid (E/Z isomer ratio: 95/5). Mp¼131–132 ꢁC; IR (NaCl,
film) nmax¼3064, 3033, 2935, 2838, 1767, 1728, 1627, 1601, 1510,
1455,1424,1379,1347,1282,1252,1219,1183,1158,1104,1081,1038,
963, 938, 833, 771, 734, 696, 643, 612, 518 cmꢀ1; 1H NMR (400 MHz,
117.1, 107.4, 76.7, 52.4; HRMS (ESI-TOF) (m/z): calcd for
C
26H19ClNaO5 [MþNa]þ 469.0819, found: 469.0816.
4.8.5. Methyl (3-benzyloxy-5-oxo-4-phenyl-5H-furan-2-
ylidene)(4-benzyloxyphenyl)acetate (12e)
Orange solid (E/Z isomer ratio: 89/11). Mp¼149–151 ꢁC; IR
(NaCl, film) nmax¼2924, 2859, 2355, 2337, 1769, 1732, 1627, 1598,
1510, 1453, 1349, 1305, 1281, 1252, 1228, 1187, 1159, 1131, 1046, 936,
CDCl3):
d
¼7.60 (d, J¼9.0 Hz, 2H, Ar–H), 7.49–7.28 (m, 13H, Ar–H),
7.24 (m, 2H, Ar–H), 7.17 (m, 2H, Ar–H), 6.98 (d, J¼8.6 Hz, 2H, Ar–H),
6.96 (d, J¼8.9 Hz, 2H, Ar–H), 5.10 (s, 2H, OCH2Ph), 4.92 (s, 2H,
OCH2Ph), 4.79 (s, 2H, OCH2Ph), 3.86 (s, 3H, CH3); 13C NMR
912, 841 cmꢀ1; 1H NMR (400 MHz, CDCl3):
Ar–H), 7.53 (m, 2H, Ar–H), 7.48–7.32 (m, 11H, Ar–H), 7.23 (m,
2H, Ar–H), 7.01 (d, J¼8.8 Hz, 2H, Ar–H), 5.11 (s, 2H, OCH2Ph), 4.95 (s,
2H, OCH2Ph), 3.37 (s, 3H, CO2CH3); 13C NMR (100 MHz, CDCl3):
d
¼7.65 (d, J¼9.2 Hz, 2H,
(100 MHz, CDCl3):
d
¼168.2, 166.4, 160.9, 160.0, 159.4, 140.3, 136.4,
134.9, 134.5, 131.3, 130.8, 128.9, 128.6, 128.5, 128.40, 128.38, 128.3,
128.1, 127.4, 123.9, 120.8, 116.0, 115.1, 114.0, 108.1, 74.7, 70.0, 67.4,
55.3; MS (ESI-TOF) m/z 647 (100, [MþH]þ); HRMS (ESI-TOF) (m/z):
calcd for C40H32NaO7 [MþNa]þ 647.2046, found: 647.2038.
d
¼168.0, 167.0, 161.5, 159.6, 140.1, 136.4, 134.2, 130.8, 130.2, 129.0,
128.94, 128.85, 128.8, 128.63, 128.58, 128.5, 128.1, 127.4, 123.8, 116.5,
115.2, 107.8, 75.4, 70.0, 52.3; MS (ESI-TOF) m/z 519 (100, [MþH]þ);
HRMS (ESI-TOF) (m/z): calcd for C33H26NaO6 [MþNa]þ 541.1627,
found: 541.1631.
4.8.10. Benzyl [3-benzyloxy-4-(3,4-bis-benzyloxyphenyl)-5-oxo-
5H-furan-2-ylidene](4-benzyloxyphenyl)acetate (12j)
Yellow solid (E/Z isomer ratio: 93/7). IR (NaCl, film) nmax¼3057,
3026, 2934, 2872, 1767, 1728, 1629, 1599, 1510, 1455, 1381, 1347,
1323, 1308, 1274, 1255, 1216, 1185, 1135, 1078, 1040, 1026, 971, 907,
4.8.6. Methyl [3-benzyloxy-4-(4-methoxyphenyl)-5-oxo-5H-furan-
2-ylidene](4-benzyloxy-phenyl)acetate (12f)
Solid (E/Z isomer ratio: 95/5). Mp¼155–156 ꢁC; IR (NaCl, film)
nmax¼3033, 2947, 2846, 1770, 1727, 1624, 1600, 1511, 1452, 1382,
1345, 1285, 1252, 1183, 1160, 1050, 1024, 961, 942, 918, 834, 777,
879, 855, 838, 809, 735, 696 cmꢀ1 1H NMR (400 MHz, CDCl3):
;
d¼7.61 (d, J¼8.8 Hz, 2H, Ar–H), 7.49–7.28 (m, 21H, Ar–H), 7.20 (m,
2H, Ar–H), 7.15 (m, 2H, Ar–H), 7.07 (m, 2H, Ar–H), 6.98 (m, 3H,

8936
Y. Bourdreux et al. / Tetrahedron 64 (2008) 8930–8937
Ar–H), 5.23 (s, 2H, OCH2Ph), 5.12 (s, 2H, OCH2Ph), 10 (s, 2H,
OCH2Ph), 4.85 (s, 2H, OCH2Ph), 4.83 (s, 2H, OCH2Ph); 13C NMR
NMR (100 MHz, acetone-d6):
d
¼173.1, 166.8, 160.5, 160.0, 158.5,
154.6, 132.6, 129.9, 124.5, 122.8, 116.7, 115.6, 114.7, 104.9, 55.6, 54.8;
MS (ESI-TOF) m/z 369 (100, [MþH]þ); HRMS (ESI-TOF) (m/z): calcd
for C20H16NaO7 [MþNa]þ 391.0794, found: 391.0803.
(100 MHz, CDCl3):
d
¼168.1, 166.4, 160.9, 159.5, 149.5, 148.5, 140.2,
136.9, 136.4, 134.9, 134.5, 130.8, 128.1, 128.6, 128.51, 128.49, 128.43,
128.41, 128.36, 128.3, 128.1, 127.9, 127.4, 127.3, 127.2, 123.8, 123.6,
121.6, 116.4, 116.1, 115.1, 114.4, 107.9, 74.5, 71.07, 71.04, 69.99, 67.5;
HRMS (ESI-TOF) (m/z): calcd for C53H42NaO8 [MþNa]þ 829.2777,
found: 829.2757.
4.9.5. [4-(3,4-Dihydroxyphenyl)-3-hydroxy-5-oxo-5H-furan-2-
ylidene](4-hydroxy-phenyl)acetic acid; xerocomic acid (13j)
Red solid. Mp¼292–293 ꢁC (lit.13e 295–297 ꢁC); IR (KBr pellet)
nmax¼3493, 3185, 2926, 24.78, 1736, 1679, 1593, 1513, 1480, 1434,
1368, 1306, 1256, 1210, 1191, 1149, 1133, 1095, 1057, 980, 956, 894,
4.9. Typical procedure for the hydrogenolysis
873, 831, 814, 796, 744, 701, 663, 582, 561, 531 cmꢀ1
(400 MHz, acetone-d6):
¼7.73 (d, J¼2.0 Hz, 1H, Ar–H), 7.58 (dd,
J¼8.4, 2.0 Hz, 1H, Ar–H), 7.28 (d, J¼8.6 Hz, 2H, Ar–H), 6.89 (m, 3H,
Ar–H); 13C NMR (100 MHz, acetone-d6):
;
1H NMR
To a suspension of 10% Pd/C (26 mg) and compound 12b (23 mg,
0.052 mmol) in DMF (2 mL) was added two drops of concentrated
HCl. The reaction mixture was placed under a hydrogen atmo-
sphere at 1 atm, under vigorous stirring, for 2.5 h. Hydrogen was
replaced by argon, then the suspension was filtered over a short pad
of Celite, which was washed with THF. After concentration, ether
(20 mL) was added and the organic phase was washed several
times with water, dried (Na2SO4), filtered, and concentrated under
vacuum. Silica gel chromatography (9:1 to 1:3 pentane/AcOEt)
afforded pinastric acid 13b as a yellow solid (13 mg, 71%).
d
d
¼174.1, 166.9, 159.6, 158.3,
155.2, 146.3, 145.5, 132.5, 125.2, 122.3, 121.1, 116.7, 116.0, 115.5, 115.4,
104.9; HRMS (ESI-TOF negatif) (m/z): calcd for C18H11O8 [MꢀH]þ
355.0454, found: 355.0459.
Acknowledgements
A
financial support by the CNRS to C.W. is gratefully
acknowledged.
4.9.1. Methyl [3-benzyloxy-4-(4-methoxyphenyl)-5-oxo-5H-furan-
2-ylidene](4-benzyloxy-phenyl)acetate; vulpinic acid (13a)
Yellow solid. Mp¼151 ꢁC (lit.10b 146–147 ꢁC, lit.13e 146–148 ꢁC,
lit.10c 150–151 ꢁC); TLC: Rf¼0.15 (8:2 pentane/AcOEt); IR (KBr
pellet) nmax¼2962, 2513, 1768, 1679, 1609, 1436, 1302, 1070, 952,
References and notes
1. For reviews, see: (a) Zografos, A. L.; Georgiadis, D. Synthesis 2006, 3157–3188;
(b) Gill, M.; Steglich, W. Prog. Chem. Org. Nat. Prod. 1987, 51, 1–317; (c) Rao, Y. S.
Chem. Rev. 1976, 76, 625–694.
2. Benedict, R. G.; Brady, L. R. J. Pharm. Sci. 1972, 1820–1822.
3. Foden, F.; McCormick, J.; O’Mant, D. J. Med. Chem. 1975, 18, 199–203.
4. So¨derberg, U. Acta Physiol. Scand. 1952, 27, 97–98.
5. Dias, D.; White, J. M.; Urban, S. Nat. Prod. Res. 2007, 21, 366–376.
6. Singh, S. B.; Jayasuriya, H.; Dewey, R.; Polishook, J. D.; Dombrowski, A. W.; Zink,
D. L.; Guan, Z.; Collado, J.; Platas, G.; Pelaez, F.; Felock, P. J.; Hazuda, D. J. J. Ind.
Microbiol. Biotechnol. 2003, 30, 721–731.
689 cmꢀ1
;
1H NMR (300 MHz, CDCl3):
d
¼13.79 (br s, 1H, OH), 8.14
(m, 2H, Ar–H), 7.50–7.30 (m, 6H, Ar–H), 7.27 (m, 2H, Ar–H), 3.88 (s,
3H, CO2CH3); 13C NMR (100 MHz, CDCl3):
d¼168.2, 166.4, 160.9,
160.0, 159.4, 140.3, 136.4, 134.9, 134.5, 131.3, 130.8, 128.9, 128.6,
128.5, 128.40, 128.38, 128.3, 128.1, 127.4, 123.9, 120.8, 116.0, 115.1,
114.0, 108.1, 74.7, 70.0, 67.4, 55.3; MS (ESI-TOF) m/z 647 (100,
[MþH]þ).
7. Meunier, S.; Hane´danian, M.; Desage-El Murr, M.; Nowaczyk, S.; Le Gall, T.; Pin,
´
S.; Renault, J.-P.; Boquet, D.; Creminon, C.; Mioskowski, C.; Taran, F. Chem. Bio.
Chem. 2005, 6, 1234–1241.
4.9.2. Methyl [3-hydroxy-4-(4-methoxyphenyl)-5-oxo-5H-furan-2-
ylidene]phenylacetate; pinastric acid (13b)
8. For a report of the antioxidant properties of a pulvinic acid, variegatic acid, see:
Kasuga, A.; Aoagi, Y.; Sugahara, T. J. Food Sci. 1995, 60, 1113–1115.
9. Volhard, J. Liebigs Ann. Chem. 1894, 282, 1–21.
10. (a) Frank, R. L.; Clark, G. R.; Coker, J. N. J. Am. Chem. Soc. 1950, 72, 1824–1826; (b)
Wikholm, R. J.; Moore, H. W. J. Am. Chem. Soc. 1972, 94, 6152–6158; (c)
Pattenden, G.; Pegg, N.; Kenyon, R. J. Chem. Soc., Perkin Trans. 11991, 2363–2371.
11. Heurtaux, B.; Lion, C.; Le Gall, T.; Mioskowski, C. J. Org. Chem. 2005, 70,
1474–1477.
12. (a) Åkermark, B. Acta Chem. Scand. 1961, 15, 1695–1700; (b) Beaumont, P. C.;
Edwards, R. L.; Elsworthy, G. J. Chem. Soc. C 1968, 2968–2974; (c) Edwards, R. L.;
Gill, M. J. Chem. Soc., Perkin Trans. 1 1973, 1529–1537.
13. (a) Weinstock, J.; Blank, J. E.; Oh, H. J.; Sutton, B. M. J. Org. Chem. 1979, 44, 673–
675; (b) Knight, D. W.; Pattenden, G. J. Chem. Soc., Perkin Trans. 1 1979, 84–88;
(c) Pattenden, G.; Pegg, N.; Smith, A. G. Tetrahedron Lett. 1986, 27, 403–406; (d)
Gedge, D. R.; Pattenden, G.; Smith, A. G. J. Chem. Soc., Perkin Trans. 1 1991, 2127–
2131; (e) Ramage, R.; Griffiths, G. J.; Sweeney, J. N. A. J. Chem. Soc., Perkin Trans. 1
1984, 1547–1553; (f) Pattenden, G.; Turvill, M. W.; Chorlton, A. P. J. Chem. Soc.,
Perkin Trans. 1 1991, 2357–2361.
14. (a) Desage-El Murr, M.; Nowaczyk, S.; Le Gall, T.; Mioskowski, C.; Amekraz, B.;
Moulin, C. Angew. Chem., Int. Ed. 2003, 42, 1289–1293; (b) Desage-El Murr, M.;
Nowaczyk, S.; Le Gall, T.; Mioskowski, C. Eur. J. Org. Chem. 2006, 1489–1498.
15. (a) Ahmed, Z.; Langer, P. J. Org. Chem. 2004, 69, 3753–3757; (b) Ahmed, Z.;
Langer, P. Tetrahedron 2005, 61, 2055–2063.
16. Bourdreux, Y.; Nowaczyk, S.; Billaud, C.; Mallinger, A.; Willis, C.; Desage-El
Murr, M.; Toupet, L.; Lion, C.; Le Gall, T.; Mioskowski, C. J. Org. Chem. 2008, 73,
22–26.
17. (a) Langer, P.; Schneider, T.; Stoll, M. Chem.dEur. J. 2000, 6, 3204–3214; (b)
Langer, P.; Eckardt, T.; Schneider, T.; Go¨bel, C.; Herbst-Irmer, R. J. Org. Chem.
2001, 66, 2222–2226; (c) Langer, P. Synlett 2006, 3369–3381.
18. (a) For reviews on the Suzuki–Miyaura reaction, see: Kotha, S.; Lahiri, K.;
Kashinath, D. Tetrahedron 2002, 58,, 9633–9695; (b) Miyaura, N.; Suzuki, A.
Chem. Rev. 1995, 95, 2457–2483.
Mp¼203–205 ꢁC (lit.10c 207–209 ꢁC); IR (KBr pellet) nmax¼3745,
3018, 2959, 2841, 2535, 1772, 1674, 1600, 1514, 1493, 1441, 1370,
1308, 1278, 1254, 1189, 1063, 1024, 959, 905, 844, 700 cmꢀ1 1H
;
NMR (400 MHz, CDCl3):
d
¼8.14 (d, J¼8.9 Hz, 2H, Ar–H), 7.45–7.40
(m, 3H, Ar–H), 7.30–7.25 (m, 2H, Ar–H), 6.98 (d, J¼8.9 Hz, 2H, Ar–H),
3.89 (s, 3H, CH3), 3.86 (s, 3H, CH3); 13C NMR (100 MHz, CDCl3):
d
¼171.7, 166.1, 159.6, 158.6, 155.0, 132.1, 130.0, 129.4, 128.5, 128.1,
121.6, 115.2, 113.9, 105.3, 55.3, 54.3.
4.9.3. Methyl [3-hydroxy-4-(3-hydroxyphenyl)-5-oxo-5H-furan-2-
ylidene]phenylacetate (13c)
Yellow solid. Mp¼192–194 ꢁC; IR (KBr pellet) nmax¼3368, 3056,
2925, 2472, 2361, 1745, 1715, 1674, 1608, 1493, 1437, 1381, 1323,
1305, 1287, 1230, 1157, 1078, 1063, 998, 966, 853, 793, 733, 695, 642,
600 cmꢀ1; 1H NMR (400 MHz, acetone-d6):
d
¼8.28 (s, 1H, OH), 7.71
(m, 1H, Ar–H), 7.67 (d, J¼8.0 Hz, 1H, Ar–H), 7.50–7.35 (m, 5H, Ar–H),
7.23 (t, J¼8.0 Hz, 2H, Ar–H), 7.77 (dd, J¼8.4, 2.0 Hz, 1H, Ar–H), 3.90
(s, 3H, CO2CH3); HRMS (ESI-TOF) (m/z): calcd for C19H14NaO6
[MþNa]þ 361.0688, found: 361.0694.
4.9.4. Methyl [3-hydroxy-4-(4-methoxyphenyl)-5-oxo-5H-furan-2-
ylidene](4-hydroxyphenyl)acetate (13i)
Orange solid. Mp¼210–212 ꢁC; IR (KBr pellet) nmax¼3412, 3243,
3007, 2921, 2841, 2549, 1732, 1678, 1596, 1514, 1439, 1413, 1371,
1314, 1278, 1248, 1187, 1177, 1158, 1107, 1064, 1028, 973, 912, 885,
19. For examples of syntheses of butenolides that make use of both an alkylide-
nation and a Suzuki cross-coupling, see: (a) Boukouvalas, J.; Lachance, N.;
Ouellet, M.; Trudeau, M. Tetrahedron Lett. 1998, 39, 7665–7668; (b) Bellina, F.;
Anselmi, C.; Rossi, R. Tetrahedron Lett. 2002, 43, 2023–2027; (c) Boukouvalas, J.;
Pouliot, M. Synlett 2005, 343–345; (d) Antane, S.; Caufield, C. E.; Hu, W.;
Keeney, D.; Labthavikul, P.; Morris, K.; Naughton, S. M.; Petersen, P. J.;
Rasmussen, B. A.; Singh, G.; Yang, Y. Bioorg. Med. Chem. Lett. 2006, 176–180.
841, 784, 769, 752, 711, 682, 648, 583, 535, 522 cmꢀ1 1H NMR
;
(400 MHz, acetone-d6):
d
¼8.80 (dd, J¼7.2, 2.0 Hz, 2H, Ar–H), 7.25
(dd, J¼6.8, 2.0 Hz, 2H, Ar–H), 7.02 (d, J¼8.8 Hz, 2H, Ar–H), 6.89 (dd,
J¼6.8, 2.0 Hz, 2H, Ar–H), 3.91 (s, 3H, CH3), 3.85 (s, 3H, CH3); 13C

Y. Bourdreux et al. / Tetrahedron 64 (2008) 8930–8937
8937
20. Willis, C.; Bodio, E.; Bourdreux, Y.; Billaud, C.; Le Gall, T.; Mioskowski, C. Tet-
rahedron Lett. 2007, 48, 6421–6424.
24. Occhiato, E. G.; Trabocchi, A.; Guarna, A. J. Org. Chem. 2001, 66, 2459–
2465.
21. Bajwa, J. S.; Anderson, R. C. Tetrahedron Lett. 1990, 31, 6973–6976.
22. (a) Cossy, J.; Bellosta, V.; Ranaivosata, J. L.; Gille, B. Tetrahedron 2001, 57, 5173–
5182; (b) Narasaka, K. Org. Synth. 1987, 65, 12–14.
25. Paintner, F. F.; Allmendinger, L.; Bauschke, G. Synlett 2003, 83–86.
26. Pollet, P.; Gelin, S. Tetrahedron 1978, 34, 1453–1455.
ˇˇ
27. Gordon, E. M.; Pluscec, J. J. Org. Chem. 1979, 44, 1218–1221.
23. Zhang, F. J.; Li, Y. L. Synthesis 1993, 565–567 and references therein.
28. Mattingly, P. G.; Miller, M. J. J. Org. Chem. 1981, 46, 1557–1564.