Synthesis of pulvinic acid and norbadione A analogues by Suzuki-Miyaura cross-coupling of benzylated intermediates

Article abstract of DOI:10.1002/ejoc.200500837

Pulvinic acid and norbadione A analogues can be prepared by Suzuki-Miyaura cross-coupling of functionalized aryl-boronic esters with appropriate vinyl inflates, in which the hydroxy functions are protected either with methyl or benzyl groups, the latter being cleaved in a more reliable fashion at the end of the synthetic sequence. Wiley-VCH Verlag GmbH & Co. KGaA, 2006.

Full text of DOI:10.1002/ejoc.200500837

FULL PAPER
DOI: 10.1002/ejoc.200500837
Synthesis of Pulvinic Acid and Norbadione A Analogues by Suzuki–Miyaura
Cross-Coupling of Benzylated Intermediates
Marine Desage-El Murr,[a] Stéphanie Nowaczyk,[a] Thierry Le Gall,*[a] and
Charles Mioskowski[a,b]
Keywords: Boronic esters / Cross-coupling / Heterocycles / Natural products / Synthetic methods
Pulvinic acid and norbadione A analogues can be prepared
by Suzuki–Miyaura cross-coupling of functionalized aryl-
boronic esters with appropriate vinyl triflates, in which the
hydroxy functions are protected either with methyl or benzyl
groups, the latter being cleaved in a more reliable fashion at
the end of the synthetic sequence.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
We have recently become interested in developing a con- diacid 3, an analogue of norbadione A, would be obtained
venient synthetic approach towards the mushroom pigment from the product of such a reaction involving a bis(boron-
norbadione A (1) and analogues.[1] This compound was ate) 4 and two equivalents of a vinyl triflate 5 (Scheme 1).
first isolated by Steglich et al.[2] from the edible mushroom The method can also be applied to the synthesis of pulvinic
bay boletus [Xerocomus badius (Fr.) Kühn. ex Gilb.] and by acids by using triflate 5 and an aryl boronate 6 as the reac-
Gill et al.[3] from Pisolithus tinctorius (Pers.) Coker et tion partners in the cross-coupling step (Scheme 1).[1] Inter-
Couch. Norbadione A has been shown to have interesting estingly, this approach would be suitable for the synthesis
properties. For example, it can form a complex with caes- of unsymmetrical pulvinic acids in which the two aryl
ium cation, which may account for the high levels of radio- groups Ar and ArЈ are different, which are less easily pre-
active caesium found in bay boletus following the Cherno- pared than the symmetrical ones.[7,8] The method chosen
byl accident.[1,4,5] It was also recently shown to have antiox- for the preparation of the triflate 5 relies essentially on the
idant properties.[6] Norbadione A is structurally related to cyclocondensation of a bis(silylated) diene with oxalyl chlo-
the larger pigment family of pulvinic acids 2.[7]
ride reported by Langer et al.[9] Following the publication
by this group of the synthesis of pulvinic acids, which is
based on a similar strategy,[10] we now report our own re-
sults on the preparation of pulvinic acids and norbadione
A-related products.
Our synthetic approach towards 1 was mainly based on
the use of a double Suzuki–Miyaura cross-coupling to con-
nect the two identical enolic lactone moieties simulta-
neously to the naphthalene part of the molecule. Hence,
[a] CEA-Saclay, Service de Marquage Moléculaire et de Chimie
Bioorganique, Bât. 547,
91191 Gif-sur-Yvette, France
[b] Laboratoire de Synthèse Bio-Organique, UMR CNRS 7514,
Faculté de Pharmacie, Université Louis Pasteur,
74 route du Rhin, B.P. 24, 67401 Illkirch, France
Fax: +33-1-69087991
E-mail: legall@dsvidf.cea.fr
mioskow@aspirine.u-strasbg.fr
Scheme 1.
Eur. J. Org. Chem. 2006, 1489–1498
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M. Desage-El Murr, S. Nowaczyk, T. Le Gall, C. Mioskowski
FULL PAPER
Preparation of Triflates 5a–c
0.3 equivalents of trimethylsilyl triflate as catalyst, in
dichloromethane at –78 °C.[9] Lactones 11a and 11b were
obtained in fair yields. The yield of adduct 11c was signifi-
cantly lower, probably due to the unfavorable steric interac-
tions with the benzyl protecting group R1. In each case,
only the (E)-configured stereoisomer was obtained. The
corresponding triflates 5a–c were then obtained efficiently
by treatment with triflic anhydride in the presence of pyri-
dine. With these synthetic intermediates in hand, the prepa-
ration of pulvinic acid derivatives could be envisioned.
Triflates 5a–c were prepared as described in Scheme 2.
They differ in the groups (methyl or benzyl) employed for
the protection of the hydroxy functions. Benzyl ethers were
expected to be cleavable under milder conditions than
methyl ethers. Such protecting groups have been previously
employed in the context of pulvinic acids’ synthesis.[11] The
β-keto esters 9a–c were obtained by Claisen condensa-
tion[12] of aryl acetates 7a or 7b with the appropriate alkoxy
acetate 8a or 8b. The anion of aryl acetate 7a was generated
at –78 °C in THF by treatment with lithium diisopro-
pylamide. The less soluble anion of 7b was generated in a
THF/HMPA mixture. It was necessary to use a twofold ex-
cess of the aryl acetate vs. the alkoxy acetate.
Synthesis of Pulvinic Acid Derivatives
Cross-coupling conditions were first tested with phen-
ylboronic acid (12). The reaction of the model triflate 13[9c]
under the usual conditions {K3PO4, [Pd(PPh3)4], dioxane,
reflux} worked well, leading to compound 14 in 71% yield
(Scheme 3). Analogous conditions applied to triflate 5a
therefore allowed the preparation of the pulvinic acid deriv-
ative 15 in 86% yield. Comparison of the physical and spec-
troscopic data of compound 15 with the values reported for
both stereoisomers, which had been previously synthe-
sized,[13] allowed the unambiguous assignment of the (E)
configuration for this compound.
Scheme 2. Reagents and conditions: a) iPr2NLi, THF or THF/
HMPA, –78 °C, then methyl methoxyacetate (8a) or methyl (ben-
zyloxy)acetate (8b); b) i. Et3N, ClSiMe3, THF, room temperature,
12 h, ii. iPr2NLi, ClSiMe3, THF, –78 °C to room temperature, 3 h;
c); oxalyl chloride (1 equiv.), TfOSiMe3 (0.3 equiv.), CH2Cl2,
–78 °C to room temperature, overnight d) Tf2O (1.2 equiv.), pyri-
dine (2.5 equiv.), CH2Cl2, –78 °C to room temperature, 4 h.
Scheme 3. Reagents and conditions: a) K3PO4 (1.5 equiv.),
[Pd(PPh3)4] (3 mol-%), dioxane, reflux, 4 h.
The cleavage of the methyl protecting groups of pulvinic
acid derivative 15 with iodotrimethylsilane has been de-
scribed previously.[13] Under analogous conditions, we ob-
tained mixtures of partially and fully deprotected pulvinic
Compounds 9a–c were then converted in two steps into compounds. We thus preferred to carry out the syntheses
the corresponding bis(trimethylsilyloxy)dienes 10a–c. The of other pulvinic compounds from triflate 5b, in which the
first silylation was carried out using chlorotrimethylsilane enol and phenol functions are protected as benzyl ethers.
in the presence of triethylamine. The second one employed
In order to access norbadione A analogues containing
lithium diisopropylamide as the base and chlorotrimethyl- two pulvinic moieties, we first envisaged using a naphtha-
silane. The products were dried thoroughly and were not lenic compound substituted by two boronic acids, which
purified further. Compounds 10a and 10b are fairly stable would be obtained from the bis(boronate) 4, in the cross-
and can be stored for several months at –18 °C, while com- coupling step. However, cleavage of the boronic ester moie-
pound 10c is unstable and was thus used rapidly in the next ties was found to be difficult. Hence, the cross-coupling had
reaction. Two stereoisomers were usually observed in the to be carried out using boronate esters. Various unsuccess-
1H NMR spectra of these compounds, in varying pro- ful conditions employing either [PdCl2(dppf)] or
portions.
[Pd(PPh3)4] as catalyst were tried at first. However, the pro-
The cyclocondensation of the silylated compounds 10a– cedure developed by Occhiato et al.[14] for the cross-coup-
c with oxalyl chloride was performed in the presence of ling of vinyl triflates with pinacol boronate esters, which
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Eur. J. Org. Chem. 2006, 1489–1498

Synthesis of Pulvinic Acid and Norbadione A Analogues
FULL PAPER
employs [PdCl2(PPh3)2] as catalyst in 4:1 2  aqueous Table 2. Hydrogenolysis of pulvinic acid derivatives 16 and 17.
Na2CO3/THF at 80 °C, proved to be very satisfactory. Se-
veral arylboronates 6a–e were reacted with 5b under the
above-mentioned conditions (Table 1).
Table 1. Preparation of pulvinic acid derivatives by cross-coupling
of boronates 6 with triflates 5.
Entry Start-
ing
R
R1 R2
Prod- R1
uct
R2 18
mate-
[%
rial
yield]
1
2
3
4
5
16a
16b
16c
17d
16e
Bn
Bn OH
H
H
H
18a
18b
18c
18d
H
H
H
H
98
99
87
OH
OMe
H
Bn OMe H
OH
H
H
OH 47
OH 35
Bn OBn OBn 18e
OH
Entry Bo-
ronate
R1
R2
Yield of 16
Yield of 17
ral product atromentic acid (2b)[15,17] were in good agree-
ment with the reported values. To the best of our knowl-
edge, 4-O-methylatromentic acid (2c) has not been synthe-
sized previously. Attempted saponifications of esters 18d
and 18e in the presence of LiOH were not successful, lead-
ing to the degradation of these compounds.
[%]
[%]
1
2
3
4
5
6a
H
H
H
H
OH
OBn
97
67
85
6b
6c
6d
6e
OH
OMe
H
99
OBn
99
The reactions proceeded with good to excellent yields,
thus showing that the presence of the enol benzyl protecting
group is not detrimental to the cross-coupling. However,
adduct 17, resulting from the cleavage of this protecting
group, was obtained as a by-product in some experiments,
and the reaction of triflate 5b with boronate 6d, in which
the phenyl group is substituted by a hydroxy function in the
meta position, led exclusively to compound 17d.
The hydrogenolysis of the benzyl ethers of the cross-
coupling adducts was then carried out using 20% palladium
on carbon (Table 2). The reactions were conducted at first
in methanol or ethanol, but this led to complex mixtures.
In dichloromethane, the reactions were more satisfactory,
although some reduction of the exocyclic double bond of
the compounds occurred after long reaction times.
Scheme 4.
Compounds 18a–c were obtained in very good yields (en-
tries 1–3). These compounds have been described previously
(18a,[15] 18b,[15] 18c[16]) and the spectroscopic and physical
data agree well with the reported values. Compounds 18d
and 18e were obtained in much lower yields. The deprotec-
tion of 16e, which contains four benzyl groups, required the
Preparation of a Naphthalene-Derived Compound
Containing Two Pulvinic Moieties
The possibility to carry out a double cross-coupling
use of a larger amount of palladium. Besides the expected using triflate 5a–c and the bis(boronate) 4 derived from 1,7-
methyl ester 18e, a by-product, which could not be isolated dihydroxynaphthalene (19) was then examined. Compound
in a pure form and which may correspond to the (Z)-isomer 4 was prepared from the known bis(triflate) 20,[18] obtained
of 18e, was formed.
by reaction of 19 with triflic anhydride in pyridine
Saponification of esters 18a–c using 0.25  LiOH (reflux, (Scheme 5). The palladium-catalyzed borylation of aryl tri-
2 hours) proceeded efficiently, leading to the expected acids flates using pinacolborane, according to the method devel-
19a–c (Scheme 4). The spectroscopic and physical data ob- oped by Masuda et al.,[19] enabled the preparation of
served for 4Ј-hydroxypulvinic acid (2a)[17] and for the natu- bis(boronate) 4 in 45% yield.
Eur. J. Org. Chem. 2006, 1489–1498
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M. Desage-El Murr, S. Nowaczyk, T. Le Gall, C. Mioskowski
FULL PAPER
Table 3. Treatment of compounds 21a–c with iodotrimethylsilane.
Scheme 5. Reagents and conditions: a) Tf2O, pyridine, 95%; b) pin-
acolborane (6 equiv.), [PdCl2(dppf)] (0.06 equiv.), Et3N (12 equiv.),
dioxane, 80 °C, 13 h, 45%.
En- Start- R1 R2
ing
try mate-
rial
x
y
Yield of di- Yield of diester
acid 3
22
[%]
[h]
[%]
Several attempts to cleave the boronate groups of 4, with
the aim of obtaining 1,7-naphthalenediboronic acid, were
unsuccessful. We thus employed 4 directly in the cross-
coupling reactions with the three triflates 5a–c (two equiva-
lents), again under the conditions described above, which
allowed the formation of the corresponding bis(pulvinic)
acid adducts 21a–c (Scheme 6).
[a]
[a]
1
2
3
4
21a
21b
21b
21c
Me Me 15 48
Me Bn 15 18
Me Bn 20 8.5
–
–
–
37[b]
65
–
[b]
–
60
Bn Bn 15
2
[a] A mixture of deprotected products was obtained. [b] A mixture
of deprotected products was also obtained as by-products.
aryl group rather than to the naphthalene). Treatment of
compound 21b with 15 equivalents of iodotrimethylsilane
for 18 h led to a mixture of compounds from which the
expected deprotected diacid 3 was isolated in 37% yield (en-
try 2). Increasing the quantity of iodotrimethylsilane to
20 equivalent allowed us to reduce the reaction time to
8.5 hours and to improve the yield of 3 to 65% (entry 3).
As benzyl groups are cleaved much more easily than the
methyl groups, it was possible to prepare diester 22 in 60%
yield by treatment of 21c with iodotrimethylsilane
(15 equivalents) for 2 h (entry 4).
Eventually, the preparation of bis(pulvinic acid) 3 was
performed under the conditions previously described for the
preparation of pulvinic acid derivatives 2a–c. Thus, hydro-
genolysis of compound 21c proceeded efficiently, leading to
diester 22 in 90% yield. Hydrolysis of the two methyl ester
functions in the presence of 2.5  NaOH then afforded di-
acid 3 in 90% yield. (Scheme 7).
Scheme 6.
Although it was suspected that the boron environment in
the compounds arising from the first cross-coupling would
be significantly sterically crowded, thus threatening the oc-
currence of the second cross-coupling, fair yields of adducts
21a–c were nevertheless obtained. These compounds were
characterized by 1H and 13C NMR spectroscopy and by
HRMS.
Cleavage of the protecting groups of compounds 21a–c
was then attempted, first by treatment with iodotrimethyl-
silane in CDCl3 at 60 °C (Table 3).
Scheme 7. Reagents and conditions: a) i. H2, Pd/C, CH2Cl2, room
temp., 40 h, 90%; ii. 2.5  aq. Na2CO3, reflux, 2 h, 90%.
We observed that, when applied to the permethylated de-
In conclusion, the synthesis of several pulvinic acid de-
rivative 21a, the deprotection of all the hydroxy groups re- rivatives has been described. The general procedure makes
quired 48 hours, even in the presence of 15 equivalents of use of the cyclocondensation developed by Langer and of
iodotrimethylsilane (entry 1); however, this actually led to a Suzuki–Miyaura coupling of vinyl triflates and arylboronic
mixture of compounds, probably formed by isomerization esters. Benzyl protecting groups have been shown to be
of the double bonds as well as shift of the lactone moieties cleaved more reliably than methyl groups in this context. A
(i.e. to compounds where a lactone moiety is bonded to the route to norbadione A analogues has been developed,
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Synthesis of Pulvinic Acid and Norbadione A Analogues
FULL PAPER
743, 700 cm–1. H NMR (CDCl3, 300 MHz): δ = 7.30–7.39 (m, 5
H, Ph-H), 4.64 (s, 2 H, OCH2CO), 4.12 (s, 2 H, CH2Ph), 3.76 (s,
2 H, CH3O) ppm. 13C NMR (CDCl3, 75 MHz): δ = 170.5, 135.5,
128.2, 128.1, 127.9, 73.1, 66.9, 51.6 ppm.
1
which should be useful in view of the chemical synthesis of
this unusual mushroom pigment.
General Procedure for the Preparation of β-Keto Esters. Synthesis
of Methyl 4-Methoxy-2-(4-methoxyphenyl)-3-oxobutanoate (9a): A
solution of lithium diisopropylamide (2  in THF; 42 mL,
83.8 mmol) was added over 20 min, from a dropping funnel, to a
solution of methyl (4-methoxyphenyl)acetate (7a; 13.3 mL,
83.8 mmol) and HMPA (3.0 mL, 16.8 mmol) in THF (50 mL) co-
oled to –78 °C. After stirring for 1 h at –78 °C, methyl methoxyace-
tate (8a; 4.2 mL, 41.9 mmol) was added dropwise with a syringe.
The reaction mixture was warmed to room temperature overnight
whilst stirring. A saturated aqueous NH4Cl solution was added
and the aqueous phase was extracted with CH2Cl2. The combined
organic phases were washed with saturated aqueous NH4Cl solu-
tion, dried with MgSO4, filtered, and concentrated under vacuum.
Silica gel chromatography (9:1 pentane/AcOEt) afforded keto ester
9a as a white solid (8.1 g, 77%). M.p. 44 °C. TLC: Rf = 0.45
Experimental Section
General: THF was freshly distilled from sodium benzophenone ke-
tyl. Dichloromethane was freshly distilled from over P2O5. Moist-
ure-sensitive reactions were performed in a flame-dried flask, under
argon. TLC: silica gel 60F254 plates, with detection by UV light
and with an ethanol solution of phosphomolybdic acid. Column
chromatography: 40–63-µm silica gel. Melting points are uncor-
rected. NMR: 300.13 MHz for 1H, 75.47 MHz MHz for 13C.
Chemical shifts (δ) are in ppm; coupling constants (J) are in Hz.
Methyl (4-Hydroxyphenyl)acetate:[20]
A
solution of (4-hy-
droxyphenyl)acetic acid (8.9 g, 59 mmol, 1 equiv.) and BF3·Et2O
(0.9 mL) in methanol (100 mL) was stirred under argon at room
temperature for 11 h. Saturated aqueous NaHCO3 solution
(100 mL) was then added. The aqueous phase was extracted with
ethyl acetate (3×40 mL) and the combined organic phases were
dried with MgSO4, filtered, and concentrated under vacuum to af-
ford methyl (4-hydroxyphenyl)acetate (9.6 g, 98%) as a colorless
oil, which was used in the next reaction without further purifica-
tion. TLC: Rf = 0.30 (8:2 pentane/AcOEt). 1H NMR (CDCl3,
300 MHz): δ = 7.11 (d, J = 8.5 Hz, 2 H, Ar-H), 6.77 (d, J = 8.5 Hz,
2 H, Ar-H), 3.72 (s, 3 H, CH3O), 3.58 (s, 2 H, CH2) ppm. 13C
NMR (CDCl3, 75 MHz): δ = 173.3, 155.1, 130.2, 125.0, 115.4, 52.0,
40.1 ppm.
(CH Cl ). IR (KBr pellet): ν = 3434, 3013, 2960, 2836, 1741, 1612,
˜
2
2
1515, 1449, 1212, 1025, 825, 741 cm–1. 1H NMR (CDCl3,
300 MHz): δ = 7.22 (d, J = 9.1 Hz, 2 H, Ar-H), 6.86 (d, J = 9.1 Hz,
2 H, Ar-H), 4.87 (s, 1 H, CHCO2Me), 4.04 (d, J = 13.1 Hz, 1 H,
CHHOMe), 4.03 (d, J = 13.1 Hz, 1 H, CHHOMe), 3.74 (s, 3 H,
CO2Me), 3.68 (s, 3 H, CH3OAr), 3.30 (s, 3 H, CH3OCH2) ppm.
13C NMR (CDCl3, 75 MHz): δ = 202.0, 169.0, 159.5, 132.0, 130.6,
123.7, 114.2, 113.6, 69.6, 59.8, 59.3, 55.2, 52.5 ppm. C16H16O5
(252.26): calcd. C 61.90, H 6.39; found C 61.96, H 6.39.
Methyl 2-[4-(Benzyloxy)phenyl]-4-methoxy-3-oxobutanoate (9b):
Following the general procedure, keto ester 9b was prepared from
methyl [4-(benzyloxy)phenyl]acetate (7b; 11.7 g, 45.6 mmol) and
methyl methoxyacetate (8a; 2.3 mL, 22.8 mmol). After chromato-
graphic purification, keto ester 9b was obtained as a white solid
(4.3 g, 58%). M.p. 55 °C. TLC: Rf = 0.35 (9:1 pentane/AcOEt). IR
Methyl [4-(Benzyloxy)phenyl]acetate (7b):[21] Benzyl bromide
(17.85 mL, 150 mmol) was added to a suspension of methyl (4-
hydroxyphenyl)acetate (25 g, 150 mmol) and potassium carbonate
(20.73 g, 150 mmol) in acetone (300 mL). The reaction mixture was
then refluxed for 18 h. After cooling to room temperature, the sus-
pension was filtered and the filtrate was concentrated under vac-
uum. Chloroform (200 mL) was added to the residue. The organic
phase was washed successively with water (2×50 mL) and brine
(50 mL), dried with MgSO4, filtered, and concentrated under vac-
uum. Hexane was added and after overnight storage, precipitation
occurred. After filtration, methyl [4-(benzyloxy)phenyl]acetate (7b)
was obtained as colorless needles (34.94 g, 91%). M.p. 59–60 °C
(ref.[21] 61–62 °C). TLC: Rf = 0.70 (8:2 pentane/AcOEt). IR (KBr
(KBr pellet): ν = 2948, 1741, 1512, 1308, 1246, 1217, 1183, 1105,
˜
1
1008, 750, 698 cm–1. H NMR (CDCl3, 300 MHz): δ = 7.28–7.47
(m, 7 H, Ar-H and Ph-H), 7.01 (d, J = 8.6 Hz, 2 H, Ar-H), 5.08
(s, 2 H, CH2Ph), 4.95 (s, 1 H, CHCO2Me), 4.09 (d, J = 13.2 Hz, 1
H, CHHOMe), 4.07 (d, J = 13.2 Hz, 1 H, CHHOMe), 3.74 (s, 3
H, CO2Me), 3.37 (s, 3 H, CH3OCH2) ppm. 13C NMR (CDCl3,
75 MHz): δ = 201.9, 168.9, 158.7, 136.7, 132.1, 130.6, 128.4, 127.3,
123.9, 115.4, 69.8, 59.7, 59.1, 52.4 ppm. C19H20O5 (328.36): calcd.
C 69.49, H 6.14; found C 69.49, H 6.17.
pellet): ν = 2957, 2923, 1726, 1509, 1267, 1233, 1170, 1010 cm–1.
˜
1H NMR (CDCl3, 300 MHz): δ = 7.39–7.45 (m, 5 H, Ph-H), 7.23
(d, J = 8.6 Hz, 2 H, Ar-H), 6.97 (d, J = 8.6 Hz, 2 H, Ar-H), 5.08
(s, 2 H, CH2Ph), 3.72 (s, 3 H, CH3O), 3.60 (s, 2 H, CH2CO2Me)
ppm. 13C NMR (CDCl3, 75 MHz): δ = 172.1, 157.8, 136.8, 130.1,
128.4, 127.8, 127.3, 126.1, 114.7, 69.8, 51.8, 40.1 ppm. C16H16O3
(256.30): calcd. C 74.98, H 6.29; found C 74.66, H 6.29. MS (CI/
NH3): m/z = 274 [M + NH4]+.
Methyl 4-(Benzyloxy)-2-[4-(benzyloxy)phenyl]-3-oxobutanoate (9c):
Following the general procedure, keto ester 9c was prepared from
methyl [4-(benzyloxy)phenyl]acetate (7b; 29.7 g, 115.8 mmol) and
methyl (benzyloxy)acetate (8b; 10.4 g, 57.9 mmol). After chromato-
graphic purification, keto ester 9c was obtained as a white solid
(11.5 g, 49%). M.p. 56 °C. TLC: Rf = 0.05 (8:2 pentane/AcOEt).
IR (KBr pellet): ν = 2964, 1747, 1721, 1511, 1160, 823, 693 cm–1.
˜
Methyl (Benzyloxy)acetate (8b):[22] Thionyl chloride (2.6 mL,
35.6 mmol) was added dropwise with a syringe to methanol
(21 mL) at 0 °C and the resulting solution was stirred for 20 min.
A solution of (benzyloxy)acetic acid (5 g, 30 mmol) in methanol
(9 mL) was then added dropwise from a dropping funnel. After
stirring for 4 h at room temperature, the solution was concentrated
under vacuum. Methylene chloride (200 mL) was added to the resi-
due. The organic phase was washed successively with a saturated
aqueous NaHCO3 solution (2×50 mL) and water (2×50 mL),
dried with MgSO4, filtered, and concentrated under vacuum to af-
ford methyl ester 8b (5.2 g, 97%) as a colorless oil, which was used
in the next reaction without further purification. TLC: Rf = 0.55
1H NMR (CDCl3, 300 MHz): δ = 7.24–7.43 (m, 12 H, Ar-H and
Ph-H), 6.98 (d, J = 8.5 Hz, 2 H, Ar-H), 5.08 (s, 2 H, OCH2Ph),
4.97 (s, 1 H, CHCO2Me), 4.56 (d, J = 12.2 Hz, 1 H, OCHHPh),
4.51 (d, J = 12.2 Hz, 1 H, OCHHPh), 4.19 (d, J = 16.5 Hz, 1 H,
CHHOBn), 4.13 (d, J = 16.5 Hz, 1 H, CHHOBn), 3.73 (s, 3 H,
CO2Me) ppm. 13C NMR (CDCl3, 75 MHz): δ = 201.9, 168.9,
158.7, 136.8, 136.7, 130.6, 128.7, 128.5, 128.3, 127.9, 127.7, 127.3,
123.9, 115.0, 73.3, 69.9, 66.9, 59.9, 52.4 ppm. C25H24O5 (404.46):
calcd. C 74.20, H 5.98; found C 74.07, H 5.98.
General Procedure for the Preparation of Bis(silylated) Compounds
10a–c. Synthesis of 4-Methoxy-6-(methoxymethylene)-5-(4-meth-
oxyphenyl)-2,2,8,8-tetramethyl-3,7-dioxa-2,8-disilanon-4-ene (10a):
(CH Cl ). IR (NaCl, film): ν = 3031, 2952, 1755, 1439, 1211, 1128,
˜
2
2
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M. Desage-El Murr, S. Nowaczyk, T. Le Gall, C. Mioskowski
FULL PAPER
Et3N (3.8 mL, 26.8 mmol) and Me3SiCl (3.7 mL, 29.1 mmol) were
added to a solution of keto ester 9a (2.8 g, 11.1 mmol) in 20 mL of
THF and the reaction mixture was allowed to stir at room tempera-
ture overnight. The solvents were evaporated and pentane (20 mL)
was added. The resulting suspension was filtered through millipore
to yield the monosilylated derivative. A solution of this monosilyl-
ated derivative (3.9 g, 12.0 mmol) in 15 mL of THF was cooled to
–78 °C and lithium diisopropylamide (12 mL, 24 mmol) was added.
The reaction mixture was stirred at –78 °C for 1 h before Me3SiCl
(3.6 mL, 28.6 mmol) was added. Further agitation at –78 °C was
continued for 1 h, after which the reaction mixture was warmed to
room temperature over 4 h. The solvents were evaporated and pen-
tane (20 mL) was added. The resulting suspension was filtered
through millipore to yield the bis(silylated) derivative 10a as an
orange oil (4.7 g, quantitative). 1H NMR (CDCl3, 300 MHz):
major isomer δ = 7.24–7.31 (m, 2 H, Ar-H), 6.84 (d, J = 8.5 Hz, 2
H, Ar-H), 5.62 (s, 1 H, =CHOMe), 3.80 (s, 3 H, CO2Me), 3.56 (s,
3 H, CH3OAr), 3.46 (s, 3 H, -CHOCH3), 0.30 [s, 9 H, OSi(CH3)3],
0.04 [s, 9 H, OSi(CH3)3] ppm. 13C NMR (CDCl3, 75 MHz): δ =
157.2, 153.1, 134.2, 131.5, 130.4, 128.7, 112.8, 97.5, 58.9, 56.1, 54.9,
0.3, 0.1 ppm.
124.7, 114.7, 59.9, 55.4, 52.5 ppm. C15H14O7 (306.27): calcd. C
58.82, H 4.61; found C 59.07, H 4.92.
Methyl (4-Benzyloxyphenyl)[4-hydroxy-3-methoxy-5-oxofuran-
2(5H)-ylidene]acetate (11b): Following the general procedure, enol
11b was prepared from bis(silylated) derivative 10b (5.4 g,
11.5 mmol). After chromatographic purification, compound 11b
was obtained as a pale-yellow solid (2.3 g, 53%). M.p. 144 °C.
TLC: R = 0.15 (8:2 pentane/AcOEt). IR (KBr pellet): ν = 3259,
˜
f
2925, 1772, 1731, 1677, 1603, 1510, 1373, 1231, 1042, 831,
1
741 cm–1. H NMR (CDCl3, 300 MHz): δ = 7.54 (d, J = 9.2 Hz, 2
H, Ar-H), 7.40–7.45 (m, 5 H, Ph-H), 6.99 (d, J = 9.2 Hz, 2 H, Ar-
H), 5.09 (s, 2 H, OCH2Ar), 4.20 (s, 3 H, =COCH3), 3.87 (s, 3 H,
CO2CH3) ppm. 13C NMR (CDCl3, 75 MHz): δ = 166.8, 165.6,
159.7, 159.0, 142.7, 138.5, 130.3, 128.4, 127.8, 127.2, 123.5, 114.0,
113.9, 69.8, 59.8, 52.5 ppm. HRMS: calcd. for C21H18NaO7 [M +
Na]+ 405.0950; found 405.0939.
Methyl [3-(Benzyloxy)-4-hydroxy-5-oxofuran-2(5H)-ylidene](4-ben-
zyloxyphenyl)acetate (11c): Following the general procedure, enol
11c was prepared from bis(silylated) derivative 10c (1.8 g,
3.5 mmol). After chromatographic purification, compound 11c was
obtained as a white solid (0.6 g, 38%). M.p. 119 °C. TLC: Rf =
5-(4-Benzyloxyphenyl)-4-methoxy-6-(methoxymethylene)-2,2,8,8-
tetramethyl-3,7-dioxa-2,8-disilanon-4-ene (10b): Following the gene-
ral procedure, bis(silylated) derivative 10b was prepared from keto
ester 9b (1.4 g, 4.4 mmol). Compound 10b was obtained as an
orange oil (2.1 g, quantitative). 1H NMR (CDCl3, 300 MHz):
major isomer δ = 7.10–7.52 (m, 7 H, Ar-H and Ph-H), 6.95 (d, J
= 9.2 Hz, 2 H, Ar-H), 5.68 (s, 1 H, =CHOMe), 5.09 (s, 2 H,
PhCH2O-), 3.61 (s, 3 H, CH3O), 3.51 (s, 3 H, CH3O), 0.36 [s, 9
H, OSi(CH3)3], 0.09 [s, 9 H, OSi(CH3)3] ppm. 13C NMR (CDCl3,
75 MHz): δ = 156.5, 153.1, 137.2, 134.4, 131.4, 127.3–129.9, 125.4,
114.5, 97.6, 69.7, 58.8, 56.1, 0.3, 0.1 ppm.
0.40 (7:3 pentane/AcOEt). IR (KBr pellet): ν = 3411, 1754, 1675,
˜
1356, 1255, 1143, 1116, 1045 cm–1. 1H NMR (CDCl3, 300 MHz):
δ = 7.51 (d, J = 9.2 Hz, 2 H, Ar-H), 7.40–7.45 (m, 10 H, Ph-H),
6.98 (d, J = 9.2 Hz, 2 H, Ar-H), 5.49 (s, 2 H, OCH2Ph), 5.09 (s, 2
H, ArOCH2Ph), 3.45 (s, 3 H, OCH3) ppm. 13C NMR (CDCl3,
75 MHz): δ = 165.2, 159.7, 142.5, 130.3, 128.5–127.0, 114.8, 113.5,
73.9, 69.8, 52.2 ppm. HRMS: calcd. for C27H22NaO7 [M + Na]+
481.1263; found 481.1243.
General Procedure for the Preparation of Triflates. Synthesis of
Methyl {3-Methoxy-5-oxo-4-[(trifluoromethylsulfonyl)oxy]furan-
2(5H)-ylidene}(4-methoxyphenyl)acetate (5a): Pyridine (1.2 mL,
14.8 mmol) and triflic anhydride (1.2 mL, 7.1 mmol) were added to
a solution of enol 11a (1.8 g, 5.9 mmol) in CH2Cl2 (60 mL) cooled
to –78 °C. The reaction mixture was warmed to room temperature
whilst stirring over 4 h. Water was added and the organic layer was
washed with water, dried with MgSO4, filtered, and concentrated
under vacuum. Silica gel chromatography (8:2 pentane/AcOEt) af-
forded triflate 5a as a yellow solid (2.3 g, 89%). M.p. 93 °C. TLC:
4-(Benzyloxy)-6-(benzyloxymethylene)-5-(4-benzyloxyphenyl)-
2,2,8,8-tetramethyl-3,7-dioxa-2,8-disilanon-4-ene (10c): Following
the general procedure, bis(silylated) derivative 10c was prepared
from keto ester 9c (7.2 g, 17.8 mmol). Compound 10c was obtained
1
as a yellow oil (9.8 g, quantitative). H NMR (CDCl3, 300 MHz):
major isomer δ = 7.20–7.49 (m, 12 H, Ar-H and Ph-H), 6.92 (d, J
= 8.6 Hz, 2 H, Ar-H), 5.83 (s, 1 H, =CHOBn), 5.08 (s, 2 H, Ar-
OCH2Ph), 4.79 (s, 2 H, CH–OCH2Ph), 3.47 (s, 3 H, CO2Me), 0.28
[s, 9 H, OSi(CH3)3], 0.06 [s, 9 H, OSi(CH3)3] ppm.
R = 0.30 (8:2 pentane/AcOEt). IR (KBr pellet): ν = 2961, 1802,
˜
f
1783, 1744, 1733, 1667, 1643, 1604 cm–1 1H NMR (CDCl3,
.
300 MHz): δ = 7.57 (d, J = 9.2 Hz, 2 H, Ar-H), 6.91 (d, J = 9.2 Hz,
2 H, Ar-H), 4.26 (s, 3 H, CH3O–C=), 3.87 (s, 3 H, ArOCH3), 3.80
(s, 3 H, CO2CH3) ppm. 13C NMR (CDCl3, 75 MHz): δ = 165.7,
160.9, 159.9, 155.5, 131.0, 122.2, 120.5, 114.2, 60.8, 55.1, 52.7 ppm.
General Procedure for the Cyclization. Synthesis of Methyl [4-Hy-
droxy-3-methoxy-5-oxofuran-2(5H)-ylidene](4-methoxyphenyl)-
acetate (11a): A solution of bis(silylated) derivative 10a (4.7 g,
11.8 mmol) in 220 mL of degassed CH2Cl2 was placed in a three-
necked, round-bottomed flask fitted with an addition funnel. The
solution was cooled to –78 °C before oxalyl chloride (1.4 mL,
15.3 mmol) was added dropwise with a syringe. A solution of
TMSOTf (0.6 mL, 3.5 mmol) in 40 mL of degassed CH2Cl2 was
placed in the addition funnel and slowly added to the reaction mix-
ture over 45 min. The reaction mixture was warmed to room tem-
perature whilst stirring overnight. A saturated aqueous NaCl solu-
tion was added and the aqueous phase was extracted with CH2Cl2.
The combined organic phases were dried with MgSO4, filtered, and
concentrated under vacuum. Silica gel chromatography (9:1 pen-
tane/AcOEt) afforded compound 11a as a pale-yellow solid (1.9 g,
54%). M.p. 160 °C. TLC: Rf = 0.35 (6:4 pentane/AcOEt). IR (KBr
Methyl (4-Benzyloxyphenyl){3-methoxy-5-oxo-4-[(trifluoromethyl-
sulfonyl)oxy]furan-2(5H)-ylidene}acetate (5b): Following the gene-
ral procedure, triflate 5b was prepared from alcohol 11b (1.7 g,
4.4 mmol). After chromatographic purification, compound 5b was
obtained as a pale-yellow solid (1.9 g, 85%). M.p. 85 °C. TLC: Rf
= 0.40 (8:2 pentane/AcOEt). 1H NMR (CDCl3, 300 MHz): δ = 7.60
(d, J = 5.7 Hz, 2 H, Ar-H), 7.37–7.43 (m, 5 H, Ph-H), 7.02 (d, J =
5.7 Hz, 2 H, Ar-H), 5.12 (s, 2 H, OCH2Ph), 4.30 (s, 3 H, CH3O–
C=), 3.91 (s, 3 H, CO2CH3) ppm. 13C NMR (CDCl3, 75 MHz): δ
= 168.2, 166.8, 159.7, 159.1, 131.1, 128.5, 128.1, 127.2, 121.3, 115.1,
69.9, 60.2, 52.8. MS (CI/NH3): m/z 532 [M + NH4]+.
Methyl {3-(Benzyloxy)-5-oxo-4-[(trifluoromethylsulfonyl)oxy]furan-
2(5H)-ylidene}(4-benzyloxyphenyl)acetate (5c): Following the gene-
pellet): ν = 3309, 2954, 1737, 1669, 1513, 1378, 1113, 828 cm–1. 1H
˜
NMR ([D6]acetone, 300 MHz): δ = 8.90 (s, 1 H, OH), 7.52 (d, J = ral procedure, triflate 5c was prepared from alcohol 11c (206 mg,
9.2 Hz, 2 H, Ar-H), 7.01 (d, J = 9.2 Hz, 2 H, Ar-H), 4.19 (s, 3 H, 0.5 mmol). After chromatographic purification, compound 5c was
OCH3), 3.86 (s, 3 H, OCH3), 3.85 (s, 3 H, OCH3) ppm. 13C NMR obtained as a white solid (263 mg, 99%). M.p. 61 °C. TLC: Rf =
([D6]acetone, 75 MHz): δ = 167.3, 164.7, 160.6, 140.0, 130.9, 124.8, 0.75 (7:3 pentane/AcOEt). IR (KBr pellet): ν = 3037, 2951, 1791,
˜
1494
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 1489–1498

Synthesis of Pulvinic Acid and Norbadione A Analogues
FULL PAPER
1735, 1652, 1600, 1510, 1422, 1236, 1087, 1045, 609 cm–1. 1H NMR
(CDCl3, 300 MHz): δ = 7.57 (d, J = 9.2 Hz, 2 H, Ar-H), 7.27–7.42
(m, 10 H, Ph-H), 7.00 (d, J = 9.2 Hz, 2 H, Ar-H), 5.50 (s, 2 H,
OCH2Ph), 5.11 (s, 2 H, ArOCH2Ph), 3.27 (s, 3 H, OCH3) ppm.
bined organic layers were dried with MgSO4, filtered, and concen-
trated under vacuum. Silica gel chromatography (8:2 pentane/Ac-
OEt) afforded 16a as a yellow solid (599 mg, 97%). M.p. 142 °C.
TLC: R = 0.65 (CH Cl ). IR (KBr pellet): ν = 3411, 1757, 1728,
˜
f
2
2
13C NMR (CDCl3, 75 MHz): δ = 160.0, 132.8, 131.0, 130.7, 129.7, 1593, 1511, 1350, 1305, 1280, 1255, 1230, 1188, 1152 cm–1
.
1H
129.1, 128.9, 128.8, 128.5, 127.2, 115.1, 75.6, 69.9, 52.2 ppm. NMR (CDCl3, 300 MHz): δ = 7.66 (d, J = 8.6 Hz, 2 H, Ar-H),
C28H21F3O9S (590.52): calcd. C 56.94, H 3.58, F 9.65; found C
56.93, H 3.73, F 9.80.
7.54 (dd, J = 1.2 and 7.6 Hz, 2 H, Ph-H), 7.50 (t, J = 3.2 Hz, 1 H,
Ph-H), 7.36–7.45 (m, 10 H, Ph-H), 7.26 (m, 2 H, Ph-H), 7.02 (d, J
= 8.6 Hz, 2 H, Ar-H), 5.12 (s, 2 H, ArOCH2Ph), 4.96 (s, 2 H,
OCH2Ph), 3.38 (s, 3 H, CO2CH3) ppm. 13C NMR (CDCl3,
75 MHz): δ = 171.0, 166.8, 161.3, 159.4, 139.9, 136.3, 134.1, 130.6,
129.9, 128.8, 128.7, 128.6, 128.4, 128.3, 127.9, 127.1, 123.6, 116.3,
114.9, 75.2, 69.9, 52.1 ppm. HRMS: calcd. for C33H26NaO6 [M +
Na]+ 541.1627; found 541.1646.
Methyl [3-Methoxy-5-oxo-4-phenylfuran-2(5H)-ylidene](4-meth-
oxyphenyl)acetate (15):[13,23] Triflate 5a (130 mg, 0.30 mmol), phen-
ylboronic acid (40 mg, 0.34 mmol), K3PO4 (95 mg, 0.45 mmol),
[Pd(PPh3)4] (10 mg, 3 mol-%), and 1.5 mL of degassed dioxane
were placed in a round-bottomed flask fitted with a reflux con-
denser. The reaction mixture was heated to reflux for 4 h and then
saturated aqueous NaCl was added. The aqueous layer was ex-
tracted thrice with diethyl ether and the combined organic layers
were washed with water, dried with MgSO4, filtered, and concen-
trated under vacuum. Silica gel chromatography (7:3 pentane/Ac-
Methyl [3-Benzyloxy-4-(4-hydroxyphenyl)-5-oxofuran-2(5H)-ylid-
ene](4-benzyloxyphenyl)acetate (16b): Following the general pro-
cedure, pulvinic derivative 16b was prepared from (4-hy-
droxyphenyl)boronic acid pinacol ester (31 mg, 0.14 mmol) and
OEt) afforded 15 as a yellow solid (96 mg, 86 %). M.p. 168 °C triflate 5c (50 mg, 0.08 mmol). After chromatographic purification,
(ref.[13] 172–173°C; ref.[23] 171–172 °C). TLC: Rf = 0.55 (CH2Cl2).
compound 16b was obtained as a yellow-orange solid (19 mg,
1
IR (KBr pellet): ν = 3428, 2934, 1768, 1725, 1622, 1597 cm–1. H 42%). M.p. 108 °C. TLC: Rf = 0.70 (1:1 pentane/AcOEt). IR (KBr
˜
NMR (CDCl3, 300 MHz): δ = 7.67 (d, J = 9.2 Hz, 2 H, Ar-H), pellet): ν = 3400, 2921, 2852, 1728, 1601, 1510 cm–1
.
1H NMR
(CDCl3, 300 MHz): δ = 7.63 (d, J = 9.2 Hz, 2 H, Ar-H), 7.26–7.44
(m, 12 H, Ar-H and Ph-H), 7.00 (d, J = 8.6 Hz, 2 H, Ar-H), 6.91
˜
7.53 (dd, J = 2.1 and 7.1 Hz, 2 H, Ph-H), 7.47 (dd, J = 2.1 and
7.1 Hz, 2 H, Ph-H), 7.43 (t, J = 2.1 Hz, 1 H, Ph-H), 6.95 (d, J =
9.2 Hz, 2 H, Ar-H), 3.92 (s, 3 H, CO2Me), 3.86 (s, 3 H, ArOCH3), (d, J = 8.6 Hz, 2 H, Ar-H), 5.11 (s, 2 H, ArOCH2Ph), 4.96 (s, 2 H,
3.79 (s, 3 H, OCH3) ppm. 13C NMR (CDCl3, 75 MHz): δ = 168.0,
167.4, 162.9, 160.7, 140.2, 130.9, 130.1, 129.0, 128.7, 128.6, 123.6,
116.5, 114.5, 107.9, 61.4, 55.5, 52.9 ppm. MS (CI/NH3): m/z = 384
[M + NH4]+.
OCH2Ar), 3.39 (s, 3 H, CO2CH3) ppm. 13C NMR (CDCl3,
75 MHz): δ = 168.5, 167.1, 160.2, 159.3, 140.1, 131.3, 130.6, 128.9,
128.8, 128.5, 128.4, 128.3, 127.9, 127.2, 123.6, 115.9, 115.3, 114.9,
74.9, 69.8, 52.2 ppm. HRMS: calcd. for C33H26NaO7 [M + Na]+
557.1576; found 557.1591.
2-[3,4-Bis(benzyloxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxa-
borolane (6e): A 1.6  solution of butyllithium in hexanes
(0.910 µL, 1.45 mmol) was added dropwise to a solution of 1,2-
bis(benzyloxy)-4-bromobenzene[24] (413 mg, 1.12 mmol) in anhy-
drous THF (10 mL) cooled to –78 °C under argon. After 1 h stir-
ring at –78 °C, trimethyl borate (0.256 mL, 1.34 mmol) was added
dropwise. The reaction mixture was stirred for 1 h at –78 °C, and
then warmed to room temperature. A 1  HCl aqueous solution
(5 mL) was added and the aqueous phase was extracted with di-
ethyl ether (3×10 mL). The combined organic phases were dried
with MgSO4, filtered, and concentrated under vacuum. Pinacol
(160 mg, 1.34 mmol) and MgSO4 (10.9 g) were added to a solution
of the residue obtained in CH2Cl2 (8 mL). After stirring for 2 h at
room temperature, the suspension was filtered and the filtrate was
concentrated under vacuum. Silica gel chromatography (99:1 to
95:5 pentane/AcOEt) afforded compound 6e as a colorless oil
Methyl [3-Benzyloxy-4-(4-methoxyphenyl)-5-oxofuran-2(5H)-ylid-
ene](4-benzyloxyphenyl)acetate (16c): Following the general pro-
cedure, pulvinic derivative 16c was prepared from (4-meth-
oxyphenyl)boronic acid pinacol ester (77 mg, 0.33 mmol) and trifl-
ate 5c (130 mg, 0.22 mmol). After chromatographic purification,
compound 16c was obtained as a yellow solid (103 mg, 85%). M.p.
113 °C. TLC: R = 0. 45 (7:3 pentane/AcOEt). IR (KBr pellet): ν
˜
f
= 3035, 2932, 1756, 1729, 1508, 1252, 1156, 1041, 941, 834,
1
698 cm–1. H NMR (CDCl3, 300 MHz): δ = 7.65 (d, J = 9.2 Hz, 2
H, Ar-H), 7.51 (d, J = 8.5 Hz, 2 H, Ar-H), 7.37–7.44 (m, 8 H, Ph-
H), 7.29 (m, 2 H, Ph-H), 6.99–7.03 (m, 4 H, Ar-H), 5.11 (s, 2 H,
ArOCH2Ph), 4.97 (s, 2 H, OCH2Ph), 3.87 (s, 3 H, OCH3), 3.39 (s,
3 H, CO2CH3) ppm. 13C NMR (CDCl3, 75 MHz): δ = 168.0, 166.9,
160.7, 159.9, 140.1, 136.3, 134.2, 131.08, 130.6, 128.8, 128.7, 128.6,
128.4, 128.3, 127.9, 127.2, 120.7, 115.9, 114.9, 107.9, 74.8, 69.8,
55.2, 52.2 ppm. HRMS: calcd. for C34H28NaO7 [M + Na]+
571.1733; found 571.1749.
(308 mg, 66%). TLC: R = 0.70 (CH Cl ). IR (KBr pellet): ν =
˜
f
2
2
2973, 1600, 1524, 1420, 1354, 1265, 1135, 1018, 965, 856, 734,
682 cm–1. 1H NMR (CDCl3, 300 MHz): δ = 7.37–7.52 (m, 12 H,
Ar-H, Ph-H), 6.99 (d, J = 7.9 Hz, 1 H, Ar-H), 5.22 and 5.21 (2 s,
2 H each, 2 CH2Ph), 1.38 (s, 12 H, CH3) ppm. 13C NMR (CDCl3,
75 MHz): δ = 151.6, 148.4, 137.3, 129.1, 128.9, 128.3, 128.2, 128.1,
127.6, 127.3, 127.2, 127.0, 126.4, 126.0, 120.6, 113.8, 83.5, 71.2,
70.6, 24.7 ppm. MS (ESI-TOF): m/z = 439 [M + Na]+.
Methyl (4-Benzyloxyphenyl)[3-hydroxy-4-(3-hydroxyphenyl)-5-oxo-
furan-2(5H)-ylidene]acetate (17d): Following the general procedure,
pulvinic derivative 17d was prepared from (3-hydroxyphenyl)bo-
ronic acid pinacol ester (87 mg, 0.40 mmol) and triflate 5c (156 mg,
0.26 mmol). After chromatographic purification, compound 17d
was obtained as a yellow solid (122 mg, 86%). M.p. 134 °C. TLC:
General Procedure for the Suzuki–Miyaura Coupling. Synthesis of
R = 0.45 (AcOEt). IR (KBr pellet): ν = 3483, 2925, 2856, 1713,
˜
f
Methyl [3-(Benzyloxy)-5-oxo-4-phenylfuran-2(5H)-ylidene](4-ben- 1570, 1508, 1444, 1256, 1177, 1044, 961, 851, 789, 743, 693,
1
zyloxyphenyl)acetate (16a): [PdCl2(PPh3)2] (42 mg, 0.06 mmol) as a
suspension in degassed THF (5 mL), phenylboronic acid pinacol
ester (363 mg, 1.79 mmol) dissolved in degassed THF (25 mL), and
an aqueous solution of Na2CO3 (2 , 26 mL) were added to a solu-
tion of triflate 5c (700 mg, 1.18 mmol) in degassed THF (75 mL).
The reaction mixture was refluxed for 2 h and water (50 mL) was
added. The aqueous layer was extracted with CH2Cl2 and the com-
639 cm–1. H NMR (CDCl3, 300 MHz): δ = 8.17 (br. s, 1 H, OH),
7.81 (s, 1 H, Ar-H), 7.76 (d, J = 7.9 Hz, 1 H, Ar-H), 7.32–7.55 (m,
7 H, Ar-H and Ph-H), 7.13 (dd, J = 7.9 and 7.3 Hz, 1 H, Ar-H),
7.07 (d, J = 8.5 Hz, 2 H, Ar-H), 6.66 (d, J = 7.3 Hz, 1 H, Ar-H),
5.11 (s, 2 H, OCH2Ph), 3.89 (s, 3 H, CO2CH3) ppm. 13C NMR
(CDCl3, 75 MHz): δ = 172.8, 172.1, 169.2, 159.2, 157.6, 134.6,
132.5, 131.2, 130.4, 129.3, 129.2, 129.0, 128.3, 128.1, 126.3, 118.2,
Eur. J. Org. Chem. 2006, 1489–1498
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1495

M. Desage-El Murr, S. Nowaczyk, T. Le Gall, C. Mioskowski
FULL PAPER
115.0, 113.4, 113.2, 70.2, 53.6 ppm. HRMS: calcd. for C26H20NaO7
[M + Na]+ 467.1107; found 467.1111.
H), 7.28 (d, J = 7.3 Hz, 2 H, Ar-H), 7.04 (d, J = 7.3 Hz, 2 H, Ar-
H), 6.91 (d, J = 9.2 Hz, 2 H, Ar-H), 3.93 (s, 3 H, OCH3), 3.86 (s,
3 H, -CO2CH3) ppm. 13C NMR ([D6]acetone, 75 MHz): δ = 171.9,
162.6, 157.8, 141.5, 134.3, 131.5, 127.8, 122.3, 117.7, 116.0, 113.7,
55.1, 53.9 ppm. HRMS: calcd. for C20H16NaO7 [M + Na]+
391.0794; found 391.0765.
Methyl {3-Benzyloxy-4-[3,4-bis(benzyloxy)phenyl]-5-oxofuran-
2(5H)-ylidene}(4-benzyloxyphenyl)acetate (16e): Following the ge-
neral procedure, pulvinic derivative 16e was prepared from [3,4-
bis(benzyloxy)phenyl]boronic acid pinacol ester (237 mg,
0.57 mmol) and triflate 5c (224 mg, 0.38 mmol). After chromato-
graphic purification, compound 16e was obtained as a yellow solid
(282 mg, 99%). M.p. 136–138 °C. TLC: Rf = 0.30 (8:2 pentane/
Methyl [3-Hydroxy-4-(3-hydroxyphenyl)-5-oxofuran-2(5H)-ylid-
ene](4-hydroxyphenyl)acetate (Methyl 3,4Ј-Dihydroxypulvinate,
18d): Following the general procedure, pulvinic derivative 18d was
prepared from protected pulvinic acid derivative 17d (48 mg,
0.11 mmol). After chromatographic purification, compound 18d
was obtained as a yellow solid (18 mg, 47%). M.p. Ͼ 300 °C. TLC:
AcOEt). IR (KBr pellet): ν = 1762, 1597, 1510, 1255, 1132, 1042,
˜
736, 694 cm–1
.
1H NMR (CDCl3, 300 MHz): δ = 7.63 (d, J =
9.2 Hz, 2 H, Ar-H), 7.30–7.47 (m, 20 H, Ph-H), 7.10 (d, J = 1.8 Hz,
1 H, Ar-H), 6.98–7.05 (m, 4 H, Ar-H), 5.24 (s, 2 H, OCH2Ph), 5.15 R = 0.35 (AcOEt). IR (KBr pellet): ν = 3238, 1706, 1555, 1509,
˜
f
(s, 2 H, OCH2Ph), 5.12 (s, 2 H, OCH2Ph), 4.89 (s, 2 H, OCH2Ph), 1436, 1233, 1045, 974, 839, 789, 689, 626 cm–1. 1H NMR ([D6]-
3.46 (s, 3 H, CO2CH3) ppm. 13C NMR (CDCl3, 75 MHz): δ =
167.9, 166.9, 160.7, 159.3, 140.0, 136.7, 136.3, 134.3, 130.6, 128.9,
128.7, 128.4, 128.3, 128.2, 127.9, 127.7, 127.6, 127.3, 127.0, 126.1,
123.6, 121.3, 116.2, 114.9, 107.8, 70.9, 69.9, 69.8, 52.2 ppm.
HRMS: calcd. for C47H38NaO8 [M + Na]+ 753.2464; found
753.2455.
acetone, 300 MHz): δ = 8.73 (br. s, 1 H, OH), 7.93 (s, 1 H, Ar-H),
7.82 (d, J = 7.9 Hz, 1 H, Ar-H), 7.52 (d, J = 8.5 Hz, 2 H, Ar-H),
7.04 (t, J = 7.9 Hz, 1 H, Ar-H), 6.89 (d, J = 9.2 Hz, 2 H, Ar-H),
6.49 (d, J = 6.7 Hz, 1 H, Ar-H), 3.85 (s, 3 H, CO2CH3) ppm. 13C
NMR ([D6]acetone, 75 MHz): δ = 171.6, 170.9, 157.3, 157.2, 132.3,
130.5, 128.8, 128.7, 125.4, 116.9, 115.5, 111.9, 52.3 ppm.
General Procedure for the Hydrogenolysis. Synthesis of Methyl [3-
Methyl [4-(3,4-Dihydroxyphenyl)-3-hydroxy-5-oxofuran-2(5H)-ylid-
Hydroxy-5-oxo-4-phenylfuran-2(5H)-ylidene](4-hydroxyphenyl)- ene](4-hydroxyphenyl)acetate (Methyl 3,4,4Ј-Trihydroxypulvinate,
acetate (Methyl 4Ј-Hydroxypulvinate, 18a): Protected pulvinic acid
derivative 16a (22 mg, 0.04 mmol), Pd/C (9 mg, 0.01 mmol) and
CH2Cl2 (2 mL) were placed in a round-bottomed flask. The reac-
tion mixture was stirred under hydrogen atmosphere for 28 h before
being filtered through celite (elution with AcOEt). The filtrate was
then concentrated under vacuum. Silica gel chromatography (7:3
pentane/AcOEt then pure AcOEt) afforded 18a as a yellow solid
(14 mg, 98%). M.p. 226 °C (ref.[15] 235–236 °C). TLC: Rf = 0.30
18e): Following the general procedure, pulvinic derivative 18e was
prepared from protected pulvinic acid derivative 16e (189 mg,
0.26 mmol). After chromatographic purification, compound 18e
was obtained as a deep-red solid (33 mg, 35%). M.p. 259 °C (ref.[16]
258–259 °C). TLC: R = 0.20 (AcOEt). IR (KBr pellet): ν = 3287,
˜
f
2927, 2360, 1752, 1677, 1602, 1276, 1062, 962, 869, 819 cm–1. 1H
NMR ([D6]acetone, 300 MHz): δ = 8.65 (br. s, 1 H, OH), 8.17 (br.
s, 1 H, OH), 7.74 (d, J = 1.8 Hz, 1 H, Ar-H), 7.60 (dd, J = 8.5 and
1.8 Hz, 1 H, Ar-H), 7.27 (d, J = 8.5 Hz, 2 H, Ar-H), 6.90 (m, 3 H,
Ar-H), 3.91 (s, 3 H, CO2CH3) ppm. 13C NMR ([D6]acetone,
75 MHz): δ = 172.6, 169.3, 166.8, 158.1, 153.9, 145.3, 132.2, 124.4,
122.2, 120.8, 115.8, 115.3, 115.2, 113.1, 54.4 ppm. HRMS: calcd.
for C19H14NaO8 [M + Na]+ 393.0586; found 393.0605.
(1:1 pentane/AcOEt). IR (KBr pellet): ν = 3404, 1767, 1710, 1605,
˜
1561, 1280, 1063 cm–1. 1H NMR ([D6]acetone, 300 MHz): δ = 8.66
(br. s, 1 H, OH), 8.25 (dd, J = 8.6 and 1.2 Hz, 2 H, Ph-H), 7.41
(d, J = 8.6 Hz, 2 H, Ar-H), 7.34 (t, J = 7.3 Hz, 2 H, Ph-H), 7.16
(t, J = 7.3 Hz, 1 H, Ph-H), 6.89 (d, J = 9.2 Hz, 2 H, Ar-H), 3.90
(s, 3 H, CO2CH3) ppm. 13C NMR ([D6]acetone, 75 MHz): δ =
172.1, 169.2, 168.6, 158.1, 150.9, 132.7, 131.6, 131.4, 128.4, 126.9,
126.3, 124.6, 115.6, 113.7, 98.2, 53.7 ppm. HRMS: calcd. for
C19H14NaO6 [M + Na]+ 361.0688; found 361.0689.
General Procedure for the Saponification. Synthesis of [3-Hydroxy-
5-oxo-4-phenylfuran-2(5H)-ylidene](4-hydroxyphenyl)acetic Acid
(4Ј-Hydroxypulvinic Acid, 2a): Pulvinic ester 18a (6 mg,
0.018 mmol) and an aqueous solution of LiOH (205 µL, 0.5 )
were placed in a round-bottomed flask fitted with a reflux con-
Methyl [3-Hydroxy-4-(4-hydroxyphenyl)-5-oxofuran-2(5H)-ylid-
ene](4-hydroxyphenyl)acetate (Methyl 4,4Ј-Dihydroxypulvinate, denser. The reaction mixture was heated to reflux for 2 h. The reac-
18b): Following the general procedure, pulvinic derivative 18b was
prepared from protected pulvinic acid derivative 16b (38 mg,
0.57 mmol). After chromatographic purification, compound 18b
was obtained as a yellow solid (24 mg, quantitative). M.p. Ͼ 300 °C
(ref.[15] 330–332 °C). TLC: Rf = 0.15 (1:1 pentane/AcOEt). IR (KBr
tion mixture was acidified to pH 1 with a solution of HCl 1 . The
aqueous layer was extracted with AcOEt and the combined organic
layers were dried with MgSO4, filtered, and concentrated under
vacuum. Reverse phase chromatography (8:2 water/MeOH) af-
forded acid 2a as a yellow solid (5 mg, quantitative). M.p. 162 °C
(ref.[17] 160–163 °C). TLC: Rf = 0.35 (9:1 AcOEt/MeOH). IR (KBr
pellet): ν = 3331, 1734, 1605, 1513, 1435, 1312, 1275, 1068, 970,
˜
1
835 cm–1. H NMR ([D6]acetone, 300 MHz): δ = 8.58 (br. s, 1 H,
pellet): ν = 3451, 2925, 1742, 1581, 1510, 1464, 1392, 1175, 964,
˜
OH), 8.09 (d, J = 9.2 Hz, 2 H, Ar-H), 7.44 (d, J = 9.2 Hz, 2 H,
Ar-H), 6.88 (d, J = 6.7 Hz, 2 H, Ar-H), 6.83 (d, J = 8.6 Hz, 2 H,
836, 782, 692 cm–1. 1H NMR ([D6]acetone, 300 MHz): δ = 8.27 (d,
J = 8.6 Hz, 2 H, Ar-H), 7.34 (t, J = 7.3 Hz, 2 H, Ar-H), 7.18 (d, J
Ar-H), 3.87 (s, 3 H, CO2CH3) ppm. 13C NMR ([D6]acetone, = 7.3 Hz, 2 H, Ar-H), 7.17 (t, J = 7.3 Hz, 1 H, Ar-H), 6.82 (d, J
75 MHz): δ = 172.1, 168.1, 157.7, 156.9, 134.0, 131.9, 128.4, 128.2,
124.7, 123.0, 116.2, 115.8, 115.6, 53.8 ppm.
= 7.3 Hz, 2 H, Ar-H) ppm. 13C NMR ([D6]acetone, 75 MHz): δ =
169.7, 168.9, 157.1, 151.2, 132.4, 131.0, 128.3, 128.2, 126.6, 126.1,
115.3, 114.5, 97.9 ppm. MS (EI/TOF): m/z = 325 [M + H]+.
Methyl [3-Hydroxy-4-(4-methoxyphenyl)-5-oxofuran-2(5H)-ylid-
ene](4-hydroxyphenyl)acetate (Methyl 4-Methoxy-4Ј-hydroxypulvin-
ate, 18c): Following the general procedure, pulvinic derivative 18c
was prepared from protected pulvinic acid derivative 16c (56 mg,
0.10 mmol). After chromatographic purification, compound 18c
was obtained as a yellow solid (33 mg, quantitative). TLC: Rf =
[3-Hydroxy-4-(4-hydroxyphenyl)-5-oxofuran-2(5H)-ylidene](4-hy-
droxyphenyl)acetic Acid (Atromentic Acid, 2b): Following the gene-
ral procedure, pulvinic derivative 2b was prepared from pulvinic
ester 18b (11 mg, 0.03 mmol). After chromatographic purification,
compound 2b was obtained as a yellow solid (9 mg, 85%). M.p. Ͼ
300 °C (ref.[15] 360–362 °C; ref.[17] 287–289 °C). TLC: Rf = 0.30 (9:1
0.65 (AcOEt). IR (KBr pellet): ν = 3244, 2927, 1737, 1599, 1276,
˜
1
1064, 838 cm–1. H NMR ([D6]acetone, 300 MHz): δ = 13.74 (br.
AcOEt /MeOH). IR (KBr pellet): ν = 3800–3000, 2360, 1730, 1601,
˜
s, 1 H, OH), 8.62 (br. s, 1 H, OH), 8.12 (d, J = 8.6 Hz, 2 H, Ar-
1571, 1513, 1391, 1231, 1173, 968, 836 cm–1. 1H NMR ([D6]ace-
1496
www.eurjoc.org
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 1489–1498

Synthesis of Pulvinic Acid and Norbadione A Analogues
FULL PAPER
tone, 300 MHz): δ = 13.77 (br. s, 1 H, OH), 8.18 (d, J = 8.6 Hz, 2
Dimethyl 2,2Ј-[Naphthalene-1,7-diylbis(3-methoxy-5-oxofuran-4-yl-
H, Ar-H), 7.16 (d, J = 8.6 Hz, 2 H, Ar-H), 6.79–6.84 (m, 4 H, Ar- 2-ylidene)]bis[(4-benzyloxyphenyl)acetate] (21b): Following the ge-
H) ppm. 13C NMR ([D6]acetone, 75 MHz): δ = 172.1, 169.2, 168.6,
158.1, 150.9, 132.7, 131.6, 131.4, 126.3, 124.6, 115.6, 113.7, 98.2,
53.7 ppm.
neral procedure, bis(pulvinic) derivative 21b was prepared from
bis(boronate) 4 (164 mg, 0.43 mmol) and triflate 5b (466 mg,
0.91 mmol). After chromatographic purification, compound 21b
was obtained as a brown solid (250 mg, 68%). M.p. 140 °C. TLC:
[3-Hydroxy-4-(4-methoxyphenyl)-5-oxofuran-2(5H)-ylidene](4-hy-
droxyphenyl)acetic Acid (4Ј-Hydroxy-4-methoxypulvinic Acid, 2c):
Following the general procedure, pulvinic derivative 2c was pre-
pared from pulvinic ester 18c (6 mg, 0.015 mmol). After chromato-
graphic purification, compound 2c was obtained as a yellow solid
(3 mg, 56%). TLC: Rf = 0.45 (9:1 AcOEt /MeOH). IR (KBr pellet):
R = 0.20 (8:2 pentane/AcOEt). IR (KBr pellet): ν = 2360, 1769,
˜
f
1732, 1601, 1509, 1229, 1182, 1043, 977, 911, 834, 744, 694 cm–1.
1H NMR (CDCl3, 300 MHz): δ = 7.97 (m, 2 H, naphthyl-H), 7.90
(s, 1 H, naphthyl-H), 7.66–7.73 (m, 5 H, naphthyl-H and Ar-H),
7.59 (m, 1 H, naphthyl-H), 7.57 (m, 1 H, naphthyl-H), 7.35–7.44
(m, 10 H, Ph-H), 7.00–7.06 (m, 4 H, Ar-H), 5.13 (s, 2 H, CH2),
5.12 (s, 2 H, CH2), 3.92 (s, 3 H, CO2CH3), 3.90 (s, 3 H, CO2CH3),
3.79 (s, 3 H, CH3O), 3.62 (s, 3 H, CH3O) ppm. 13C NMR (CDCl3,
75 MHz): δ = 165.3, 163.3, 159.9, 151.3, 147.5, 136.2, 131.3, 130.8,
130.2, 129.9, 129.5, 129.3, 128.7, 128.6, 128.5, 128.2, 127.9, 127.7,
127.3, 126.9, 126.4, 126.2, 125.9, 124.2, 115.0, 114.7, 105.4, 102.3,
69.8, 60.7, 61.6, 52.6 ppm. HRMS: calcd. for C52H40O12 [M]+
856.2520; found 856.2519.
ν = 3424, 1727, 1601, 1570, 1513, 1391, 1245, 1174, 968, 835 cm–1.
˜
1H NMR ([D6]acetone, 300 MHz): δ = 8.27 (d, J = 8.6 Hz, 2 H,
Ar-H), 7.16 (d, J = 8.6 Hz, 2 H, Ar-H), 6.90 (d, J = 8.6 Hz, 2 H,
Ar-H), 6.80 (d, J = 8.6 Hz, 2 H, Ar-H), 3.79 (s, 3 H, -OCH3) ppm.
13C NMR ([D6]acetone, 75 MHz): δ = 146.9, 132.5, 130.9, 127.5,
125.8, 123.1, 114.3, 113.6, 112.9, 54.9 ppm. MS (EI/TOF): m/z =
355 [M + H]+.
2,2Ј-Naphthalene-1,7-diyl(4,4,5,5-tetramethyl-1,3,2-dioxoborolane)
(4): A solution of bis(triflate) 20[18] (2.44 g, 5.75 mmol) in 10 mL
of dioxane, triethylamine (9.6 mL, 69 mmol), 4,4,5,5-tetramethyl-
[1,3,2]-dioxaborolane (5 mL, 34 mmol), and dioxane (20 mL) were
added successively, with a syringe, to a suspension of [PdCl2(dppf)]
(280 mg, 0.35 mmol) in degassed dioxane (10 mL). The reaction
mixture was heated to reflux for 10 h and hexane was added. The
layers were separated and the organic layer was washed with brine,
dried with MgSO4, filtered, and concentrated under vacuum. After
chromatographic purification (99:1 pentane/AcOEt), compound 4
was obtained as a translucent oil (979 mg, 45%). TLC: Rf = 0.60
Dimethyl 2,2Ј-[Naphthalene-1,7-diylbis(3-benzyloxy-5-oxofuran-4-
yl-2-ylidene)]bis[(4-benzyloxyphenyl)acetate] (21c): Following the
general procedure, bis(pulvinic) derivative 21c was prepared from
bis(boronate) 4 (81 mg, 0.21 mmol) and triflate 5c (266 mg,
0.45 mmol). After chromatographic purification, compound 21c
was obtained as a brown solid (123 mg, 58%). M.p. 175–176 °C.
TLC: R = 0.20 (8:2 pentane/AcOEt). IR (KBr pellet): ν = 3034,
˜
f
2925, 1767, 1731, 1603, 1509, 1310, 1284, 1230, 1182, 1042, 970,
912, 835, 739, 696 cm–1. 1H NMR (CDCl3, 300 MHz): δ = 7.95–
8.06 (m, 3 H, naphthyl-H), 7.86 (s, 1 H, naphthyl-H), 7.73 (d, J =
9.2 Hz, 2 H), 7.69 (d, J = 9.2 Hz, 2 H), 7.59–7.63 (m, 5 H, Ph-H),
7.42–7.45 (m, 10 H, Ph-H), 7.27–7.29 (m, 2 H, naphthyl-H), 7.21–
7.24 (m, 5 H, Ph-H), 7.04 (d, J = 9.2 Hz, 2 H), 7.02 (d, J = 9.2 Hz,
2 H, Ar-H), 5.14 (s, 2 H, OCH2Ph), 5.12 (s, 2 H, OCH2Ph), 5.09
(s, 2 H, OCH2Ph), 4.93 (d, J = 10.9 Hz, 1 H, benzylic H), 4.89 (d,
J = 10.9 Hz, 1 H, benzylic H), 3.35 (s, 3 H, CO2CH3), 3.30 (s, 3
H, CO2CH3) ppm. 13C NMR (CDCl3, 75 MHz): δ = 168,1, 167.9,
166.7, 166.6, 163.0, 159.4, 125.9–132.3, 123.7, 123.6, 116.5, 114.9,
114.0, 77.3, 76.9, 69.9, 52.1, 51.9 ppm. HRMS: calcd. for [M]+
1008.3146; found 1008.3200.
(9:1 pentane/AcOEt). IR (KBr pellet): ν = 2978, 1454, 1357,
˜
1138 cm–1. 1H NMR (CDCl3, 300 MHz): δ = 9.32 (s, 1 H, H-8),
8.08 (d, J = 8.3 Hz, 1 H, H-4), 7.95 (d, J = 7.8 Hz, 1 H, H-2), 7.87
(d, J = 8.3 Hz, 1 H, H-5 or H-6), 7.83 (d, J = 8.3 Hz, 1 H, H-5 or
H-6), 7.54 (dd, J = 8.2 and 9.5 Hz, 1 H, H-3), 1.49 (s, 12 H, CH3),
1.43 (s, 12 H, CH3) ppm. 13C NMR (CDCl3, 75 MHz): δ = 136.6,
136.0, 134.8, 134.6, 131.0, 129.8, 127.2, 125.7, 83.6, 24.8 ppm. MS
(CI/NH3): m/z = 398 [M+ NH4]+.
General Procedure for the Suzuki Coupling. Synthesis of Dimethyl
2,2Ј-[Naphthalene-1,7-diylbis(3-methoxy-5-oxofuran-4-yl-2-yl-
idene)]bis[(4-methoxyphenyl)acetate] (21a): A suspension of
[PdCl2(PPh3)2] (19 mg, 1 mol-%) in THF (5 mL), a solution of
bis(boronate) 4 (89 mg, 0.43 mmol) in THF (5 mL), and 5 mL of
an aqueous Na2CO3 solution (2 ) were added to a solution of
triflate 5a (214 mg, 0.488 mmol) in degassed THF (10 mL). The
reaction mixture was heated to reflux for 3 h and water was added.
The aqueous layer was extracted with CH2Cl2 and the combined
organic layers were dried with MgSO4, filtered, and concentrated
under vacuum. After chromatographic purification (8:2 pentane/
AcOEt), compound 21a was obtained as a green-yellow solid
(104 mg, 63%). TLC: Rf = 0.10 (6:4 hexane/AcOEt). IR (KBr pel-
Synthesis of Dimethyl 2,2Ј-[Naphthalene-1,7-diylbis(3-hydroxy-5-
oxofuran-4-yl-2-ylidene)]bis[(4-hydroxyphenyl)acetate] (22) by Hy-
drogenolysis of Compound 21c (Method A): A suspension of com-
pound 21c (20 mg, 0.019 mmol) and 10% Pd/C (16 mg) in dichloro-
methane (5 mL) was stirred under a hydrogen atmosphere for 26 h.
The suspension was filtered through a pad of celite, which was
washed with ethyl acetate. The solution was concentrated under
vacuum. After chromatographic purification on a C-18 column
(gradient from 9:1 H2O/MeOH to pure MeOH), compound 22 was
obtained as a yellow solid (11 mg, 90%).
Synthesis of 22 by Treatment of Compound 21c with Iodotrimethyl-
silane (Method B): Iodotrimethylsilane (22 µL, 0.15 mmol) was
added with a syringe to a solution of compound 21c (10 mg,
let): ν = 3447, 3007, 2950, 1769, 1732, 1626, 1603, 1512, 1285, 1256,
˜
1158, 1042, 975, 917, 836, 757 cm–1. 1H NMR (CDCl3, 300 MHz):
δ = 7.96–7.99 (m, 2 H, naphthyl-H), 7.90 (s, 1 H, naphthyl-H), 0.01 mmol) in CDCl3 (1 mL), placed in an NMR tube, under ar-
7.66–7.74 (m, 5 H, naphthyl-H and Ar-H), 7.57–7.59 (m, 2 H, gon. The tube was sealed and then heated in an oil bath at 60 °C
naphthyl-H), 6.94–6.99 (m, 4 H, Ar-H), 3.92 (s, 3 H, CO2CH3), for 2 h. After cooling to room temperature, the tube was opened
3.90 (s, 3 H, CO2CH3), 3.87 (s, 3 H, CH3O), 3.86 (s, 3 H, CH3O), and water (1 mL) was added. The mixture was stirred for 1 h then
3.80 (s, 3 H, CH3O), 3.63 (s, 3 H, CH3O) ppm. 13C NMR (CDCl3,
75 MHz): δ = 168.4, 168.0, 166.9, 166.8, 164.0, 163.0, 160.4, 160.3,
139.5, 139.4, 130.7, 130.6, 133.1, 131.3, 130.1, 129.8, 129.3, 128.7,
127.5, 127.3, 126.5, 125.9, 123.2, 116.9, 114.1, 106.5, 103.4, 61.5,
60.6, 55.2, 52.6 ppm. C40H32O12 (704.68): calcd. C 68.18, H 4.58;
found C 68.03, H 4.83.
concentrated under vacuum. After chromatographic purification
on a C-18 column (4:1 H2O/MeOH), compound 22 was obtained
as a yellow solid (4 mg, 60%). M.p. Ͼ 300 °C. TLC: Rf = 0.25
(AcOEt). IR (KBr pellet): ν = 3428, 3245, 2961, 1716, 1559, 1510,
˜
1
1266, 1039, 803 cm–1. H NMR (CD3OD, 300 MHz): δ = 8.53 (s,
1 H, naphthyl-H), 8.17 (d, J = 8.6 Hz, 2 H, naphthyl-H), 7.69 (d,
Eur. J. Org. Chem. 2006, 1489–1498
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1497

M. Desage-El Murr, S. Nowaczyk, T. Le Gall, C. Mioskowski
FULL PAPER
[6] a) S. Meunier, M. Desage-El Murr, S. Nowaczyk, T. Le Gall,
S. Pin, J.-P. Renault, D. Boquet, C. Créminon, E. Saint-Aman,
A. Valleix, F. Taran, C. Mioskowski, ChemBioChem 2004, 5,
832–840; b) S. Meunier, M. Hanédanian, M. Desage-El Murr,
S. Nowaczyk, T. Le Gall, S. Pin, J.-P. Renault, D. Boquet, C.
Créminon, C. Mioskowski, F. Taran, ChemBioChem 2005, 6,
1234–1241.
J = 8.6 Hz, 2 H, naphthyl-H), 7.60 (d, J = 9.2 Hz, 2 H, naphthyl-
H), 7.44–7.50 (m, 2 H, naphthyl-H), 7.36 (d, J = 7.3 Hz, 2 H, Ar-
H), 7.27 (d, J = 7.3 Hz, 2 H, Ar-H), 6.78(d, J = 8.6 Hz, 2 H, Ar-
H), 6.74 (d, J = 8.6 Hz, 2 H, Ar-H), 3.85 (s, 3 H, CO2CH3), 3.81
(s, 3 H, CO2CH3) ppm. 13C NMR ([D6]acetone, 75 MHz): δ =
177.4, 177.3, 171.7, 169.5, 168.2, 161.9, 159.6, 157.1, 152.9, 152.3,
142.3, 132.2, 131.9, 130.2, 128.9, 127.4, 127.1, 126.9, 126.2, 125.8,
121.3, 120.3, 115.8, 100.3, 56.4 ppm. HRMS: calcd. for [M +
Na]+ 671.1165; found 671.1192.
[7] M. Gill, W. Steglich, Prog. Chem. Org. Nat. Prod. 1987, 51, 1–
317.
[8] B. Heurtaux, C. Lion, T. Le Gall, C. Mioskowski, J. Org.
Chem. 2005, 70, 1474–1477.
2,2Ј-[Naphthalene-1,7-diylbis(3-hydroxy-5-oxofuran-4-yl-2-ylidene)]-
bis[(4-hydroxyphenyl)acetic Acid] (3): A 0.5- NaOH aqueous solu-
tion (300 µL) was added to compound 22 (10 mg, 0.015 mmol) and
the mixture was heated at 100 °C for 1 h. After cooling to room
temperature, 1  aqueous HCl was added until pH 1. The aqueous
phase was extracted with AcOEt (2×5 mL). The combined organic
phases were dried with MgSO4, filtered, and then concentrated un-
der vacuum. After chromatographic purification on a C-18 column
(9:1 H2O/MeOH), diacid 3 was obtained as a yellow solid (9 mg,
90%). M.p. 175–176 °C. TLC: Rf = 0.15 (AcOEt). IR (KBr pellet):
[9] a) P. Langer, M. Stoll, Angew. Chem. 1999, 111, 1919–1922;
Angew. Chem. Int. Ed. 1999, 38, 1803–1805; b) P. Langer, T.
Schneider, M. Stoll, Chem. Eur. J. 2000, 6, 3204–3214; c) P.
Langer, T. Eckardt, T. Schneider, C. Göbel, R. Herbst-Irmer,
J. Org. Chem. 2001, 66, 2222–2226.
[10] a) Z. Ahmed, P. Langer, J. Org. Chem. 2004, 69, 3753–3757; b)
Z. Ahmed, P. Langer, Tetrahedron 2005, 61, 2055–2063; c) See
also: Z. Ahmed, U. Albrecht, P. Langer, Eur. J. Org. Chem.
2005, 3469–3474.
[11] R. Ramage, G. J. Griffiths, J. N. A. Sweeney, J. Chem. Soc.,
Perkin Trans. 1 1984, 1547–1553.
[12] W.-B. Choi, J. Lee, J. E. Lynch, R. P. Volante, P. J. Reider, R. A.
Reamer, Chem. Commun. 1998, 1817–1818.
ν = 3449, 1743, 1563, 1511, 1389, 1147, 1062, 974, 837, 767 cm–1.
˜
1H NMR ([D6]acetone, 300 MHz): δ = 8.64 (s, 1 H, naphthyl-H),
8.30 (d, J = 8.6 Hz, 2 H, naphthyl-H), 7.78 (d, J = 8.6 Hz, 2 H,
naphthyl-H), 7.73 (dd, J = 7.2, 2.5 Hz, 2 H, naphthyl-H), 7.39–7.42
(m, 2 H, naphthyl-H), 7.19 (d, J = 8.6 Hz, 2 H, Ar-H), 7.12 (d, J
= 8.6 Hz, 2 H, Ar-H), 6.77 (d, J = 8.6 Hz, 2 H, Ar-H), 6.73 (d, J
= 8.6 Hz, 2 H, Ar-H) ppm. 13C NMR ([D6]acetone, 75 MHz): δ =
172.2, 157.9, 133.8, 133.7, 133.1, 132.8, 132.7, 130.4, 129.5, 128.5,
128.1, 125.8, 124.9, 121.6, 115.3 ppm.
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Received: October 26, 2005
Published Online: January 17, 2006
1498
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Eur. J. Org. Chem. 2006, 1489–1498