Synthesis of natural pulvinic acids based on a '[3+2] cyclization-Suzuki cross-coupling' strategy

Article abstract of DOI:10.1016/j.tet.2004.12.048

A number of pulvinic acid natural products were prepared based on Suzuki cross coupling reactions of α-hydroxy-γ-alkylidenebutenolides which are readily available by cyclization of 1,3-bis-silyl enol ethers with oxalyl chloride. The formal total synthesis

Full text of DOI:10.1016/j.tet.2004.12.048

Tetrahedron 61 (2005) 2055–2063
Synthesis of natural pulvinic acids based on a
‘[3C2] cyclization–Suzuki cross-coupling’ strategy
*
Zafar Ahmed and Peter Langer
¨
¨
Institut fur Chemie, Universitat Rostock, Albert-Einstein-Str. 3a, D-18051 Rostock, Germany
Received 2 November 2004; revised 10 December 2004; accepted 21 December 2004
Available online 19 January 2005
Abstract—A number of pulvinic acid natural products were prepared based on Suzuki cross coupling reactions of a-hydroxy-g-
alkylidenebutenolides which are readily available by cyclization of 1,3-bis-silyl enol et0hers with oxalyl chloride. The formal total synthesis
of pulvinic acid, atromentic acid, gomphidic acid and of 4-hydroxypulvinic acid, 4 -hydroxypulvinic acid and iso-gomphidic acid are
reported. In addition, total syntheses of pinastric acid, xerocomic acid and variegatic acid were accomplished.
q 2005 Elsevier Ltd. All rights reserved.
Pulvinic acids constitute a group of natural products
containing a g-alkylidenebutenolide ring system.1 They
have been isolated from several lichens and higher fungi and
represent bright yellow and orange pigments. A number of
regioselective and non-regioselective syntheses of unsym-
metrical pulvinic acids have been reported.2–4 For example,
pulvinic acids are available by cleavage of one lactone
moiety of pulvinic bis-lactones. The latter can be prepared,
for example, by reaction of arylacetonitriles with diethyl
oxalate2a or ethyl 2-chloro-2-oxoacetate2b,c or by bio-
mimetic rearrangements of terphenylquinones.2d However,
mixtures of regioisomeric products were obtained for
reactions of unsymmetrical bis-lactones, due to the very
similar chemical environment of the two lactone moieties.
An alternative synthesis of permethylated pulvinic acids
relies on Reformatsky-type reactions of maleic anhydrides.3
Unfortunately, the yields are low and the procedure is
relatively tedious, since the transformations have to be
carried out over three steps ((a) Reformatsky condensation,
(b) mesylation and (c) elimination). Pulvinic acids have
been prepared also based on biomimetic transformations
(Scheme 1).4
analogue of the natural product norbadion A.10 Herein, we
wish to report the application of our methodology to the
synthesis of the natural products pinastric acid,2d,11
atromentic acid,3,12 xerocomic acid,4,13,14 variegatic
acid15,16b and gomphidic acid3,16 and of their analogues
4-hydroxypulvinic acid,2d,3 40-hydroxypulvinic acid2d,3 and
iso-gomphidic acid.3 The method reported herein allows a
regioselective synthesis of pulvinic acids, since the aryl
substituents are introduced independently from each other.
In addition, the method is robust, the starting materials are
readily available, the yields are good to very good and the
number of steps is low.
1. Results and discussion
The reaction of methyl methoxyacetate (1) with the
arylacetic esters 2a–d afforded the b-ketoesters 3a–d
(Scheme 2, Table 1). The reaction of 3a–d with NEt3/
Me3SiCl gave the silyl enol ethers 4a–d. The latter were
transformed into the 1,3-bis-silyl enol ethers 5a–d. The
TMSOTf-catalyzed cyclization of 5a–d with oxalyl chloride
afforded the g-alkylidenebutenolides 6a–d with very good
E-diastereoselectivity. The configuration of the exocyclic
double bond was established based on NOESY measure-
ments, on analogy to related findings7–10 and on the
transformation of 6 into natural products with known
configuration (vide infra). The synthesis of 6a and 6b has
been recently reported.9,10 Butenolides 6a–d were trans-
formed into the corresponding triflates 7a–d.
We and others have recently reported the functionalization
of a-hydroxy-g-alkylidenebutenolides, readily available by
cyclization of 1,3-bis-silyl enol ethers5,6 with oxalyl
chloride,7 by Stille and Suzuki cross coupling reactions.8–11
The application of the Suzuki reaction allowed a convenient
synthesis of the natural product vulpinic acid2d,9 and of an
Keywords: Butenolides; Cyclizations; Natural products; Pulvinic acids;
Silyl enol ethers.
The Suzuki reaction of 7a with (p-methoxyphenyl)boronic
acid afforded O-methylpinastric acid (10) in 70% yield
* Corresponding author. Tel.: C49 3834 864461; fax: C49 3834 864373;
e-mail: peter.langer@uni-greifswald.de
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.12.048

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Z. Ahmed, P. Langer / Tetrahedron 61 (2005) 2055–2063
Scheme 2. Synthesis of butenolides 7a–d: (i) (1) LDA, THF, (2) 2
(0.5 equiv), K78/20 8C; (ii) Me3SiCl, NEt3, toluene, 20 8C; (iii) (1)
LDA, THF, K78 8C, (2) Me3SiCl, K78/20 8C; (iv) oxalyl chloride,
Me3SiOTf (0.3 equiv), CH2Cl2, K78/20 8C; (v) Tf2O, pyridine,
K78/K10 8C.
acid (12) in 60% yield. The high regioselectivity of the
reaction of 10 with BBr3 can be explained (a) by chelation
of BBr3 to the ester carbonyl group (intermediate A, Scheme
4) and (b) by the better leaving group ability of the tetronate
compared to the phenolate moiety. The chelation exerts a
regiodirective bias and results in the activation and
subsequent cleavage of the butenolide methyl ether
(intermediate B). The spectroscopic data of pinastric acid
12 are identical with those reported in the literature.2d The
transformation of 12 into 4-hydroxypulvinic acid (13) was
accomplished earlier by Pattenden et al. by employment of
Me3SiI.2d
Scheme 1. Pulvinic acid natural products and analogues.
(Scheme 3). The configuration of the exocyclic double bond
proved stable under the reaction conditions. Treatment of 10
with BBr3 (4 equiv, 0 8C, 2 h) resulted in cleavage of both
methyl ether groups to give 11 in 69% yield. However, the
synthesis of pinastric acid required the regioselective
cleavage of the butenolide methyl ether in the presence of
the aryl methyl ether. Much to our satisfaction, treatment of
10 with only 1 equiv of BBr3 (0 8C, 6 h) afforded pinastric
The Suzuki reaction of 7b with phenylboronic acid gave
butenolide 14a in 85% yield (Scheme 5). The transform-
ation of 14a into 40-hydroxypulvinic acid (15a) has been
Table 1. Products and yields
3–7
R1
R2
R3
% (3)a
% (4)a
% (5)a
% (6)a
% (7)a
ab
bc
c
H
H
OMe
OMe
H
H
H
H
OMe
67
58
62
62
84
90
83
72
90
95
89
96
54
57
61
61
61
77
66
74
OMe
OMe
OMe
d
a Yields of isolated products, E/ZO98:2 for 6a–d and 7a–d.
b See Ref. 9.
c See Ref. 10.

Z. Ahmed, P. Langer / Tetrahedron 61 (2005) 2055–2063
2057
Scheme 5. Synthesis of pulvinic acids 15a–d: (i) Pd(PPh3)4 (3 mol%),
K3PO4 (1.5 equiv), dioxane, reflux; (ii) Me3SiI, CDCl3, 55 8C.
reported by Pattenden.2d Permethylatromentic acid (14b)
was prepared in 62% yield by Suzuki reaction of 7b with
(4-methoxyphenyl)boronic acid. Treatment of 14b with
Me3SiI has been reported to give atromentic acid (15b) in
70% yield.3 The reaction of 7b with (3,4-dimethoxy-
phenyl)boronic acid afforded permethylxerocomic acid
(14c) in 81% yield. Treatment of 14c with Me3SiI afforded
xerocomic acid (15c) in 72% yield. The Suzuki reaction of
7b with (3,4,5-trimethoxyphenyl)boronic acid afforded
permethylgomphidic acid (14d) in 88% yield. The Me3SiI
mediated transformation of 14d into gomphidic acid (15d)
has been reported to proceed in 65% yield.3 All pulvinic
acids were obtained as E-configured isomers. The spectro-
scopic data of all permethylated pulvinic acids were
identical with those reported (Table 2).2b,3
Scheme 3. Synthesis of pinastric acid and 4-hydroxypulvinic acid:
(i) Pd(PPh3)4 (3 mol%), K3PO4 (1.5 equiv), dioxane, reflux; (ii) BBr3
(4 equiv), CH2Cl2, 0 8C; (iii) BBr3 (1 equiv), CH2Cl2, 0 8C, 6 h; (iv) Me3SiI,
CDCl3, 55 8C.
The synthesis of variegatic acid (17) was studied next
(Scheme 6). The Suzuki reaction of 7c with (3,4-di-
methoxyphenyl)boronic acid gave permethylvariegatic
acid (16) in 80% yield. Treatment of 16 with Me3SiI
afforded variegatic acid (17) in 68% yield. The spectro-
scopic data of the synthetic material were identical to those
reported in the literature for the natural product.14,16b
Scheme 4. Possible mechanism of the regioselective deprotection of 10.
Table 2. Synthesis of pulvinic acids 15
The Suzuki reaction of 7d with (4-methoxyphenyl)boronic
a
%
14, 15
R1
R2
R3
14a
14b
14c
14d
15a
15b
15c
15d
H
H
OMe
OMe
H
H
OH
OH
H
H
H
H
OMe
H
H
H
OH
85
62
81
OMe
OMe
OMe
H
OH
OH
OH
88
342d
703
72
653
a Yields of isolated products, E/Z O98:2 for all products.

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Z. Ahmed, P. Langer / Tetrahedron 61 (2005) 2055–2063
chloride, a method previously developed by us, secondly
the functionalization of the butenolides by Suzuki reactions
and finally their transformation into natural products. All
reactions are robust, easy to carry out and proceed in good
yield and with excellent selectivity.
2. Experimental
2.1. General comments
All solvents were dried by standard methods and all
reactions were carried out under an inert atmosphere. For
the 1H and 13C NMR spectra the deuterated solvents
indicated were used. Mass spectral data (MS) were obtained
by electron ionization (70 eV), chemical ionization (CI,
H2O) or the electrospray ionization (ESI). For preparative
scale chromatography silica gel (60–200 mesh) was used.
Melting points are uncorrected.
2.2. Typical procedure for the synthesis of b-ketoesters
(3a–d)
Scheme 6. Synthesis of variegatic acid: (i) Pd(PPh3)4 (3 mol%), K3PO4
(1.5 equiv), dioxane, reflux; (ii) Me3SiI, CDCl3, 55 8C.
The reaction was carried out analogously to a known
procedure.10 The synthesis of 3a,b has been reported
earlier.9,10 To a stirred solution of LDA (58.0 mmol) in
THF (150 ml) was added methyl phenylacetate (8.10 ml,
57.6 mmol) at K78 8C. After stirring for 1 h methyl
methoxyacetate (3.00 g, 28.8 mmol) was added. The
temperature of the solution was allowed to rise to 20 8C
during 12 h. A saturated aqueous solution of NH4Cl was
added, the layers were separated and the aqueous layer was
extracted with dichloromethane (3!150 ml). The com-
bined organic layers were dried (Na2SO4), filtered and the
solvent of the filtrate was removed in vacuo. The residue
was purified by chromatography (silica gel, hexane/EtOAc)
to give 3a as a colorless oil (4.58 g, 67%). The spectroscopic
data are identical with those reported.9
acid afforded butenolide 18 in 73% yield (Scheme 7). The
spectroscopic data of 18 are identical with those reported.3
The transformation of 18 into iso-gomphidic acid (19) has
been reported to proceed in 63% yield.3
2.2.1. Compound 3b. Starting with methyl methoxyacetate
(9.00 g, 86.4 mmol), methyl (4-methoxyphenyl)acetate
(27.90 ml, 172.9 mmol), LDA (172 mmol) and THF
(432 ml), 3b was isolated as a colourless solid (12.59 g,
58%), mp 55–56 8C. The spectroscopic data are identical
with those reported.10 1H NMR (300 MHz, CDCl3): dZ3.33
(s, 3H, OCH3), 3.76 (s, 3H, OCH3), 3.79 (s, 3H, OCH3), 4.05
(d, 2H, JZ3.3 Hz, CH2), 4.89 (s, 1H, CH), 6.88 (dd, 2H,
JZ2.1, 1.5 Hz, ArH), 7.24 (dd, 2H, JZ2.1, 1.8 Hz, ArH);
13C NMR (75 MHz, CDCl3): dZ52.32, 54.98, 59.06 (CH3),
59.60 (CH), 76.23 (CH2), 114.04 (2C, CH), 123.59 (C),
130.42 (2C, CH), 159.36, 168.82, 201.80 (C); IR (KBr):
n~Z2953 (s), 1748 (s), 1727 (s), 1610 (m), 1513 (s), 1441 (s),
1301 (m), 1251 (s), 1180 (m), 1161 (m), 832 (s) cmK1; MS
(EI, 70 eV): m/z (%): 252.0 (MC, 34), 219.9 (24), 179.0
(100), 147.4 (82), 77.4 (15), 45.1 (47); elemental analysis:
calcd (%) for C13H16O5 (252.26): C 61.89, H 6.39; found: C
61.55, H 6.00.
Scheme 7. Synthesis of iso-gomphidic acid: (i) Pd(PPh3)4 (3 mol%), K3PO4
(1.5 equiv), dioxane, reflux; (ii) Me3SiI, CDCl3, 55 8C.
In summary, we have reported efficient formal syntheses of
the natural products pulvinic acid, atromentic acid, and
gomphidic acid and their analogues 4-hydroxypulvinic acid,
40-hydroxypulvinic acid and iso-gomphidic acid. In
addition, total syntheses of pinastric acid, xerocomic acid
and variegatic acid were accomplished. The synthesis of
pinastric acid relies on the regioselective deprotection of
O-methylpinastric acid. The key steps of our synthetic
strategy are firstly the synthesis of g-alkylidenebutenolides
by cyclization of 1,3-bis-silyl enol ethers with oxalyl
2.2.2. Compound 3c. Starting with methyl methoxyacetate
(1.75 ml, 17.83 mmol), methyl (3,4-dimethoxyphenyl)-
acetate (7.50 g, 35.67 mmol), LDA (35.66 mmol) and
THF (90 ml), 3c was isolated as a yellow oil (3.12 g,
62%). 1H NMR (300 MHz, CDCl3): dZ3.36 (s, 3H, OCH3),

Z. Ahmed, P. Langer / Tetrahedron 61 (2005) 2055–2063
2059
3.75 (s, 3H, OCH3), 3.87 (s, 3H, OCH3), 3.88 (s, 3H, OCH3),
4.08 (d, 2H, JZ3.9 Hz, CH2), 4.88 (s, 1H, CH), 6.85 (s, 3H,
ArH); 13C NMR (75 MHz, CDCl3): dZ51.77, 55.07, 55.12.
58.47 (CH3), 59.52 (CH), 75.69 (CH2), 110.63, 111.88,
121.39 (CH), 123.61, 148.42 (2C), 168.26, 201.21 (C); IR
(KBr): n~Z3626 (w), 3545 (w), 2949 (s), 2836 (m), 1749 (s),
1728 (s), 1595 (m), 1515 (s), 1460 (s), 1301 (m), 1262 (s),
1201 (s), 1146 (s), 1101 (m), 1026 (s) cmK1; MS (EI,
70 eV): m/z (%): 282.0 (MC, 53), 209.0 (100), 181.1 (50),
150.0 (66), 45.1 (56); elemental analysis: calcd (%) for
C14H18O6 (282.29): C 59.56, H 6.42; found: C 59.20, H
6.48.
dZ0.08 (s, 9H, CH3), 3.39 (s, 3H, OCH3), 3.73 (s, 3H,
OCH3), 3.85 (s, 3H, OCH3), 3.86 (s, 3H, OCH3), 4.43 (s, 2H,
CH2), 6.79 (s, 3H, ArH).
2.3.3. Compound 4d. Starting with b-ketoester 3d (3.26 g,
10.43 mmol), NEt3 (2.40 ml, 16.70 mmol), TMSCl
(2.38 ml, 18.79 mmol) and benzene (26 ml), 4d was isolated
as a yellow oil (2.73 g, 72%); 1H NMR (300 MHz, CDCl3):
dZ0.07 (s, 9H, CH3), 3.69 (s, 3H, OCH3), 3.72 (s, 3H,
OCH3), 3.81 (s,6H, OCH3), 3.84 (s, 3H, OCH3), 4.43 (s, 2H,
CH2), 6.45 (s, 2H, ArH).
2.4. Typical procedure for the synthesis of bis-silyl enol
ethers (5a–d)
2.2.3. Compound 3d. Starting with methyl methoxyacetate
(2.00 g, 19.2 mmol), methyl (3,4,5-trimethoxyphenyl)-
acetate (9.24 g, 38.4 mmol), LDA (38.4 mmol) and THF
(96 ml), 3d was isolated as a colourless solid (3.70 g, 62%),
The reaction was carried out analogously to a known
procedure.7b The synthesis of 5a,b has been reported
earlier.9,10 To a stirred THF solution (100 ml) of LDA
(20.4 mmol, 1.5 equiv) was added 4a (4.00 g, 13.6 mmol) at
K78 8C. After stirring for 1 h, trimethylchlorosilane
(2.57 ml, 20.4 mmol) was added. The solution was allowed
to warm to room temperature during 12 h with stirring. The
solvent was removed in vacuo and to the residue was added
Hexane (100 ml) to give a suspension. The latter was
filtered under Argon atmosphere. The filtrate was distilled in
vacuo to give 5a as a colorless oil (4.50 g, 90%). The
compound was used directly after its preparation. The
spectroscopic data are identical with those reported.9 1H
NMR (300 MHz, CDCl3): dZ0.04 (s, 9H, CH3), 0.31 (s,
9H, CH3), 3.41 (s, 3H, OCH3), 3.56 (s, 3H, OCH3), 5.63 (s,
1H, ]CH), 7.22–7.35 (m, 5H, ArH).
1
mp 52 8C. H NMR (600 MHz, CDCl3): dZ3.36 (s, 3H,
OCH3), 3.73 (s, 3H, OCH3), 3.82 (s, 9H, OCH3), 4.11 (s, 2H,
CH2), 4.92 (s, 1H, CH), 6.58 (s, 2H, ArH); 13C NMR
(150 MHz, CDCl3): dZ52.12, 55.68, 58.78 (2C), 60.04
(CH3), 60.24 (CH), 76.05 (CH2), 106.46 (2C, CH), 126.96,
137.72, 152.90 (2C), 168.34, 201.23 (C); IR (KBr): n~Z3627
(w), 3544 (w), 3452 (w), 2997 (s), 2942 (s), 2836 (s), 1752
(s), 1726 (s), 1591 (s), 1507 (s), 1462 (s), 1426 (s), 1318 (s),
1241 (s), 1199 (s), 1126 (s), 1104 (s), 730 (w) cmK1; MS
(EI, 70 eV): m/z (%): 312.1 (MC, 68), 265.1 (9), 239.0
(100), 181.0 (32), 44.1 (37); elemental analysis: calcd (%)
for C15H20O7 (312.31): C 57.69, H 6.45; found: C 57.25, H
7.14.
2.3. Typical procedure for the synthesis of silyl enol
ethers (4a–d)
2.4.1. Compound 5b. Starting with 4b (6.00 g, 18.5 mmol),
LDA (27.7 mmol, 1.5 equiv), TMSCl (4.20 ml, 33.3 mmol)
and THF (92 ml), 5b was isolated as a yellow oil (7.00 g,
95%). The spectroscopic data are identical with those
reported.10 1H NMR (300 MHz, CDCl3): dZ0.01 (s, 9H,
CH3), 0.27 (s, 9H, CH3), 3.45 (s, 3H, OCH3), 3.52 (s, 3H,
OCH3), 3.77 (s,3H, OCH3), 5.91 (s, 1H, ]CH), 6.78 (d, 2H,
JZ9.0 Hz, ArH), 7.22 (d, 2H, JZ8.7 Hz, ArH).
The reaction was carried out analogously to a known
procedure.7b The synthesis of 4a,b has been reported
earlier.9,10 To a stirred benzene solution (10 ml) of 7
(4.50 g) was added triethylamine (4.50 ml, 32.4 mmol).
After stirring for 2 h trimethylchlorosilane (4.60 ml,
36.4 mmol) was added. After stirring for 72 h, the solvent
was removed in vacuo and to the residue was added Hexane
(100 ml) to give a suspension. The latter was filtered under
Argon atmosphere. The filtrate was distilled in vacuo to give
4a as a colorless oil (5.00 g, 84%). The compound was used
2.4.2. Compound 5c. Starting with 4c (3.00 g, 8.46 mmol),
LDA (13.54 mmol, 1.5 equiv), TMSCl (1.92 ml,
15.23 mmol) and THF (67 ml), 5c was isolated as a yellow
oil (3.25 g, 89%); 1H NMR (300 MHz, CDCl3): dZ0.03 (s,
9H, CH3), 0.30 (s, 9H, CH3), 3.46 (s, 3H, OCH3), 3.71 (s,
3H, OCH3), 3.85 (s,3H, OCH3), 3.86 (s, 3H, OCH3), 5.62 (s,
1H, ]CH), 6.79 (s, 3H, ArH).
1
directly after its preparation. H NMR (300 MHz, CDCl3):
dZ0.08 (s, 9H, CH3), 3.26 (s, 3H, OCH3), 3.44 (s, 3H,
OCH3), 3.77 (s, 2H, CH2), 7.21–7.39 (m, 5H, ArH). The
spectroscopic data are identical with those reported.8
2.3.1. Compound 4b. Starting with b-ketoester 3b
(6.0 g, 23.78 mmol), NEt3 (5.28 ml, 38.05 mmol), TMSCl
(5.38 ml, 42.80 mmol) and benzene (60 ml), 4b was isolated
as a yellow oil (7.00 g, 90%). The spectroscopic data are
identical with those reported.10 1H NMR (300 MHz,
CDCl3): dZ0.08 (s, 9H, CH3), 3.23 (s, 3H, OCH3), 3.58
(s, 3H, OCH3), 3.71 (s, 3H, OCH3), 4.39 (s, 2H, CH2), 6.78
(dd, 2H, JZ1.2, 8.7 Hz, ArH), 7.07 (dd, 2H, JZ1.5, 8.7 Hz,
ArH).
2.4.3. Compound 5d. Starting with 4d (2.70 g, 7.0 mmol),
LDA (10.53 mmol, 1.5 equiv) and TMSCl (1.60 ml,
12.6 mmol) and THF (50 ml), 5d was isolated as a yellow
1
oil (3.0 g, 96%); H NMR (300 MHz, CDCl3): dZ0.05 (s,
9H, CH3), 0.30 (s, 9H, CH3), 3.71 (s, 3H, OCH3), 3.80 (s,
3H, OCH3), 3.84 (s, 6H, OCH3), 3.86 (s, 3H, OCH3), 5.47 (s,
1H, CH), 6.61 (s, 2H, ArH).
2.5. Typical procedure for the synthesis of butenolides (6)
2.3.2. Compound 4c. Starting with b-ketoester 3c (3.0 g,
10.62 mmol), NEt3 (2.36 ml, 17.00 mmol), TMSCl
(2.41 ml, 19.11 mmol) and benzene (27 ml), 4c was isolated
as a yellow oil (3.15 g, 83%); 1H NMR (300 MHz, CDCl3):
The reaction was carried out analogously to a known
procedure.7b The synthesis of 6a,b has been previously
reported.9,10 To a CH2Cl2 solution (60 ml) of oxalyl
chloride (0.70 ml, 7.8 mmol) and of 5a (2.20 g, 6.0 mmol)

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Z. Ahmed, P. Langer / Tetrahedron 61 (2005) 2055–2063
was added a CH2Cl2 solution (5 ml) of Me3SiOTf (0.6 ml,
3.6 mmol) at K78 8C. The temperature of the reaction
mixture was allowed to rise to 20 8C during 12 h. After
stirring for 2 h at 20 8C, a saturated aqueous solution of
NaCl was added. The aqueous layer was separated and
extracted with CH2Cl2. The combined organic layers were
washed with an aqueous solution of HCl (10%), dried
(Na2SO4) and filtered. The solvent of the filtrate was
removed in vacuo and the residue was purified by column
chromatography (silica gel, hexane/EtOAc) to give 6a as a
yellow solid (900 mg, 54%). The spectroscopic data were
identical with those reported.9 1H NMR (300 MHz, CDCl3):
dZ3.84 (s, 3H, OCH3), 4.18 (s, 3H, OCH3), 7.31–7.56 (m,
5H, ArH), 12.93 (s, 1H, OH); MS (EI, 70 eV): m/z (%)Z276
(MC, 100); elemental analysis: calcd for C14H12O6
(276.25): C 60.87, H 4.38; found: C 60.62, H 4.52.
(s), 1681 (s), 1655 (m), 1584 (m), 1508 (m), 1461 (m), 1422
(m), 1344 (m), 1312 (m), 1254 (m), 1138 (s), 1052 (m) cmK1
;
MS (EI, 70 eV): m/z (%): 366.0 (MC, 100), 312.0 (45),
279.0 (36), 239.0 (90), 181.1 (39), 45.0 (23); elemental
analysis: calcd (%) for C17H18O9 (366.30): C 55.74, H 4.95;
found: C 55.92, H 5.27.
2.6. General procedure for the preparation of triflates
(7)
The synthesis of 7a,b has been reported.9,10 To a
dichloromethane solution (10 ml per 1 mmol of 6) of
butenolide 6 (1.0 equiv) and triflic anhydride (1.2 equiv)
was added pyridine (2.0 equiv) at K78 8C. The solution was
allowed to warm to K10 8C within 4 h. The product was
isolated by rapid chromatography (silica gel, dichloro-
methane) of the reaction mixture.
2.5.1. Compound 6b. Starting with 5b (4.0 g, 10.08 mmol),
oxalyl chloride (1.05 ml, 12.10 mmol), TMSOTf (0.55 ml,
3.02 mmol) and CH2Cl2 (100 ml), 6b was isolated as a
yellow solid (1.75 g, 57%), mp 163 8C. The spectroscopic
data are identical with those reported.10 1H NMR
(300 MHz, (CD3)2CO): dZ3.83 (s, 6H, OCH3), 4.16 (s,
3H, OCH3), 6.98 (d, 2H, JZ9.0 Hz, ArH), 7.49 (d, 2H, JZ
9.0 Hz, ArH); 13C NMR (75 MHz, (CD3)2CO): dZ53.44,
56.34, 60.88 (CH3), 115.62 (2C, CH), 125.65 (2C), 125.74
(C), 131.78 (2C, CH), 141.00, 144.43, 161.57, 165.59,
168.21 (C); IR (KBr): n~Z3309 (s), 2954 (w), 1736 (s), 1672
(s), 1634 (m), 1603 (m), 1514 (s), 1462 (m), 1377 (s), 1312
(m), 1258 (m), 1194 (s), 1142 (s), 1113 (s), 1057 (m), 831
(m) cmK1; MS (EI, 70 eV): m/z (%): 305.9 (MC, 100),
273.9 (54), 247.0 (84), 218.9 (25), 191.0 (28), 159.0 (32),
119.1 (15), 28.1 (68); elemental analysis: calcd (%) for
C15H14O7 (306.27): C 58.82, H 4.60; found: C 58.84, H
4.61.
2.6.1. Compound 7b. Starting with 6b (980 mg,
3.19 mmol), triflic anhydride (0.65 ml, 3.82 mmol), pyri-
dine (0.52 ml, 6.38 mmol) and CH2Cl2 (32 ml), 7b was
isolated as a yellow solid (1.06 g, 77%), mp 101–103 8C.
The spectroscopic data are identical with those reported.10
1H NMR (300 MHz, CDCl3): dZ3.84 (s, 3H, OCH3), 3.89
(s, 3H, OCH3), 4.28 (s, 3H, OCH3), 6.93 (dd, 2H, JZ2.1,
6.9 Hz, ArH), 7.58 (dd, 2H, JZ2.1, 6.9 Hz, ArH); 13C NMR
(50 MHz, CDCl3): dZ52.96, 55.41, 61.05 (CH3), 113.97
(C), 114.50 (2C, CH), 118.40 (q, JZ319.50 Hz, CF3),
120.78, 122.50 (C), 131.27 (2C, CH), 135.60, 155.73,
160.18, 161.17, 165.97 (C); IR (KBr): n~Z2980 (w), 1787
(s), 1737 (s), 1663 (s), 1646 (m), 1602 (m), 1513 (m), 1428
(s), 1317 (m), 1290 (m), 1233 (s), 1213 (s), 1133 (m), 1087
(s), 1045 (s), 629 (m) cmK1; MS (EI, 70 eV): m/z (%): 438.6
(MC, 63), 304.9 (67), 249.0 (100), 220.9 (33), 205.9 (18),
135.0 (34), 28.0 (51); elemental analysis: calcd (%) for
C16H13O9SF3 (437.74): C 43.90, H 2.99, S 7.32; found: C
43.86, H 3.17, S 7.41.
2.5.2. Compound 6c. Starting with 5c (3.25 g, 7.61 mmol),
oxalyl chloride (0.80 ml, 9.14 mmol), TMSOTf (0.42 ml,
2.28 mmol) and CH2Cl2 (71 ml), 6c was isolated as a yellow
2.6.2. Compound 7c. Starting with butenolide 6c (375 mg,
1.11 mmol), triflic anhydride (0.22 ml, 1.34 mmol), pyri-
dine (0.19 ml, 2.24 mmol) and CH2Cl2 (11 ml), 7c was
isolated as a yellow solid (736 mg, 66%), mp 122–123 8C;
1H NMR (300 MHz, CDCl3): dZ3.89 (s, 3H, OCH3), 3.90
(s, 3H, OCH3), 3.92 (s, 3H, OCH3), 4.29 (s, 3H, OCH3), 6.89
(d, 1H, JZ8.5 Hz, ArH), 7.14 (dd, 1H, JZ2.1, 8.5 Hz,
ArH), 7.24 (d, 1H, JZ2.1 Hz, ArH); 13C NMR (75 MHz,
CDCl3): dZ53.04, 56.04 (2C), 61.11 (CH3), 111.08, 112.25
(CH), 113.94 (C), 118.40 (q, JZ319.5 Hz, CF3), 120.83,
122.63 (C), 123.19 (CH), 135.69, 149.04, 150.99, 155.68,
160.13, 165.91 (C); IR (KBr): n~Z3600 (w), 1788 (s), 1734
(s), 1650 (s), 1521 (s), 1426 (s), 1295 (m), 1250 (s), 1137 (s),
1083 (s), 1056 (m), 615 (m) cmK1; MS (EI, 70 eV): m/z (%):
467.8 (MC, 40), 335.0 (18), 275.0 (100), 247.0 (25), 148.3
(20); elemental analysis: calcd (%) for C17H15O10SF3
(468.36): C 43.60, H 3.23; found: C 44.09, H 3.23.
1
solid (1.55 g, 61%), mp 156–157 8C. H NMR (300 MHz,
(CD3)2CO): dZ3.80 (s, 6H, OCH3), 3.83 (s, 3H, OCH3),
3.84 (s, 3H, OCH3), 4.18 (s, 3H, OCH3), 6.98 (d, 1H, JZ
8.5 Hz, ArH), 7.06 (dd, 1H, JZ2.1, 8.5 Hz, ArH), 7.18 (d,
1H, JZ2.1 Hz, ArH); 13C NMR (75 MHz, (CD3)2CO): dZ
53.46, 56.69, 56.80, 60.88 (CH3), 113.08, 114.04 (CH),
114.94, 115.82 (C), 123.49 (CH), 125.75, 141.01, 144.37,
150.70, 151.64, 165.56, 168.16 (C); IR (KBr): nZ3327 (m),
2954 (w), 1743 (s), 1731 (s), 1671 (m), 1519 (m), 1374 (m),
1262 (m), 1132 (m), 1108 (m), 745 (w) cmK1; MS (EI,
70 eV): m/z (%): 336.1 (MC, 100), 277.1 (97), 249.1 (21),
150.1 (6); elemental analysis: calcd (%) for C16H16O8
(336.29): C 57.14, H 4.79; found: C 56.76, H 5.13.
2.5.3. Compound 6d. Starting with 5d (3.0 g, 6.56 mmol),
oxalyl chloride (0.68 ml, 7.87 mmol), TMSOTf (0.35 ml,
1.96 mmol) and CH2Cl2 (61 ml), 6d was isolated as a
yellow solid (1.45 g, 61%), mp 129 8C; 1H NMR (600 MHz,
(CD3)2CO): dZ3.79 (s, 3H, OCH3), 3.82 (s, 6H, OCH3),
3.83 (s, 3H, OCH3), 4.17 (s, 3H, OCH3), 6.82 (s, 2H, ArH);
13C NMR (150 MHz, (CD3)2CO): dZ52.97, 56.69 (2C),
60.36, 60.75 (CH3), 107.76 (2C, CH), 115.14, 125.57,
127.89, 140.19, 141.46, 143.60, 154.37, 154.43, 164.88,
167.41 (C); IR (KBr): n~Z3330 (s), 2953 (w), 1754 (s), 1727
2.6.3. Compound 7d. Starting with butenolide (655 mg,
1.79 mmol), triflic anhydride (0.37 ml, 2.14 mmol), pyri-
dine (0.30 ml, 3.57 mmol) and CH2Cl2 (18 ml), 7d was
isolated as a yellow solid (659 mg, 74%), mp 143–144 8C.
1H NMR (600 MHz, CDCl3): dZ3.87 (s, 6H, OCH3), 3.89
(s, 6H, OCH3), 4.30 (s, 3H, OCH3), 6.82 (s, 2H, ArH); 13
C
NMR (150 MHz, CDCl3): dZ53.25, 56.52 (2C), 61.13,

Z. Ahmed, P. Langer / Tetrahedron 61 (2005) 2055–2063
2061
61.34 (CH3), 107.15 (2C, CH), 114.37 (C), 118.40 (q, JZ
319.50 Hz, CF3), 120.88, 125.21, 136.90, 140.38, 153.51,
155.67, 160.15, 165.82 (C); IR (KBr): n~Z3580 (w), 2952
(w), 1791 (s), 1739 (s), 1654 (m), 1510 (m), 1425 (s), 1237
(m), 1220 (s), 1130 (s), 1086 (s), 1044 (w) cmK1; MS (EI,
70 eV): m/z (%): 497.6 (MC, 51), 364.9 (22), 304.9 (100),
250.9 (21), 69.9 (14), 28.0 (27).
(%) for C21H18O6 (366.36): C 68.84, H 4.83; found: C
68.51, H 5.12.
2.7.3. Permethylatromentic acid (14b). The reaction was
carried out following the general procedure for Suzuki
reactions. Starting with 7b (200 mg, 0.45 mmol), (4-meth-
oxyphenyl)boronic acid (90 mg, 0.59 mmol), potassium
phosphate (155 mg, 0.72 mmol), tetrakis(triphenylphos-
phine) palladium (16 mg, 0.013 mmol) and dioxane
(2.2 ml), 14b was isolated as a yellow solid (110 mg,
62%), mp 168–169 8C. The spectroscopic data are identical
with those reported.3 1H NMR (300 MHz, CDCl3): dZ3.76
(s, 3H, OCH3), 3.83 (s, 6H, OCH3), 3.90 (s, 3H, OCH3), 6.94
(t, 4H, JZ8.9 Hz, ArH), 7.49 (d, 2H, JZ8.7 Hz, ArH), 7.64
(d, 2H, JZ9.0 Hz, ArH); 13C NMR (75 MHz, CDCl3): dZ
52.68, 55.12, 55.28, 60.89 (CH3), 108.03 (C), 113.93 (2C),
114.23 (2C, CH), 115.82, 120.51, 123.48 (C), 130.69 (2C),
130.95 (2C, CH), 140.15, 159.96, 160.32, 162.04, 167.31,
168.05 (C); IR (KBr): n~Z2957 (w), 1764 (s), 1732 (s), 1627
(m), 1599 (s), 1511 (s), 1459 (m), 1367 (m), 1288 (s), 1252
(s), 1160 (s), 1041 (m), 840 (w) cmK1; MS (EI, 70 eV): m/z
(%): 396.0 (MC, 100), 337.0 (57), 281.0 (33), 223.0 (3),
119.1 (26), 28.1 (55); elemental analysis: calcd (%) for
C22H20O7 (396.40): C 66.66, H 5.08; found: C 67.31, H
5.45.
2.7. General procedure for the synthesis of butenolides
10, 14a–d, 16 and 18 by Suzuki reactions
A dioxane solution (5 ml per 1 mmol of triflate) of triflate 3
(1.0 equiv), boronic acid (1.3 equiv), K3PO4 (1.5 equiv) and
Pd(PPh3)4 (3 mol%) was refluxed for 4 h. A saturated
aqueous solution of ammonium chloride was added. The
organic and the aqueous layer were separated and the latter
was extracted (3!) with ether. The combined organic
layers were dried (Na2SO4), filtered and the filtrate was
concentrated in vacuo. The residue was purified by
chromatography (silica gel, EtOAc/hexane).
2.7.1. O-Methylpinastric acid (10). Starting with 7a
(125 mg, 0.30 mmol), (4-methoxyphenyl)boronic acid
(60 mg, 0.39 mmol), potassium phosphate (102 mg,
0.48 mmol), tetrakis(triphenylphosphine) palladium
(11 mg, 0.009 mmol) and dioxane (1.5 ml), 10 was isolated
as a colourless solid (80 mg, 70%), mp 154 8C. The
spectroscopic data are identical with those reported.2d 1H
NMR (300 MHz, CDCl3): dZ3.79 (s, 3H, OCH3), 3.84 (s,
3H, OCH3), 3.90 (s, 3H, OCH3), 6.96 (dd, 2H, JZ2.1,
6.9 Hz, ArH), 7.35–7.50 (m, 5H, ArH), 7.67 (dd, 2H, JZ
1.8, 6.9 Hz, ArH); 13C NMR (75 MHz, CDCl3): dZ52.80,
55.35, 61.01 (CH3), 108.63 (C), 114.05 (2C, CH), 115.95,
120.38 (2C, C), 128.76 (2C), 129.05, (2C),129.31, 131.10
(2C, CH), 141.62, 160.14, 161.90, 167.13, 167.97 (C); IR
(KBr): n~Z2952 (w), 1774 (s), 1733 (s), 1628 (m), 1603 (s),
1513 (s), 1368 (m), 1300 (m), 1252 (s), 1164 (m), 1044 (m),
938 (m), 766 (w) cmK1; MS (EI, 70 eV): m/z (%): 366.0
(MC, 100), 334.9 (5), 306.9 (20), 279.0 (24), 251.0 (33),
146.5 (14), 119.0 (22); elemental analysis: calcd (%) for
C21H18O6 (366.369): C 68.84, H 4.83; found: C 68.64, H
4.83.
2.7.4. Permethylxerocomic acid (14c). The reaction was
carried out following the general procedure for Suzuki
reactions. Starting with 7b (200 mg, 0.45 mmol), (4,5-
dimethoxyphenyl)boronic acid (107 mg, 0.59 mmol), pot-
assium phosphate (155 mg, 0.72 mmol), tetrakis(triphenyl-
phosphine) palladium (16 mg, 0.013 mmol) and dioxane
(2.2 ml), 14c was isolated as a yellow solid (157 mg, 81%),
mp 147–148 8C (lit.13 mp 146–148 8C). The spectroscopic
data are identical with those reported.13 1H NMR
(300 MHz, CDCl3): dZ3.79 (s, 3H, OCH3), 3.84 (s, 3H,
OCH3), 3.91 (s, 9H, OCH3), 6.94 (br, 3H, ArH), 7.10–7.40
(m, 2H, ArH), 7.65 (d, 2H, JZ7.8 Hz, ArH); 13C NMR
(75 MHz, CDCl3): dZ52.73, 55.32, 55.88, 55.98, 60.91
(CH3), 108.25 (C), 110.95, 112.46, 114.27 (2C, CH),
115.97, 120.76 (C), 122.76 (CH), 123.46 (C), 130.73 (2C,
CH), 140.07, 148.76, 149.59, 160.37, 162.15, 167.31,
167.96 (C); IR (KBr): n~Z2952 (w), 1766 (s), 1728 (s),
1626 (m), 1601 (s), 1514 (s), 1462 (m), 1281 (s), 1257 (s),
1231 (s), 1185 (m), 1142 (s), 1047 (s), 1027 (m), 864 (w)
cmK1; MS (EI, 70 eV): m/z (%): 426.1 (MC, 100), 367.1
(40), 311.0 (21), 148.2 (9), 69.8 (11); elemental analysis:
calcd (%) for C23H22O8 (426.40): C 64.78, H 5.20; found: C
64.32, H 5.63.
2.7.2. Permethyl-40-hydroxypulvinic acid (14a). The
reaction was carried out following the general procedure
for Suzuki reactions. Starting with 7b (150 mg, 0.34 mmol),
phenylboronic acid (55 mg, 0.45 mmol), potassium phos-
phate (115 mg, 0.54 mmol), tetrakis(triphenylphosphine)
palladium (12 mg, 0.01 mmol) and dioxane (1.7 ml), 14a
was isolated as a yellow solid (106 mg, 85%), mp 174 8C.
The spectroscopic data are identical with those reported.2d
1H NMR (600 MHz, CDCl3): dZ3.76 (s, 3H, OCH3), 3.83
(s, 3H, OCH3), 3.90 (s, 3H, OCH3), 6.93 (d, 2H, JZ8.4 Hz,
ArH), 7.39 (t, 3H, JZ7.2 Hz, ArH), 7.43 (d, 2H, JZ7.8 Hz,
ArH), 7.51 (d, 2H, JZ7.8 Hz, ArH); 13C NMR (150 MHz,
CDCl3): dZ52.93, 55.55, 61.43 (CH3), 107.99 (C), 114.52
(2C, CH), 116.53, 123.69 (C), 128.63 (2C), 129.06, 130.08
(2C), 131.02 (2C, CH), 131.40, 140.21, 160.67, 163.02,
167.47, 168.05 (C); IR (KBr): n~Z3100 (w), 1768 (s), 1728
(s), 1624 (s), 1598 (s), 1511 (m), 1440 (w), 1367 (m), 1288
2.7.5. Permethylgomphidic acid (14d). The reaction
was carried out following the general procedure for
Suzuki reactions. Starting with 7b (394 mg, 0.90 mmol),
(3,4,5-trimethoxyphenyl)boronic acid (248 mg, 1.17 mmol),
potassium phosphate (306 mg, 1.44 mmol), tetrakis (tri-
phenylphosphine)palladium (32 mg, 0.027 mmol) and diox-
ane (4.5 ml), 14d was isolated as a yellow solid (361 mg,
88%), mp 151–152 8C. The spectroscopic data are identical
with those reported.3 1H NMR (300 MHz, CDCl3): dZ3.82
(s, 3H, OCH3), 3.84 (s, 3H, OCH3), 3.88 (s, 3H, OCH3), 3.89
(s, 6H, OCH3), 3.91 (s, 3H, OCH3), 6.77 (s, 2H, ArH), 6.94
(d, 2H, JZ9.0 Hz, ArH), 7.65 (d, 2H, JZ9.0 Hz, ArH); 13C
NMR (150 MHz, CDCl3): dZ52.94, 55.52, 56.43 (2C),
(s), 1257 (m), 1183 (m), 1159 (m), 1042 (m), 935 (m) cmK1
;
MS (EI, 70 eV): m/z (%): 366.1 (MC, 100), 307.0 (48),
251.1 (40), 165.0 (2), 89.0 (21); elemental analysis: calcd

2062
Z. Ahmed, P. Langer / Tetrahedron 61 (2005) 2055–2063
61.05, 61.25 (CH3), 107.33 (2C, CH), 108.30 (C), 114.51
(2C, CH), 116.60, 123.60, 123.91 (C), 130.99 (2C, CH),
138.85, 140.07, 153.36 (2C), 160.68, 162.78, 167.42,
167.95 (C); IR (KBr): n~Z3006 (w), 2951 (w), 1768 (s),
1733 (s), 1623 (m), 1596 (s), 1508 (s), 1457 (m), 1372 (m),
1284 (s), 1262 (m), 1129 (s), 1043 (m), 842 (w) cmK1; MS
(EI, 70 eV): m/z (%): 455.8 (MC, 13), 396.6 (2), 287.9 (5),
183.8 (5), 152.4 (25), 69.9 (16), 28.0 (100); elemental
analysis: calcd (%) for C24H24O9 (456.40): C 63.16, H 5.30;
found: C 63.44, H 5.81.
(Na2SO4), filtered and the solvent of the filtrate was
removed in vacuo. The residue was purified by column
chromatography (silica gel, hexane/EtOAc) to give 11 as a
red solid (35 mg, 69%), mp 226–227 8C. 1H NMR
(300 MHz, acetone-d6): dZ3.87 (s, 3H, OCH3), 6.89 (d,
2H, JZ9.0 Hz, ArH), 7.24–7.41 (m, 5H, ArH), 8.07 (d, 2H,
JZ9.0 Hz, ArH); 13C NMR (75 MHz, DMSO): dZ53.13
(CH3), 113.00 (C), 115.06 (2C, CH), 120.33 (C), 128.36
(3C), 128.56 (2C), 128.82 (2C, CH), 131.93, 147.08, 156.54
(2C), 167.67, 168.5 (2C, C); IR (KBr): n~Z3375 (s), 2925
(w), 2252 (w), 1746 (s), 1674 (m), 1599 (s), 1435 (m), 1301
(s), 1276 (s), 1179 (m), 1062 (s), 966 (m), 840 (m) cmK1
;
2.7.6. Permethylvariegatic acid (16). Starting with triflate
7c (200 mg, 0.42 mmol) and 3,4-dimethoxyphenylboronic
acid (101 mg, 0.55 mmol), potassium phosphate (145 mg,
0.68 mmol), tetrakis (triphenylphosphine)palladium
(15 mg, 0.012 mmol) and dioxane (2.1 ml), 16 was isolated
as a yellow solid (156 mg, 80%), mp 132–133 8C; 1H NMR
(300 MHz, CDCl3): dZ3.80 (s, 3H, OCH3), 3.91 (s, 3H,
OCH3), 3.92 (s, 9H, OCH3), 3.93 (s, 3H, OCH3), 6.89 (d,
1H, JZ8.7 Hz, ArH), 6.93 (d, 1H, JZ8.4 Hz, ArH), 7.10 (d,
1H, JZ8.4 Hz, ArH), 7.14 (dd, 1H, JZ2.1, 8.4 Hz, ArH),
7.20 (dd, 1H, JZ2.1, 8.7 Hz, ArH), 7.32 (d, 1H, JZ2.1 Hz,
ArH); 13C NMR (75 MHz, CDCl3): dZ52.73, 55.83 (2C),
55.91 (2C), 60.88 (CH3), 108.28 (C), 110.86, 110.93,
111.92, 112.34 (CH), 115.96, 120.65 (C), 122.48, 122.71
(CH), 123.61, 140.20, 148.68, 148.83, 149.53, 150.08,
162.02, 167.21, 167.79 (C); IR (KBr): n~Z2949 (w), 2838
(w), 1771 (s), 1731 (s), 1600 (m), 1516 (s), 1462 (m), 1296
(m), 1261 (s), 1138 (s), 1024 (m) cmK1; MS (EI, 70 eV):
m/z (%): 455.9 (MC, 100), 397.0 (36), 319.9 (57), 260.9
(42), 148.2 (14); elemental analysis: calcd (%) for C24H24O9
(456.44): C 63.15, H 5.30; found: C 62.86, H 5.48.
MS (EI, 70 eV): m/z (%): 338.1 (MC, 38), 306.1 (100),
250.1 (40), 194.0 (36), 144.8 (41), 89.0 (40); elemental
analysis: calcd (%) for C19H14O6 (338.31): C 67.45, H 4.17;
found: C 67.36, H 4.88.
2.7.9. Synthesis of pinastric acid (12). To a CH2Cl2
(13 ml) solution of 10 (230 mg, 0.62 mmol) was added BBr3
(0.06 ml, 0.62 mmol) at 0 8C, and the mixture was stirred for
6 h at 0 8C. An aqueous solution of HCl (5%) was added.
The aqueous layer was separated and extracted with CH2Cl2
(3!). The combined organic layers were dried (Na2SO4),
filtered and the solvent of the filtrate was removed in vacuo.
The residue was purified by column chromatography (silica
gel) to give pinastric acid (12) as an orange solid (130 mg,
60%), mp 203 8C. The spectroscopic data are identical with
those reported.2d 1H NMR (300 MHz, CDCl3): dZ3.84 (s,
3H, OCH3), 3.87 (s, 3H, OCH3), 6.96 (d, 2H, JZ9.0 Hz,
ArH), 7.24–7.42 (m, 5H, ArH), 8.12 (d, 2H, JZ9.0 Hz,
ArH); 13C NMR (75 MHz, CDCl3): dZ54.32, 55.25 (CH3),
105.25 (C), 113.90 (2C, CH), 115.17, 121.62 (C), 128.07
(2C), 128.47, 129.34 (2C), 129.93 (2C, CH), 132.06,
154.99, 158.56, 159.52, 166.08, 171.66 (C); IR (KBr): n~Z
2960 (w), 2554 (w), 1771 (s), 1674 (s), 1601 (s), 1515 (s),
1457 (m), 1442 (m), 1308 (s), 1279 (s), 1255 (s), 1189 (m),
1064 (m), 960 (m), 843 (m) cmK1; MS (EI, 70 eV): m/z (%):
352.0 (MC, 37), 319.9 (100), 264.0 (41), 208.0 (54), 146.5
(8); elemental analysis: calcd (%) for C20H16O6 (352.34): C
68.18, H 4.58; found: C 68.51, H 4.60.
2.7.7. Permethyl-iso-gomphidic acid (18). The reaction
was carried out following the general procedure for
Suzuki reactions. Starting with 7d (300 mg, 0.60 mmol),
(4-methoxyphenyl)boronic acid (120 mg, 0.78 mmol), pot-
assium phosphate (206 mg, 0.96 mmol), tetrakis(triphenyl-
phosphine) palladium (22 mg, 0.018 mmol) and dioxane
(3.0 ml), 18 was isolated as a yellow solid (200 mg, 73%),
mp 204–205 8C. The spectroscopic data are identical with
those reported.3 1H NMR (300 MHz, CDCl3): dZ3.37 (s,
3H, OCH3), 3.78 (s, 3H, OCH3), 3.84 (s, 3H, OCH3), 3.88 (s,
9H, OCH3), 6.90 (s, 2H, ArH), 6.96 (d, 2H, JZ9.0 Hz,
ArH), 7.56 (d, 2H, JZ9.0 Hz, ArH); 13C NMR (150 MHz,
CDCl3): dZ52.99, 56.44 (3C), 61.09, 61.17 (CH3), 106.84
(2C, CH), 108.86, 114.05 (C), 114.22 (2C, CH), 115.94,
126.48, 128.22 (C), 131.25 (2C, CH), 139.56, 141.52,
144.51, 153.40, 162.09, 167.25, 167.91 (C); IR (KBr): n~Z
2950 (w), 1773 (s), 1728 (s), 1632 (m), 1602 (m), 1578 (m),
1509 (s), 1455 (m), 1420 (m), 1342 (m), 1302 (m), 1256 (s),
1150 (m), 1127 (s), 953 (m), 644 (m) cmK1; MS (EI,
70 eV): m/z (%): 456.1 (MC, 100), 397.1 (34), 270.1 (99),
123.1 (61), 93.0 (51), 65.8 (15); elemental analysis: calcd
(%) for C24H24O9 (456.40): C 63.15, H 5.30; found: C
62.95, H 5.33.
2.7.10. Synthesis of xerocomic acid and variegatic acid.
A solution of the corresponding permethylated pulvinic acid
and trimethylsilyl iodide (10 equiv) in CDCl3 (4 ml per
1 mmol of permethylated acid) sealed under argon in a
NMR tube, was kept at 55 8C for ca. 72 h. The reaction was
monitored by 1H NMR. The solvent was removed in vacuo
and the residue was dissolved in methanol. The solution was
kept at 25 8C for 30 min and then the methanol was removed
in vacuo. The residue was purified by chromatography
(silica gel, benzene/ethyl acetate/formic acidZ13:5:4).
2.7.11. Xerocomic acid (15c). Starting with permethylated
xerocomic acid (100 mg, 0.23 mmol), trimethylsilyl iodide
(0.33 ml, 2.34 mmol) and CDCl3 (0.9 ml), 15c was isolated
as an orange solid (60 mg, 72%), mp 296 8C (lit.4 295–
1
297 8C); H NMR (300 MHz, (CD3)2CO): dZ6.89 (d, 3H,
2.7.8. Synthesis of butenolide (11). To a CH2Cl2 solution
(3.0 ml) of 10 (55 mg, 0.15 mmol) was added BBr3
(0.11 ml, 1.2 mmol) at 0 8C and the mixture was stirred
for 2 h at 0 8C. An aqueous solution of HCl (5%) was added.
The aqueous layer was separated and extracted with CH2Cl2
(3!50 ml). The combined organic layers were dried
JZ8.5 Hz, ArH), 7.27 (d, 2H, JZ8.5 Hz, ArH), 7.59 (dd,
1H, JZ2.1, 8.5 Hz, ArH), 7.73 (d, 1H, JZ2.1 Hz, ArH); 13C
NMR (150 MHz, (CD3)2CO): dZ104.50 (C), 115.49 (2C),
116.10 (CH), 117.01 (C), 121.08 (CH), 122.64, 123.47 (C),
130.22, 132.63 (2C, CH), 145.64, 146.31, 155.30, 158.37,
160.44, 167.14, 174.28 (C); IR (KBr): n~Z3263 (s), 2956

Z. Ahmed, P. Langer / Tetrahedron 61 (2005) 2055–2063
2063
2. (a) Volhard, J.; Henke, F. Liebigs Ann. Chem. 1894, 282, 45.
(b) Knight, D. W.; Pattenden, G. J. Chem. Soc., Chem.
Commun. 1976, 660. (c) Knight, D. W.; Pattenden, G. J. Chem.
Soc. Perkin Trans. 1 1979, 84. (d) Pattenden, G.; Pegg, N. A.;
Kenyon, R. W. J. Chem. Soc. Perkin Trans. 1 1991, 2363.
(e) Weinstock, J.; Blank, J. E.; Oh, H.-J.; Sutton, B. M. J. Org.
Chem. 1979, 44, 673. (f) Wikholm, R. J.; Moore, H. W. J. Am.
Chem. Soc. 1972, 94, 6152.
(w), 2501 (w), 1739 (s), 1680 (m), 1600 (s), 1513 (m), 1370
(m), 1257 (s) cmK1; IR (Nujol): 3174 (s), 2673 (w), 1736
(s), 1600 (s), 1460 (s), 1376 (s) cmK1; UV–Vis (EtOH):
lmax (log 3)Z258 (4.14), 405 (4.02); MS (EI, 70 eV): m/z
(%): 356.0 (MC, 2), 337.9 (6), 277.0 (3), 180.9 (4), 44.0
(90), 28.1 (100); elemental analysis: calcd (%) for C18H12O8
(356.28): C 60.68, H 3.39; found: C 61.28, H 3.52.
2.7.12. Variegatic acid (17). Starting with permethylated
variegatic acid (184 mg, 0.40 mmol), trimethylsilyl iodide
(0.58 ml, 4.03 mmol) and CDCl3 (1.6 ml), 17 was isolated
3. Gedge, D. R.; Pattenden, G.; Smith, A. G. J. Chem. Soc. Perkin
Trans. 1 1986, 2127.
4. Ramage, R.; Griffiths, G. J.; Sweeney, J. N. A. J. Chem. Soc.
Perkin Trans. 1 1984, 1547.
1
as an orange yellow solid (102 mg, 68%), mp 235 8C; H
NMR (300 MHz, (CD3)2CO): dZ6.76 (dd, 1H, JZ2.1,
8.1 Hz, ArH), 6.86 (d, 1H, JZ8.1 Hz, ArH), 6.88 (d, 1H,
JZ8.5 Hz, ArH), 6.91 (d, 1H, JZ2.1 Hz, ArH), 7.59 (dd,
1H, JZ2.1, 8.5 Hz, ArH), 7.73 (d, 1H, JZ2.1 Hz, ArH); 13C
NMR (150 MHz, (CD3)2CO): dZ104.20 (C), 115.49 (2C),
116.09 (CH), 117.30 (C), 118.56, 121.01 (CH), 122.78 (C),
123.26 (CH), 126.09, 145.20, 145.63, 146.23 (2C), 155.12,
160.82, 167.30, 174.25 (C); IR (KBr): n~Z3390 (s), 2968
(m), 1741 (s), 1606 (s), 1583 (m), 1520 (m), 1364 (m), 1275
(s), 1114 (w) cmK1; UV–Vis (EtOH): lmax (log 3)Z275
(4.16), 408 (3.94); MS (EI, 70 eV): m/z (%): 372.1 (MC, 3),
354.0 (94), 328.0 (56), 298.0 (46), 242.0 (41), 148.2 (100),
44.1 (97); elemental analysis: calcd (%) for C18H12O9
(372.29): C 58.07, H 3.24; found: C 58.64, H 3.34.
5. (a) Krohn, K.; Ostermeyer, H.-H.; Tolkiehn, K. Chem. Ber.
1979, 112, 2640. (b) Chan, T.-H.; Brownbridge, P. J. Am.
Chem. Soc. 1980, 102, 3534. (c) Simoneau, B.; Brassard, P.
Tetrahedron 1986, 14, 3767. (d) Molander, G. A.; Cameron,
K. O. J. Am. Chem. Soc. 1993, 115, 830.
6. For a review of 1,3-bis-silyl enol ethers, see: Langer, P.
Synthesis 2002, 441.
7. (a) Langer, P.; Stoll, M. Angew. Chem. 1999, 111, 1919.
Angew. Chem., Int. Ed. 1999, 38, 1803. (b) Langer, P.;
Schneider, T.; Stoll, M. Chem. Eur. J. 2000, 6, 3204.
¨
8. Langer, P.; Eckardt, T.; Schneider, T.; Gobel, C.; Herbst-
Irmer, R. J. Org. Chem. 2001, 66, 2222.
9. Ahmed, Z.; Langer, P. J. Org. Chem. 2004, 69, 3753.
10. Desage-El Murr, M.; Nowaczyk, S.; Le Gall, T.; Mioskowski,
C.; Amekraz, B.; Moulin, C. Angew. Chem. 2003, 115, 1327.
Angew. Chem., Int. Ed. 2003, 42, 1289.
Acknowledgements
11. For cross coupling reactions of related butenolides, see:
(a) Siegel, K.; Bru¨ckner, R. Chem. Eur. J. 1998, 4, 1116.
(b) Goerth, F.; Umland, A.; Bru¨ckner, R.; Eur J. Org. Chem.
1998, 1055.
Financial support from the Deutsche Forschungsge-
meinschaft and from the state of Mecklenburg-Vorpom-
mern (scholarship for Z. A.) is gratefully acknowledged.
12. (a) Agarwal, S.; Seshadri, T. Ind. J. Chem. 1964, 2, 17.
(b) Singh, P.; Anchel, M. Phytochemistry 1971, 10, 3259.
13. Edwards, R. L.; Gill, M. J. Chem. Soc., Perkin Trans. 1 1973,
1529.
References and notes
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