Total synthesis of norbadione A

Article abstract of DOI:10.1021/jo702106u

(Chemical Equation Presented) A short, convergent synthesis of the mushroom pigment norbadione A is described. The construction of an appropriately substituted naphtholactone intermediate involved a regioselective Diels-Alder reaction between a bis(triisopropylsilyloxy)diene and 2,6-dichlorobenzo-1,4- quinone. A double Suzuki-Miyaura cross-coupling between a diboronate and two identical enol triflates was another key feature of the synthesis.

Full text of DOI:10.1021/jo702106u

Total Synthesis of Norbadione A†
Yann Bourdreux,‡ Ste´phanie Nowaczyk,‡ Ce´lia Billaud,‡ Aure´lie Mallinger,‡
Catherine Willis,‡ Marine Desage-El Murr,‡ Lo¨ıc Toupet,§ Claude Lion,|
Thierry Le Gall,*,‡ and Charles Mioskowski‡
CEA, iBiTecS, SerVice de Chimie Bioorganique et de Marquage, Baˆt. 547, 91191, Gif-sur-YVette, France;
Groupe Matie`re Condense´e et Mate´riaux, UMR CNRS 6626, UniVersite´ de Rennes 1, Baˆt. 11A, 35042
Rennes, France; ITODYS, UniVersite´ de Paris 7, UMR CNRS 7086, 1 rue Guy de la Brosse,
75005 Paris, France
thierry.legall@cea.fr
ReceiVed September 26, 2007
A short, convergent synthesis of the mushroom pigment norbadione A is described. The construction of
an appropriately substituted naphtholactone intermediate involved a regioselective Diels-Alder reaction
between a bis(triisopropylsilyloxy)diene and 2,6-dichlorobenzo-1,4-quinone. A double Suzuki-Miyaura
cross-coupling between a diboronate and two identical enol triflates was another key feature of the
synthesis.
Introduction
norbadione A was then further characterized.5-7 This compound
was also shown to display important antioxidant properties.8
Structurally, 1 is a naphtholactone related to a more common
family of mushroom pigments, the pulvinic acids. Indeed, it
has been proposed that the biosynthesis of norbadione A as well
as badione A involves two molecules of a pulvinic acid,
xerocomic acid.1,2b,9 Here we report the first total synthesis of
this natural product.
Norbadione A (1) is a pigment of the common edible
mushroom bay boletus [Xerocomus badius (Fr.) Ku¨hn. ex Gilb.],
which was first isolated by Steglich.1 It was also found in
another mushroom, Pisolithus tinctorius (Pers.) Coker & Couch,
by Gill.2 Following the Chernobyl nuclear reactor accident, it
was found that specimens of several mushrooms, including bay
boletus, collected in Europe contained significant amounts of
cesium 137.3 Steglich et al. showed that in contaminated bay
boletus, 137Cs was associated with norbadione A and with
badione A, a related pigment.4 Complexation of cesium by
(5) Garaude´e, S.; Elhabiri, M.; Kalny, D.; Robiolle, C.; Trendel, J.-M.;
Hueber, R.; Van Dorsselaer, A.; Albrecht, P.; Albrecht-Gary, A.-M. Chem.
Commun. 2002, 944-945.
(6) Desage-El Murr, M.; Nowaczyk, S.; Le Gall, T.; Mioskowski,
C.; Amekraz, B.; Moulin, C. Angew. Chem., Int. Ed. 2003, 42, 1289-
1293.
† Dedicated to the memory of Dr. Charles Mioskowski (deceased June 2,
2007).
‡ CEA, iBiTecS.
(7) Kuad, P.; Borkovec, M.; Desage-El Murr, M.; Le Gall, T.; Miosk-
owski, C.; Spiess, B. J. Am. Chem. Soc. 2005, 127, 1323-1333.
(8) (a) Meunier, S.; Desage-El Murr, M.; Nowaczyk, S.; Le Gall, T.;
Pin, S.; Renault, J.-P.; Boquet, D.; Cre´minon, C.; Saint-Aman, E.; Valleix,
A.; Taran, F.; Mioskowski, C. ChemBioChem 2004, 5, 832-840. (b)
Meunier, S.; Hane´danian, M.; Desage-El Murr, M.; Nowaczyk, S.; Le Gall,
T.; Pin, S.; Renault, J.-P.; Boquet, D.; Cre´minon, C.; Mioskowski, C.; Taran,
F. ChemBioChem 2005, 6, 1234-1241.
§ Universite´ de Rennes 1.
| Universite´ de Paris 7.
(1) Steffan, B.; Steglich, W. Angew. Chem., Int. Ed. 1984, 23, 445-
447.
(2) (a) Gill, M.; Lally, D. A. Phytochemistry 1985, 24, 1351-1354. (b)
Gill, M.; Kiefel, M. J. Aust. J. Chem. 1994, 47, 1967-1977.
(3) Kalacˇ, P. Food Chem. 2001, 75, 29-35.
(4) Aumann, D. C.; Clooth, G.; Steffan, B.; Steglich, W. Angew. Chem.,
Int. Ed. 1989, 28, 453-454.
(9) Steglich, W.; Huppertz, H.-T.; Steffan, B. Angew. Chem., Int. Ed.
1985, 24, 711-712.
10.1021/jo702106u CCC: $40.75 © 2008 American Chemical Society
Published on Web 12/01/2007
22
J. Org. Chem. 2008, 73, 22-26

Total Synthesis of Norbadione A
SCHEME 1. Retrosynthetic Analysis of Norbadione A (1)
SCHEME 2. Preparation of Lactone 9
Results and Discussion
The strategy for this synthesis was based primarily on two
bond disconnections (Scheme 1). Suzuki-Miyaura cross-
couplings between naphtholactone 2 containing two boronate
functions and 2 equiv of alkenyl triflate 3 would lead to a
protected precursor of norbadione A.
Pulvinic compounds have been synthesized from triflates such
as 3 and aryl boronates, including a 1,7-bis(boronated)naph-
thalene,10 or aryl boronic acids.11 Triflate 3 was previously
prepared from the corresponding enol,10 obtained via the
cyclocondensation of oxalyl chloride and a 1,3-bis(trimethyl-
silyloxy)diene, according to the method developed by Langer.12,13
The boronate functions of the naphtholactone 2 were intended
to be introduced from a ditriflate, derived from the correspond-
ing diphenol 9, via a palladium-mediated double borylation. The
synthesis of 9 started by the Diels-Alder reaction of com-
mercially available 2,6-dichloro-1,4-benzoquinone (4) with
bis(triisopropylsilyloxy)diene 5, prepared in one step from ethyl
2,4-dioxovalerate, in refluxing toluene (Scheme 2). Treatment
of the crude product with HCl in ethanol at reflux allowed the
aromatization to naphthoquinone 6,14 obtained in 67% yield.
It was then necessary to introduce an oxygenated function in
place of the chlorine atom, via the conjugate addition of an
oxygen-centered nucleophile, followed by chloride elimination.
In preliminary studies, treatment of 6 with KOH in ethanol led
to mixtures of regioisomers, hydroxylated on either carbon atom
C-6 or C-7. Finally, by employing excess lithium benzylate as
the nucleophile in THF at low temperature, a clean conversion
to naphthoquinone 7, obtained as a single adduct, was achieved.
Moreover, an adequate protecting group for the hydroxyl
function was thus introduced. The reduction of naphthoquinone
7 with sodium dithionite then led to hydroquinone 8, a very
unstable compound, prone to reoxidizing readily. Hence, it was
not isolated but directly engaged in an acid-mediated lacton-
ization, affording lactone 9 (57% yield over two steps). An X-ray
crystallographic analysis of lactone 9 confirmed the regiose-
lectivity of the Diels-Alder reaction and that of the introduction
of the benzyloxy group (see ORTEP drawing in Figure 1).
Lactone 9 was readily converted to the ditriflate 10 (Scheme
3). When applied to this compound, the borylation method of
Masuda et al.,15 employing pinacolborane and PdCl2(dppf) in
dioxane, did not yield any diboronate 2 but instead naphtholac-
tone 11, which formed readily at room temperature. This
indicated that pinacolborane had acted as a hydride source.
An extensive screening of conditions was performed, using
bis(pinacolato)diboron (12) as the borylation agent,16 in order
(10) Desage-El Murr, M.; Nowaczyk, S.; Le Gall, T.; Mioskowski, C.
Eur. J. Org. Chem. 2006, 1489-1498.
(11) (a) Ahmed, Z.; Langer, P. J. Org. Chem. 2004, 69, 3753-3757.
(b) Ahmed, Z.; Langer, P. Tetrahedron 2005, 61, 2055-2063.
(12) (a) Langer, P.; Stoll, M. Angew. Chem., Int. Ed. 1999, 38, 1803-
1805. (b) Langer, P.; Eckardt, T. Synlett 2000, 844-846. (c) Langer, P.;
Schneider, T.; Stoll, M. Chem. Eur. J. 2000, 6, 3204-3214. (d) Langer, P.
Synlett 2006, 3369-3381.
(13) We recently described the synthesis of an iodide analogous to triflate
3, according to a different reaction scheme, and its use in Suzuki-Miyaura
cross-couplings. See: Willis, C.; Bodio, E.; Bourdreux, Y.; Billaud, C.; Le
Gall, T.; Mioskowski, C. Tetrahedron Lett. 2007, 48, 6421-6424.
(14) For selected examples, see: (a) Boisvert, L.; Brassard, P. J. Org.
Chem. 1988, 53, 4052-4059. (b) Kelly, T. R.; Xu, W.; Ma, Z.; Li, Q.;
Bhushan, V. J. Am. Chem. Soc. 1993, 115, 5843-5844. (c) Cameron, D.
W.; Skene, C. E. Aust. J. Chem. 1996, 49, 617-624.
(15) Murata, M.; Oyama, T.; Watanabe, S.; Masuda, Y. J. Org. Chem.
2000, 65, 164-168.
(16) (a) Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995, 60,
7508-7510. (b) Ishiyama, T.; Itoh, Y.; Kitano, T.; Miyaura, N. Tetrahedron
Lett. 1997, 38, 3447-3450.
J. Org. Chem, Vol. 73, No. 1, 2008 23

Bourdreux et al.
SCHEME 4. Completion of the Total Synthesis of
Norbadione A
FIGURE 1. ORTEP drawing of the X-ray structure of lactone 9.
SCHEME 3. Preparation of Diboronate 2
The coupling procedure was then modified. Prior to the other
components of the coupling, 1 equiv of pyrrolidine was added
to a THF solution of 2. In the hydroxyamide formed interme-
diately, one of the electron-withdrawing groups, the amide
carbonyl function, should not be in the same plane as the
naphthalene ring and this should make the reacting species more
nucleophilic. To the THF solution of hydroxyamide were then
added PdCl2(PPh3)2, 2 M Na2CO3, and triflate 3. After 3.5 h at
reflux, compound 14 resulting from two cross-couplings was
obtained in 58% yield (Scheme 4). Treatment of this compound
at reflux in acetic acid for 2 h then afforded lactone 15 (74%).
The remaining, important task was the removal of the
protecting groups. We had initially scheduled to cleave the
benzyl ethers and the methyl ethers and esters in several
consecutive steps. However, treatment of 15 with iodotrimeth-
ylsilane18 (15 equiv) in deuterated chloroform at 55 °C for 11
days allowed cleavage of the seven protecting groups in a single
step, leading to 1 in 28% yield. The spectroscopic data of
synthetic norbadione A were in full agreement with those
reported for the natural product (see Supporting information).
In conclusion, the first total synthesis of the unusual
mushroom pigment norbadione A has been performed via a
convergent strategy. The key steps were a Diels-Alder cy-
cloaddition employed in the preparation of an appropriately
substituted naphtholactone intermediate and a double Suzuki-
Miyaura coupling allowing the completion of the carbon
framework of the target molecule. Application of a similar
strategy to the synthesis of badione A is under way.
to avoid any reduction. Eventually, diboronate 2 was obtained
in 59% yield by treatment of ditriflate 10 with 12, in the
presence of Pd(OAc)2, 2-(dicyclohexylphosphino)biphenyl (13),17
and diisopropylethylamine in dioxane. The reaction actually
proceeded at room temperature. To the best of our knowledge,
all the reported palladium-mediated borylations of aryl halides
or triflates using 12 require heating at 50-100 °C.
Both components necessary for the key cross-coupling were
thus available. Conditions that we had used previously in similar
couplings10 involving triflate 3 [PdCl2(PPh3)2, refluxing mixture
of THF and 2 M Na2CO3] did not lead to the expected adduct
when applied to diboronate 2. Other conditions and catalysts
tested did not give better results. The low reactivity of diboronate
2 was attributed to the presence of three electron-withdrawing
groups on the naphthalene. The lactone might also have reacted
with the base necessary for the activation of the boronates.
Examination of a crude product obtained under the conditions
described above showed that a yellow compound, much more
polar than the expected adduct, had been formed. Its spectro-
scopic characteristics corresponded to a hydroxyacid resulting
from the opening of the expected lactone. This was proved by
heating this compound in acetic acid for 6 days at 110 °C, which
led to lactone 15, albeit in a low overall yield (6%).
Experimental Section
2,4-Bis(triisopropylsilanyloxy)penta-2,4-dienoic Acid Ethyl
Ester (5). A solution of ethyl 2,4-dioxovalerate (6.92 g, 43.5 mmol)
in dichloromethane (250 mL) was stirred at 0 °C, under argon.
Triethylamine (25 mL, 180 mmol, 4.1 equiv) and triisopropylsilyl
triflate (23.5 mL, 87 mmol, 2 equiv) were successively added via
(17) For a palladium-catalyzed borylation of aryl halides using this
phosphine and pinacolborane, see: Baudouin, O.; Gue´nard, D.; Gue´ritte,
F. J. Org. Chem. 2000, 65, 9268-9271.
(18) Gedge, D. R.; Pattenden, G.; Smith, A. G. J. Chem. Soc., Perkin
Trans. 1 1986, 2127-2131.
24 J. Org. Chem., Vol. 73, No. 1, 2008

Total Synthesis of Norbadione A
syringe at 0 °C, and then the reaction mixture was allowed to warm
slowly to room temperature over 5.5 h. Ether (200 mL) was added
to the red solution obtained. The organic phase was washed
successively with 1 N aqueous NaOH solution (3 × 100 mL) and
saturated aqueous NaHCO3 solution (3 × 100 mL), dried over
MgSO4, then filtered, and concentrated under vacuum, leading to
23.6 g of crude product. Silica gel chromatography (pentane
containing 1% Et3N) afforded diene 5 as a pale yellow oil (14.2 g,
70%). A single isomer was obtained, but its configuration was not
elucidated. IR (NaCl) νmax: 680, 738, 770, 836, 883, 920, 951,
1032, 1139, 1229, 1271, 1367, 1388, 1465, 1630, 1723, 2868, 2893,
2946 cm-1. 1H NMR (400 MHz, CDCl3): δ 1.09 (d, J ) 7 Hz, 18
H), 1.10 (d, J ) 7 Hz, 18 H), 1.15-1.25 (m, 3 H), 1.28-1.37 (m,
3 H), 1.32 (t, J ) 7 Hz, 3 H), 4.23 (q, J ) 7 Hz, 2 H), 4.73 (d, J
) 1.5 Hz, 1 H), 5.21 (s, 1 H), 6.11 (d, J ) 1.5 Hz, 1 H). 13C NMR
(100 MHz, CDCl3): δ 12.7, 14.1, 14.2, 18.1, 18.2, 61.4, 99.1, 115.6,
141.6, 151.5, 165.3. MS (ESI-TOF) m/z 471 (100, [M + H]+).
HRMS (ESI-TOF) calcd for C25H50NaO4Si2 [M + Na]+ 493.3145,
found 493.3127.
solution of sodium dithionite (87 mL) was added to a solution of
naphthoquinone 7 (1 g, 2.84 mmol) in acetone (150 mL) placed
under argon, under vigorous stirring. The initial yellow solution
turned red during the addition. After stirring for 15 min at room
temperature, the reaction mixture, which had become orange, was
poured into a separatory funnel placed in a nitrogen-filled glovebox.
Water (50 mL) was added, and the aqueous phase was extracted
with ethyl acetate (2 × 50 mL). The combined organic layers were
dried over MgSO4, then filtered, and concentrated under vacuum.
All of these operations were carried out under an argon atmosphere.
The reddish oil obtained was then dissolved in a mixture of toluene
(32 mL) and acetone (10 mL). The solution was equipped with a
Dean-Stark apparatus, the trap of which was filled with 4 Å
molecular sieves, and p-toluenesulfonic acid (63.3 mg, 0.37 mmol,
0.13 equiv) was added. The reaction mixture was refluxed for 22
h. After cooling to room temperature, ethyl acetate (50 mL) was
added. The organic phase was washed with brine (2 × 30 mL),
dried over MgSO4, then filtered, and concentrated under vacuum.
Ether was added to the residue, leading to the formation of a
precipitate that was removed by filtration. The solid obtained (160
mg) was essentially the naphthoquinone 7. The filtrate was
concentrated under vacuum. Silica gel chromatography (98:2
CH2Cl2/CH3OH) afforded lactone 9 as an orange solid (500 mg,
57%). Mp ) 228 °C. TLC: Rf ) 0.30 (95:5 CH2Cl2/MeOH). IR
(KBr pellet) νmax: 708, 997, 1077, 1149, 1172, 1202, 1248, 1292,
7-Chloro-3-hydroxy-5,8-dioxo-5,8-dihydro-naphthalene-1-
carboxylic Acid Ethyl Ester (6). A solution of diene 5 (11.47 g,
24 mmol, 1.2 equiv) in toluene (25 mL) was added via syringe to
a solution of 2,6-dichloro-1,4-benzoquinone (3.6 g, 20 mmol) in
toluene (13 mL), under argon. The mixture was refluxed overnight,
then cooled to room temperature, and concentrated under vacuum.
A solution of concentrated HCl (1.8 mL) in ethanol (45 mL) was
added to the residue, and then the mixture was heated at 100 °C
for 5 h. After cooling down to room temperature, ethyl acetate (100
mL) was added. The organic phase was washed twice with water
(50 mL), dried over MgSO4, then filtered, and concentrated under
vacuum. Silica gel chromatography (8:2 pentane/AcOEt) afforded
naphthoquinone 6 as a orange solid (3.76 g, 67%). Mp ) 180 °C.
TLC: Rf ) 0.15 (8:2 pentane/AcOEt). IR (KBr pellet) νmax: 574,
857, 881, 1012, 1063, 1102, 1178, 1212, 1239, 1271, 1318, 1346,
1
1374, 1409, 1462, 1527, 1615, 1653, 1727, 3291, 3520 cm-1. H
NMR (400 MHz, acetone-d6): δ 5.47 (s, 2 H), 6.62 (s, 1 H), 7.25-
7.45 (m, 3 H), 7.53 (d, J ) 1.7 Hz, 2 H), 7.68 (d, J ) 1.7 Hz, 1
H), 7.73 (d, J ) 1.7 Hz, 1 H), 9.26 (br s, 2 H). 13C NMR (100
MHz, acetone-d6): δ 73.6, 105.4, 113.3, 117.3, 120.4, 121.0, 127.0,
127.4, 128.8, 129.0, 129.3, 137.6, 138.1, 151.0, 157.9, 167.4. HRMS
(ESI-TOF) calcd for C18H12NaO5 [M + Na]+ 331.0582, found
331.0558.
Trifluoromethanesulfonic Acid 8-Benzyloxy-2-oxo-6-trifluo-
romethanesulfonyloxy-2H-naphtho[1,8-bc]furan-4-yl Ester (10).
A solution of diphenol 9 (290 mg, 0.94 mmol) in dichloromethane
(4.5 mL) and pyridine (1.5 mL) was cooled at 0 °C, under argon.
Triflic anhydride (0.50 mL, 2.9 mmol, 3.2 equiv) was added
dropwise via syringe. The reaction mixture was allowed to warm
to room temperature over 3.3 h, and then ethyl acetate (20 mL)
was added. The organic phase was washed thrice with 1 N aqueous
HCl, dried over MgSO4, then filtered, and concentrated under
vacuum. The solid obtained was washed with pentane and dried.
Compound 10 was thus obtained as a yellow solid (538 mg,
quantitative). Mp ) 85 °C. TLC: Rf ) 0.70 (9:1 pentane/AcOEt).
IR (KBr pellet) νmax: 506, 609, 740, 752, 840, 896, 933, 965, 1001,
1030, 1070, 1116, 1139, 1223, 1250, 1270, 1358, 1428, 1455, 1481,
1500, 1616, 1653, 1803, 3091 cm-1. 1H NMR (400 MHz, acetone-
d6): δ 5.68 (s, 2 H), 7.36-7.47 (m, 3 H), 7.58-7.61 (d, J ) 6.7
Hz, 2 H), 7.83 (s, 1 H), 8.43 (d, J ) 1.7 Hz, 1 H), 8.53 (d, J ) 1.7
Hz, 1 H). 13C NMR (100 MHz, acetone-d6): δ 74.5, 119.5, 119.7
(q, JC-F ) 318 Hz), 119.7 (q, JC-F ) 318 Hz), 119.9, 120.9, 123.0,
123.5, 128.8, 129.3, 129.4, 130.4, 134.0, 136.7, 139.9, 141.6, 150.4,
164.6. HRMS (ESI-TOF) calcd for C21H14F6NaO10S2 [M + Na +
MeOH]+ 626.9830, found 626.9813.
8-Benzyloxy-4,6-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
2-yl)naphtho[1,8-bc]furan-2-one (2). Degassed 1,4-dioxane (3.5
mL) and anhydrous diisopropylethylamine (174 µL, 1 mmol, 5.7
equiv) were added to a mixture of ditriflate 10 (100 mg, 0.175
mmol, 1 equiv), palladium(II) acetate (3.9 mg, 0.0175 mmol, 0.1
equiv), 2-dicyclohexylphosphinobiphenyl (24.5 mg, 0.07 mmol, 0.4
equiv), and bis(pinacolato)diboron (133 mg, 0.52 mmol, 3 equiv)
placed in a flask under argon. The suspension obtained was stirred
for 4 h. The initial orange mixture rapidly turned to brown. A
saturated aqueous NH4Cl solution (10 mL) was added. The aqueous
phase was extracted with ethyl acetate (3 × 10 mL). The combined
organic phases were dried over MgSO4, then filtered, and concen-
trated under vacuum. Methanol was added to the solid residue
obtained. The solid that precipitated was recovered on a sintered
1
1378, 1469, 1560, 1588, 1670, 1727, 2985, 3073, 3402 cm-1. H
NMR (300 MHz, acetone-d6): δ 1.35 (t, J ) 7.3 Hz, 3 H), 4.39
(q, J ) 7.3 Hz, 2 H), 7.17 (d, J ) 2.4 Hz, 1 H), 7.33 (s, 1 H), 7.52
(d, J ) 2.4 Hz, 1 H). 13C NMR (75 MHz, acetone-d6): δ 14.2,
62.4, 114.2, 120.0, 121.3, 135.9, 136.2, 139.2, 147.0, 163.5, 168.5,
176.5, 182.7. Anal. Calcd for C13H9O5Cl: C, 55.63; H, 3.23; Cl,
12.63. Found: C, 55.83; H, 3.44; Cl, 12.70.
7-Benzyloxy-3-hydroxy-5,8-dioxo-5,8-dihydronaphthalene-1-
carboxylic Acid Ethyl Ester (7). A solution of butyllithium (55
mL, 1.58 M in hexanes, 87 mmol, 6.5 equiv) was added dropwise
via syringe to a solution of benzyl alcohol (12.5 mL, 120 mmol, 9
equiv) in THF (55 mL), cooled at -40 °C, under argon. After 1 h
of stirring at -40 °C, a solution of naphthoquinone 6 (3.76 g, 13.4
mmol) in THF (30 mL) was added dropwise, and then the stirring
was continued for 1 h at -40 °C. The reaction mixture turned to
red. It was allowed to warm to room temperature over 5 h. Aqueous
3 N HCl (50 mL) was added, and then the layers were separated.
The aqueous phase was extracted with ethyl acetate (3 × 40 mL).
The combined organic phases were dried over MgSO4, then filtered,
and concentrated under vacuum, leading to a solid that was washed
with ether. Naphthoquinone 7 was thus obtained as a yellow solid
(3.64 g, 77%). Mp ) 245 °C. TLC: Rf ) 0.18 (8:2 pentane/AcOEt).
IR (KBr pellet) νmax: 699, 743, 848, 1022, 1099, 1184, 1232, 1293,
1350, 1379, 1456, 1494, 1602, 1633, 1675, 1733, 2987, 3065, 3269
1
cm-1. H NMR (400 MHz, acetone-d6): δ 1.33 (t, J ) 7.2 Hz, 3
H,), 4.37 (q, J ) 7.2 Hz, 2 H), 5.22 (s, 2 H), 6.37 (s, 1 H), 7.10 (s,
1 H), 7.35-7.55 (m, 6 H), 10.25 (br s, 1 H). 13C NMR (100 MHz,
acetone-d6): δ 14.3, 62.2, 71.9, 111.0, 113.7, 119.2, 121.3, 129.0,
129.4, 129.5, 136.1, 136.13, 138.5, 160.8, 163.3, 168.8, 178.3,
184.4. HRMS (ESI-TOF) calcd for C20H16NaO6 [M + Na]+
375.0845, found 375.0818. Anal. Calcd for C20H16O6: C, 68.18;
H, 4.58. Found: C, 67.86; H, 4.55.
8-Benzyloxy-4,6-dihydroxynaphtho[1,8-bc]furan-2-one (9). The
solvents and aqueous solutions used in this synthesis were all
degassed with a stream of argon for 30 min. A saturated aqueous
J. Org. Chem, Vol. 73, No. 1, 2008 25

Bourdreux et al.
glass and dried. The filtrate was concentrated, and methanol was
added. The solid that precipitated was recovered. The two portions
were combined, leading to diboronate 2 as a beige solid (55 mg,
59%). Mp ) 221-224 °C. TLC: Rf ) 0.50 (9:1 pentane/AcOEt).
IR (KBr pellet) νmax: 700, 740, 847, 970, 1046, 1084, 1145, 1214,
ylidene](4-benzyloxyphenyl)acetic Acid Methyl Ester (15). A
solution of hydroxyamide 14 (68 mg, 0.063 mmol) in acetic acid
(8 mL) was heated at reflux under argon for 2 h. After cooling to
room temperature, water (40 mL) was added, and the aqueous phase
was extracted with ethyl acetate (3 × 50 mL). The combined
organic layers were dried over MgSO4, filtered, and concentrated
under vacuum. Silica gel chromatography (gradient from 1:9 to
1:1 AcOEt/pentane) afforded lactone 15 as an yellow solid (47 mg,
74%). Mp ) 132-134 °C. TLC: Rf ) 0.45 (6:4 pentane/AcOEt).
IR (NaCl) νmax: 515, 548, 614, 696, 736, 780, 834, 901, 1510,
920, 976, 1045, 1132, 1183, 1227, 1284, 1310, 1375, 1454, 1431,
1
1345, 1374, 1500, 1628, 1790, 2929, 2980 cm-1. H NMR (400
MHz, CDCl3): δ 1.41 (s, 12 H), 1.43 (s, 12 H), 5.61 (s, 2 H),
7.25-7.45 (m, 3 H), 7.52 (d, J ) 7.0 Hz, 2 H), 7.90 (s, 1 H), 8.57
(s, 1 H), 9.19 (s, 1 H). 13C NMR (75 MHz, CDCl3): δ 25.1, 73.4,
84.3, 84.4, 118.4, 128.0, 128.4, 128.7, 128.8, 132.5, 133.4, 136.8,
138.6, 141.1, 167.2. HRMS (ESI-TOF) calcd for C30H3411B2NaO7
[M + Na]+ 551.2388, found 551.2408.
1
1600, 1630, 1732, 1772, 2949, 3032 cm-1. H NMR (400 MHz,
8-Benzyloxynaphtho[1,8-bc]furan-2-one (11). A reaction car-
ried out as above but using pinacolborane instead of bis(pinaco-
lato)diboron did not lead to diboronate 2 but afforded lactone 11,
isolated as the main product. This compound was identified on the
basis of its 1H NMR spectrum and its mass spectrum. TLC: Rf )
0.16 (95:5 pentane/ether). IR (NaCl) νmax: 2924, 2854, 1774, 1457,
1253 cm-1. 1H NMR (400 MHz, CDCl3): δ 5.61 (s, 2 H), 7.31 (d,
J ) 8 Hz, 1 H), 7.34-7.42 (m, 3 H), 7.51 (d, J ) 7.4 Hz, 1 H),
7.61 (d, J ) 9 Hz, 1 H), 7.69 (d, J ) 7.5 Hz, 1 H), 8.09 (m, 1 H),
8.15 (d, J ) 7.1 Hz, 1 H). MS (ESI-TOF) m/z: 277 [M + H]+
(100%). HRMS (ESI-TOF) calcd for C18H12NaO3 [M + Na]+
299.0684, found 299.0708.
{4-[3-Benzyloxy-7-{5-[(4-benzyloxyphenyl)methoxycarbon-
ylmethylene]-4-methoxy-2-oxo-2,5-dihydrofuran-3-yl}-4-hydroxy-
5-(pyrrolidine-1-carbonyl)naphthalen-1-yl]-3-methoxy-5-oxo-
5H-furan-2-ylidene}(4-benzyloxyphenyl)acetic Acid Methyl Ester
(14). Pyrrolidine (29 µL, 0.347 mmol, 1.2 equiv) was slowly added
to a solution of diboronate 2 (150 mg, 0.284 mmol) in THF (25
mL), under argon. After stirring at room temperature for 15 min,
PdCl2(PPh3)2 (80 mg, 0.114 mmol, 0.4 equiv) and triflate 3 (438
mg, 0.852 mmol, 3 equiv) were successively added. Argon was
bubbled in the suspension, and then an aqueous 2 M Na2CO3
solution (6.1 mL) was added. The reaction mixture was refluxed
under argon for 3.5 h. Its color turned from red to black after about
15 min. After cooling to room temperature, brine (50 mL) was
added, and the aqueous phase was extracted with ethyl acetate (3
× 50 mL). The combined organic layers were dried over MgSO4,
filtered, and concentrated under vacuum. Silica gel chromatography
(ether, then CH2Cl2, then 1:1 CH2Cl2/ether, then 1:1 CH2Cl2/AcOEt,
then AcOEt) afforded amide 14 as an orange solid (178 mg, 58%).
CDCl3): δ 3.68 (s, 3 H), 3.82 (s, 3 H), 3.92 (s, 6 H), 5.13 (s, 4 H),
5.64 (s, 2 H), 7.02 (d, J ) 8.9 Hz, 2 H), 7.03 (d, J ) 8.8 Hz, 2 H),
7.34-7.53 (m, 16 H), 7.67 (d, J ) 8.9 Hz, 2 H), 7.70 (d, J ) 8.8
Hz, 2 H), 8.15 (s, 1 H), 8.37 (s, 1 H). 13C NMR (100 MHz, acetone-
d6): δ 52.88, 52.90, 61.4, 62.1, 70.0, 73.6, 101.6, 105.9, 115.2,
117.7, 117.9, 119.7, 123.3, 123.4, 124.6, 127.4, 127.9, 128.1, 128.5,
128.62, 128.64, 128.9, 130.99, 131.03, 131.2, 132.4, 133.6, 135.9,
136.28, 136.30, 138.33, 138.4, 139.4, 159.8, 159.9, 163.8, 164.7,
165.7, 166.8, 166.9, 167.68, 167.74. HRMS (ESI-TOF) calcd for
C60H44NaO15 [M + Na]+ 1027.2578, found 1027.2593.
[4-(4-{5-[Carboxy-(4-hydroxyphenyl)-methylene]-4-hydroxy-
2-oxo-2,5-dihydrofuran-3-yl}-8-hydroxy-2-oxo-2H-naphtho[1,8-
bc]furan-6-yl)-3-hydroxy-5-oxo-5H-furan-2-ylidene](4-hydroxy-
phenyl)acetic Acid (Norbadione A) (1). A solution of lactone 15
(47 mg, 0.047 mmol) in deuterated chloroform (2.25 mL) was
placed in a tube wrapped in an aluminum foil, under argon.
Iodotrimethylsilane (100 µL, 0.705 mmol, 15 equiv) was added
dropwise. The tube was closed by a screwed cap, and the solution
was heated at 55 °C. Samples were taken every 2-3 days and
1
analyzed by H NMR. After 11 days, the reaction mixture was
cooled at 0 °C, and methanol (5 mL) was added. After stirring for
30 min, the solvents were eliminated under vacuum. The residue
was subjected to reverse phase chromatography (10 µm C18, 40:
60:1 water/MeOH/acetic acid). The solid obtained was dissolved
in acetone. Concentrated HCl was added until formation of a
precipitate, and the solid was recovered by filtration. This operation
was repeated twice, leading to norbadione A (1) as a red solid (8.9
mg, 28%). Mp > 300 °C (lit.1 >300 °C). Reverse phase TLC: Rf
) 0.45 (40:60:1 water/MeOH/acetic acid). IR (NaCl) νmax: 595,
671, 704, 746, 794, 904, 959, 1046, 1180, 1046, 1180, 1259, 1328,
1
1391, 1466, 1514, 1571, 1645, 1749, 2853, 2922, 3376 cm-1. H
Mp ) 106-108 °C. TLC: Rf ) 0.45 (AcOEt). IR (NaCl) νmax
:
614, 679, 697, 737, 783, 834, 887, 920, 977, 1046, 1098, 1132,
1183, 1230, 1254, 1285, 1323, 1386, 1453, 1510, 1602, 1627, 1733,
NMR (400 MHz, acetone-d6): δ 6.92 (d, J ) 8.6 Hz, 2 H), 6.94
(d, J ) 8.6 Hz, 2 H), 7.33 (d, J ) 8.6 Hz, 2 H), 7.38 (d, J ) 8.6
Hz, 2 H), 7.57 (s, 1 H), 8.91 (d, J ) 1 Hz, 1 H), 9.06 (d, J ) 1 Hz,
1 H). 13C NMR (100 MHz, acetone-d6): δ 103.4, 103.6, 115.4,
115.5, 118.4, 118.5, 120.6, 124.0, 124.4, 125.0, 125.1, 126.5, 126.6,
129.7, 131.0, 131.9, 132.59, 132.62, 133.7, 137.8, 154.3, 154.6,
158.46, 158.54, 163.3, 163.4, 166.87, 166.92, 167.1, 173.7, 173.9.
1
1769, 2875, 2950, 3033 cm-1. H NMR (400 MHz, acetone-d6):
δ 1.85 (m, 2 H), 1.92 (m, 2 H), 3.15 (m, 2 H), 3.55 (s, 3 H), 3.59
(m, 2 H), 3.83 (s, 3 H), 3.86 (s, 3 H), 3.87 (s, 3 H), 5.20 (s, 2 H),
5.21 (s, 2 H), 5.39 (s, 2 H), 7.12 (d, J ) 9.0 Hz, 2 H), 7.13 (d, J
) 9.0 Hz, 2 H), 7.32-7.43 (m, 9 H), 7.48-7.56 (m, 7 H), 7.63 (d,
J ) 9.0 Hz, 2 H), 7.67 (d, J ) 9.0 Hz, 2 H), 7.77 (s, 1 H), 8.12 (d,
J ) 1.5 Hz, 1 H). 13C NMR (100 MHz, acetone-d6): δ 24.2, 25.5,
45.3, 48.0, 52.0, 52.1, 60.2, 61.2, 69.60, 69.62, 71.5, 103.7, 106.4,
115.1, 115.5, 115.7, 118.4, 120.4, 123.95, 123.98, 125.1, 125.5,
127.5, 127.6, 127.8, 127.9, 128.0, 128.3, 128.4, 130.5, 134.4,
136.91, 136.94, 140.1, 159.55, 159.57, 162.8, 163.8, 166.45, 166.47,
167.1, 167.5, 169.2. HRMS (ESI-TOF) calcd for C64H53NNaO15
[M + Na]+ 1098.3313, found 1098.3311.
Acknowledgment. S.N. and C.W. thank the CNRS for
financial support. The authors thank A. Valleix for his advice
on norbadione A chromatographic purification.
Supporting Information Available: Crystallographic data of
lactone 9 in CIF format and NMR spectra for new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
[4-(8-Benzyloxy-4-{5-[(4-benzyloxyphenyl)methoxycarbon-
ylmethylene]-4-methoxy-2-oxo-2,5-dihydrofuran-3-yl}-2-oxo-
2H-naphtho[1,8-bc]furan-6-yl)-3-methoxy-5-oxo-5H-furan-2-
JO702106U
26 J. Org. Chem., Vol. 73, No. 1, 2008