Intramolecular Heck reactions for the synthesis of the novel antibiotic mensacarcin: Investigation of catalytic, electronic and conjugative effects in the preparation of the hexahydroanthracene core

Article abstract of DOI:10.1002/ejoc.200400786

The intramolecular Heck reaction of the three complex diphenyl substrates rac-2, 5 and rac-6, containing substituents with different electronic and conjugative properties, were examined. The Pd compounds [Pd₂(dba) ₃]/[(tBu)₃

Full text of DOI:10.1002/ejoc.200400786

FULL PAPER
Intramolecular Heck Reactions for the Synthesis of the Novel Antibiotic
Mensacarcin: Investigation of Catalytic, Electronic and Conjugative Effects in
the Preparation of the Hexahydroanthracene Core
Lutz F. Tietze,*[a] Scott G. Stewart,[a] and Marta E. Polomska[a]
Keywords: Anthracenes / Antibiotics / Aromatic substitution / Heck reaction / Palladium
The intramolecular Heck reaction of the three complex di-
phenyl substrates rac-2, 5 and rac-6, containing substituents
with different electronic and conjugative properties, were ex-
amined. The Pd compounds [Pd2(dba)3]/[(tBu)3PH]BF4,
[Pd2(OAc)2{P(o-Tol)3}2] (4), [PdCl2(PPh3)2] and Pd(OAc)2
were used as catalysts.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
Introduction
of 1 we employed a Pd0-catalysed transformation of rac-2
as the key step with the Herrmann–Beller catalyst 4. Unfor-
tunately, this reaction led to the tricycle rac-3 in only 24%
yield (Scheme 1).
Mensacarcin (1) is a novel polyfunctionalised hexahy-
droanthracene isolated from a strain of Streptomyces (Gö
C4/4) which shows cytostatic and cytotoxic activity com-
parable to doxorubicin, another anticancer agent currently
The Heck reaction has been utilized in the synthesis of
used in the treatment of malignant lymphomas and leuke- a wide variety of natural products and analogues.[2] This
mias.[1] In our investigations towards the synthesis of this coupling reaction, first observed in 1968, has recently ad-
novel anticancer agent we wanted to use an intramolecular vanced with the discovery of novel catalysts and catalytic
Heck transformation of an appropriately substituted di- systems.[3] Exploring the potential of these systems is an
phenylcarbinol. Thus, for the synthesis of the core structure important aspect in the refining of synthetic organic pro-
Scheme 1. Mensacarcin (1), synthesis of tetrahydroanthracene rac-3 and structures of substrates rac-2, 5 and rac-6: (a) nBu4NOAc, DMF/
CH3CN/H2O, 60 °C then HB cat 4, 120 °C, 4 h, 24%.
cesses. Previous studies of both inter- and intramolecular
Heck reactions have revealed that matching the appropriate
catalytic conditions with the electronic properties of the
aryl or vinyl halide substrate is essential. Initial develop-
ment of new catalysts and catalytic methodology by the
[a] Institut für Organische und Biomolekulare Chemie, Georg-Au-
gust Universität,
Tammannstraße 2, 37077 Göttingen
E-mail: ltietze@gwdg.de
Fax: +49-551-399-476
1752
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/ejoc.200400786
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Intramolecular Heck Reactions for the Synthesis of the Novel Antibiotic Mensacarcin
FULL PAPER
groups of Milstein (bulky, electron-rich chelating bisphos- propanediol in order to protect the aldehyde moiety. The
phanes),[4] Herrmann and Beller (palladacycles),[5] Reetz resulting acetal 8 was subsequently benzylated at the pheno-
(tetraphenylphosphonium salts)[6] and Beller (phosphites)[7] lic position to give 9, and the remaining hydroxyl group
has provided a variety of conditions for carrying out high oxidised to furnish compound 10 in 65% yield over two
yielding Heck transformations. Generally, from these stud- steps. For the attachment of the left fragment aryl ring, the
ies, electron-poor aryl halides were considered essential for iodobenzene 11 was treated with nBuLi to generate the cor-
the oxidative addition to the Pd0 species. More recently, Fu responding aryllithium species, followed by addition of the
et al. have developed systems {[Pd2(dba)3], [(tBu)3PH]BF4 aldehyde 10 to give the diphenylcarbinol rac-12 in a moder-
and Cy2NMe} that catalyse Heck couplings using less-reac- ate yield of 39%. Additional treatment of this latter com-
tive electron-rich aryl chlorides and bromides as sub- pound with KH and MeI afforded the methyl ether rac-13
strates.[8] Furthermore, the group of Lautens has reported in 91% yield. The desired substrate for the Heck reaction
on intramolecular Heck reactions involving dihydronaph- rac-6 was obtained in 71% yield by deprotection of the ace-
thalene substrates with a variety of electronically diverse tal moiety in rac-13 using PPTS in acetone/water.
aryl bromides.[9]
With the three substrates rac-2, 5 and rac-6 in hand, a
Here we describe our investigations on the importance
of matching certain catalytic parameters with the electronic
nature of the aryl bromide being employed as starting mate-
rial. With the intention of optimising a synthesis of tetra-
hydroanthracene compounds[10] we prepared three sub-
strates − rac-2, 5 and rac-6. Importantly, each of these com-
pounds contains a contrasting substitution pattern which
was tested in a Pd0-catalysed transformation using four dif-
ferent types of catalysts.
variety of palladium catalysts and reaction conditions were
investigated to provide their corresponding anthracene-type
compounds. Substrate rac-2, which contains a highly elec-
tron-rich aryl bromide moiety, was initially tested with the
two first-generation catalysts Pd(OAc)2 and [PdCl2-
(PPh3)2].[11] After 5 h at 90 °C both reactions afforded the
product tetrahydroanthracene (rac-3), although only in
poor yields (11% and 6%, respectively; entries 1 and 2,
Table 1). Interestingly, large amounts of starting material
remained, which prompted the screening of second-genera-
tion catalysts that can withstand higher temperatures and/
or give better TONs. Thus, we next performed Heck reac-
tions using the palladacycle developed by Herrmann and
Results and Discussion
The substrates rac-2 and 5 were synthesised using the Beller. However, even a catalyst loading of 20 mol-%
procedures reported previously,[1] whereas rac-6 was pre- [Pd2(OAc)2{P(o-Tol)3}2] (4) furnished only a low yield
pared as shown in Scheme 2 from 7, which was treated with (27%) of rac-3 after 5 h at 120 °C, with 42% of starting
acetic acid to remove the acetonide group and then with material remaining (entry 3, Table 1). Longer reaction times
Scheme 2. Synthesis of diphenylcarbinol rac-6: (a) i) AcOH, 60 °C, 4 h, 66%; ii) 1,3-propanediol, Amberlyst 15 H+, C6H6, reflux, 5 h,
98%; (b) BnBr, K2CO3, CHCl3/MeOH, 40 °C, 12 h, 80%; (c) Dess–Martin periodinane, CH2Cl2, 1 h, 81%; (d) iodobenzene 11, nBuLi,
THF, –78 °C, 20 min then 10, THF, –78 °C, 20 min, 20 °C, 39%; (e) KH, THF, 0 °C, 40 min then MeI, 20 °C, 1 h, 91%; (f) PPTS, H2O/
acetone, reflux, 12 h, 71%.
Eur. J. Org. Chem. 2005, 1752–1759
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L. F. Tietze, S. G. Stewart, M. E. Polomska
FULL PAPER
Table 1. Intramolecular Heck reaction with rac-2.
Entry
Catalyst/phosphane
Base
Solvent
Reaction time
[h]
Temp.
[°C]
Yield of rac-3
(recovered substrate) [%]
1
2[a]
3
10 mol-% [PdCl2(PPh3)2]
10 mol-% Pd(OAc)2
20 mol-% HB cat[b]
20 mol-% HB cat[b]
NaOAc
nBu4NOAc K2CO3
nBu4NOAc
MeCN
DMF
5
5
90
90
6 (58)
11 (40)
27 (42)
33 (18)
94 (5)
DMF/MeCN/H2O
DMF/MeCN/H2O
dioxane
5
120
120
120
4
nBu4NOAc
20
5
5
3 mol-% [Pd2(dba)3]/
Cy2NMe
6 mol-% P(tBu)3
6
7
3 mol-% [Pd2(dba)3]/
6 mol-% HP(tBu)3BF4
Cy2NMe
Cy2NMe
dioxane
dioxane
5
120
120
92 (5)
78 (2)
3 mol-% [Pd2(dba)3]/
6 mol-% HP(tBu)3BF4
20
[a] The Jeffery system requires K2CO3 and no phosphane.[13] [b] Herrmann–Beller catalyst trans-{di(μ-acetato)bis[ortho-(di-ortho-tolyl-
phosphanyl)benzyl]dipalladium(ii)} (4).
(entry 4, Table 1) led to decomposition of both the starting to complete the reaction a high catalyst loading (40 mol-%
material and the product. On switching to the more elec- Pd) was still necessary. A further improvement of the yield
tron-rich palladium complex [Pd2(dba)3]/P(tBu)3 we discov- to 73% was obtained when the reaction was carried out at
ered that this system is very effective for the similarly elec- 120 °C (entry 5, Table 2). As previously, longer reaction
tron-rich substrate rac-2, especially in the presence of the times resulted in decomposition of both product and start-
bulky tertiary amine Cy2NMe.[12] Using a moderate catalyst ing material. Using Pd2(dba)3 in the presence of the electron
loading (3 mol-% Pd) and 6 mol-% of phosphane [1:1 ratio rich phosphane ligand tBu3P resulted in a still slightly
of Pd to P(tBu)3], with Cy2NMe as the base, led to the higher yield (78%) of 14 than when using catalyst 4, but
desired product rac-3 in an excellent 94% yield (entry 5, more importantly this yield was slightly lower when com-
Table 1). The more stable and practical trialkylphosphon- pared with compound rac-2 (entry 7, Table 2). This result
ium salt [(tBu)3PH]BF4 gave a similar yield of 92%. The suggested that the oxidative addition in 5 occurs less rapidly
optimised temperature for this reaction was 110–120 °C with an electron rich palladium complex. Extended reaction
and, as in the papers of Fu et al., dioxane was the solvent times at these temperatures again resulted in a decomposi-
of choice. Longer reaction times once again resulted in de- tion of substrate and product and at ambient temperature
composition of the tricyclic product (entry 7, Table 1), while no reaction occurred (entry 8, Table 2).
at ambient temperature the catalytic system is completely
unreactive.
The final substrate, rac-6, which contains a para-aldehyde
moiety, was considered to contain the least electron-rich
The second olefin examined, compound 5, contains a aryl ring of the three substrates. The introduction of the
carbonyl group ortho to the bromine atom, which lowers aldehyde moiety led to an increased reactivity for Pd(OAc)2
the electron-rich nature of the aromatic ring and flattens the and the Herrmann–Beller catalyst (entries 1–4, Table 3).
molecule through conjugation. We found that the carbonyl The best result (entry 3, Table 3) was obtained with the HB
functionality causes a noticeable alteration of the yield in catalyst 4 at 120 °C for 5 h, and afforded the desired tricy-
the Heck reaction. The yield of the transformation when clic product rac-15 in 82% yield. The Heck reaction of sub-
using Pd(OAc)2 and K2CO3 as a base at 90 °C increased to strate rac-6 in the presence of the electron-rich tBu3P ligand
22%, although prolongation of the reaction time resulted also led to rac-15 in a reasonable but slightly lower yield
in decomposition of both starting material and product (en- than with the substrates rac-2 and 5. These new sets of re-
tries 2 and 3, Table 2). Reaction with the Herrmann–Beller sults substantiate the theory that the electronic properties
palladacycle 4 at 90 °C over 5 h gave a 59% yield of the of the substrate must be compatible with the catalyst, al-
anthracenone 14 (entry 4, Table 2), which is more than though the electron-rich system Pd0/tBu3P still works quite
double that obtained for the cyclisation of rac-2. However, well with electron-poor substrates.
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Intramolecular Heck Reactions for the Synthesis of the Novel Antibiotic Mensacarcin
FULL PAPER
Table 2. Intramolecular Heck reaction with 5.
Entry
Catalyst/phosphane
Base
Solvent
Reaction time
[h]
Temp.
[°C]
Yield of 14
(recovered substrate) [%]
1
2[a]
3[a]
4
10 mol-% [PdCl2(PPh3)2]
10 mol-% Pd(OAc)2
10 mol-% Pd(OAc)2
20 mol-% HB cat[b]
20 mol-% HB cat[b]
20 mol-% HB cat[b]
NaOAc
nBu4NOAc/K2CO3
nBu4NOAc/K2CO3
nBu4NOAc
MeCN
DMF
5
5
90
90
7 (70)
22 (61)
0 (25)
59 (20)
73 (6)
31 (6)
78 (5)
DMF
20
5
90
DMF/MeCN/H2O
DMF/MeCN/H2O
DMF/MeCN/H2O
dioxane
90
5
nBu4NOAc
5
120
120
120
6
nBu4NOAc
20
5
7
3 mol-% [Pd2(dba)3]/
Cy2NMe
6 mol-% HP(tBu)3BF4
8
3 mol-% [Pd2(dba)3]/
6 mol-% HP(tBu)3BF4
Cy2NMe
dioxane
5
20
0 (93)
[a] The Jeffery system requires K2CO3 and no phosphane. [b] Herrmann–Beller catalyst trans-{di(μ-acetato)bis[ortho-(di-ortho-tolylphos-
phanyl)benzyl}dipalladium(ii)] (4).
Table 3. Intramolecular Heck reaction with rac-6.
Entry
Catalyst/phosphane
Base
Solvent
Reaction time
[h]
Temp.
[°C]
Yield of rac-15
(recovered substrate) [%]
1
2[a]
3
10 mol-% [PdCl2(PPh3)2]
10 mol-% Pd(OAc)2
20 mol-% HB cat[b]
20 mol-% HB cat[b]
NaOAc
nBu4NOAc K2CO3
nBu4NOAc
MeCN
DMF
5
5
90
90
12 (48)
34 (52)
82 (3)
DMF/MeCN/H2O
DMF/MeCN/H2O
dioxane
5
120
120
120
4
nBu4NOAc
20
5
64 (__)
5
3 mol-% [Pd2(dba)3]/
Cy2NMe
77 (18)
6 mol-% HP(tBu)3BF4
6
3 mol-% [Pd2(dba)3]/
6 mol-% HP(tBu)3BF4
Cy2NMe
dioxane
20
120
67 (4)
[a] The Jeffery system requires K2CO3 and no phosphane. [b] Herrmann–Beller catalyst trans-{di(μ-acetato)-bis[ortho-(di-ortho-tolylphos-
phanyl)benzyl]dipalladium(ii)} (4).
Conclusions
and 33% yield, respectively. Introducing a carbonyl moiety
into the substrate, as in olefin 5, increased the conversion
In summary, we have developed efficient pathways to di- to the anthracene-type compound when using the so-called
hydroanthracenes through an intramolecular Heck ap- first-generation catalysts, and 73% with the Herrmann–
proach. When carrying out the transformation with rac-2 Beller catalyst 4. Employing the catalyst [Pd2(dba)3]/P(tBu)3/
the combination [Pd2(dba)3]/P(tBu)3/Cy2NMe has been Cy2NMe in the reactions of substrates 5 and rac-6 resulted
shown to be most effective by providing the desired product in a decrease of overall yield when compared to the reaction
rac-3 in an excellent yield of 94%. In contrast, Pd(OAc)2 of the more electron-rich rac-2. Hence, this work demon-
and the Herrmann–Beller catalyst led to rac-13 in only 11% strates how a modification of a substrate by changing the
Eur. J. Org. Chem. 2005, 1752–1759
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L. F. Tietze, S. G. Stewart, M. E. Polomska
FULL PAPER
(2-Benzyloxy-6-bromo-3-(1,3-dioxan-2-yl)-5-methoxy-4-methylphen-
yl)methanol (9): A magnetically stirred solution of acetal 8 (1.10 g,
3.30 mmol) and K2CO3 (1.83 g, 13.20 mmol) in CHCl3/MeOH
(30:15 mL) was heated to 40 °C for 10 min. The resulting mixture
was then treated with benzyl bromide (470 μL, 3.96 mmol) and stir-
ring continued at this temperature for a further 12 h. After cooling
to 20 °C, the mixture was diluted with CH2Cl2 (60 mL), washed
with H2O (2×10 mL), dried (MgSO4), filtered and concentrated
under reduced pressure. The resulting white solid was recrystallised
(EtOAc/hexane) to afford alcohol 9 (1.12 g, 2.64 mmol, 80%) as a
white solid; m.p. 148 °C (recrystallised from hexane/EtOAc); Rf =
electronic nature of the substituents influences the Heck re-
action. Furthermore, we observed that there is a pattern
evolving between matching the electronic nature of the cata-
lytic system and substrate.
Experimental Section
General: All reactions were performed in flame-dried glassware un-
der an argon atmosphere. Solvents were dried and purified accord-
ing to the method defined by Perin and Armarego.[14] TLC
chromatography was performed on precoated aluminium silica gel
SIL G/UV254 plates (Macherey, Nagel Co.), and silica gel 32–63
(0.032–0.064 mm; Macherey, Nagel Co.) was used for column
chromatography. Melting points: Mettler FP61. IR: Bruker IFS25.
UV/Vis: Perkin–Elmer Lambda 9. NMR: Varian VXR-200
(200 MHz, 1H), Bruker AM-300 (300 MHz, 75 MHz, for 1H and
0.4 (9:1 pentane/EtOAc). UV/Vis (CH3CN): λmax (lg ε) = 205.0 nm
1
(4.7277), 286.8 (3.3296). IR (KBr): ν = 3489 cm–1, 2852, 1448. H
˜
NMR (200 MHz, CDCl3): δ = 1.20–1.24 (m, 1 H, 5-H), 2.16–2.27
(m, 1 H, 5-H), 2.25 (s, 3 H, CH3), 3.85 (s, 3 H, OCH3), 3.89–4.17
(m, 4 H, 4-H/6-H), 4.81 (s, 2 H, CH2OH), 4.97 (s, 2 H, CH2OPh),
5.93 (s, 1 H, 2-H), 7.41–7.55 (m, 5 H, Ph) ppm. 13C NMR
(50.3 MHz, CDCl3): δ = 13.7, 25.8, 60.2, 60.5, 67.8, 79.1, 98.8,
121.3, 127.7, 128.0, 128.4, 128.5, 128.7, 130.6, 132.6, 134.4, 136.6,
152.4, 153.0 ppm. MS (EI, 70 eV): m/z (%) = 424.1 (24), 422.1 (25)
[M]+, 394.1 (5), 392.1 (7) [M – CH2O]+, 318.1 (57), 316.1 (40) [M –
HOCH2Ph]+. C20H23BrO5 (423.30). HRMS: calcd. 422.0729; found
422.0729.
1
13C, respectively). For H and 13C, CDCl3 and C6D6 were used as
solvents. Chemical shift are reported on a δ scale. MS: Varian MAT
731. HRMS was performed using a modified peak matching tech-
nique, error 2 ppm, with a resolution of about 10 000. Elemental
analysis: Mikroanalytisches Labor des Institutes für Organische
und Biomolekulare Chemie der Universität Göttingen.
2-Benzyloxy-6-bromo-3-(1,3-dioxan-2-yl)-5-methoxy-4-methylbenz-
aldehyde (10): A magnetically stirred solution of alcohol 9 (625 mg,
1.48 mmol) in CH2Cl2 (60 mL) at 20 °C was treated with Dess–
Martin periodinane (941 mg, 2.22 mmol). The resulting mixture
was stirred for 1.5 h before being treated with NaHCO3 (1×25 mL
of a saturated solution) and Na2S2O3 (1×25 mL of a 1 m solution).
Stirring was continued until the cloudy solution became clear (ca.
1 h). The resulting mixture was transferred to a separating funnel
and extracted with CH2Cl2 (3× 30 mL). The combined organic
fractions were subjected to flash chromatography (9:1 pentane/
EtOAc) and concentration of the appropriate fractions afforded
benzaldehyde 10 (505 mg, 1.20 mmol, 81%) as a white solid; m.p.
123 °C (recrystallised from hexane/EtOAc); Rf = 0.7. UV/Vis
(CH3CN): λmax (lg ε) = 209.0 nm (4.4501), 264.0 (3.8917). IR
3-Bromo-6-(1,3-dioxan-2-yl)-2-hydroxymethyl-4-methoxy-5-methyl-
phenol (8). 4-Bromo-2-hydroxy-3-hydroxymethyl-5-methoxy-6-meth-
ylbenzaldehyde: A magnetically stirred solution of aldehyde 7
(1.4 g, 4.44 mmol) in acetic acid (60 mL of 40 % solution) was
heated to 60 °C for 4 h. The resulting mixture was cooled to 20 °C,
diluted with Et2O (200 mL), washed with NaHCO3 (5×30 mL sat-
urated solution), dried (MgSO4), filtered and concentrated under
reduced pressure to afford a yellow solid. Subjection of this mate-
rial to flash chromatography (9:1 pentane/EtOAc) and concentra-
tion of the appropriate fractions afforded the desired product
(803 mg, 2.92 mmol, 66 %) as a colourless solid; m.p. 131 °C
(recrystallised from hexane/EtOAc); Rf = 0.4. UV/Vis (CH3CN):
λmax (lg ε) = 194.5 nm (4.2829), 277.0 (4.1471), 355.5 (3.6208). IR
(KBr): ν = 1646 cm–1, 1404. 1H NMR (200 MHz, CDCl ): δ = 1.22
˜
3
(KBr): ν = 2947 cm–1, 2846, 1703, 1573. 1H NMR (200 MHz,
˜
(s, 1 H, OH), 2.59 (s, 3 H, CH3), 3.77 (s, 3 H, OCH3), 4.95 (s, 2 H,
CH2OH), 10.34 (s, 1 H, CHO) ppm. 13C NMR (50.3 MHz,
CDCl3): δ = 11.2, 59.9, 60.4, 117.6, 128.1, 119.6, 130.9, 134.5,
158.2, 195.2 ppm. MS (EI, 70 eV): m/z (%) = 276.1 (60), 274.1 (58)
[M]+, 258.0 (100), 256.0 (98) [M – H2O]+. C10H11BrO4 (275.11).
HRMS: calcd. 273.9841; found 273.9841. 3-Bromo-6-(1,3-dioxan-2-
yl)-2-hydroxymethyl-4-methoxy-5-methylphenol (8): A magnetically
stirred solution of the benzaldehyde described above (800 mg,
2.90 mmol) and 1,3-propanediol (634 μL, 8.76 mmol) in benzene
(80 mL) was treated in one portion with Amberlyst 15™ (cat.) at
20 °C. The resulting mixture was heated to reflux for 5 h in a Dean–
Stark apparatus. After cooling, the mixture was dried (MgSO4),
filtered and concentrated under reduced pressure. The resulting
white solid was recrystallised (EtOAc/hexane) to afford acetal 8
(955 mg, 2.86 mmol, 98 %) as a colourless solid; m.p. 128 °C
(recrystallised from hexane/EtOAc); Rf = 0.2 (9:1 pentane/EtOAc).
CDCl3): δ = 1.18–1.34 (m, 1 H, 5-H), 2.16–2.27 (m, 1 H, 5-H), 2.57
(s, 3 H, CH3), 3.73 (s, 3 H, OCH3), 3.66–3.78 (m, 4 H, 4-H/6-H),
4.85 (s, 2 H, CH2OPh), 5.93 (s, 1 H, 2-H), 7.31–7.45 (m, 5 H, Ph),
10.24 (s, 1 H, CHO) ppm. 13C NMR (50.3 MHz, CDCl3): δ = 14.4,
25.7, 60.3, 60.9, 67.8, 79.8, 98.0, 109.3, 121.1, 126.8, 129.0, 130.2,
131.7, 132.5, 136.1, 140.9, 146.2, 153.4, 154.8, 190.3 ppm. MS (EI,
70 eV): m/z (%) = 422.0 (15), 420.0 (13) [M]+, 394.1 (10), 392.1 (9)
[M – CH2 O]+ , 316.1 (65), 314.1 (58) [M – HOCH2Ph]+.
C20H21BrO5 (421.28). HRMS: calcd. 420.0572; found 420.0572.
{2-Benzyloxy-6-bromo-3-(1,3-dioxan-2-yl)-5-methoxy-4-
methylphenyl}-(2-methoxy-6-vinylphenyl)methanol (12): A magneti-
cally stirred solution of iodobenzene 11 (251 mg, 0.97 mmol) in
THF (10 mL) at –78 °C was treated dropwise with nBuLi (425 μL,
1.06 mmol, 2.5 m solution in hexane, 1.01 mmol). The resulting
mixture was stirred at this temperature for 20 min before being
UV/Vis (CH3CN): λmax (lg ε) = 204.5 nm (4.5580), 286.0 (3.1993). treated with aldehyde 10 (277 mg, 0.88 mmol) in THF (5 mL). Stir-
IR (KBr): ν = 3528 cm–1, 2873, 1449. 1H NMR (200 MHz, CDCl ): ring was continued at this temperature for 20 min, the solution
˜
3
δ = 1.18–1.48 (m, 1 H, 5-H), 2.16–2.27 (m, 1 H, 5-H), 2.84 (br. s, warmed to 20 °C and quenched immediately with NH4Cl (4 mL of
1 H, OH), 2.22 (s, 3 H, CH3), 3.90 (s, 3 H, OCH3), 3.84–3.97 (m, a saturated aqueous solution). The resulting mixture was extracted
4 H, 4-H/6-H), 4.19–4.27 (m, 1 H, 2-H), 4.81 (s, 2 H, CH2); 5.93 (s, with diethyl ether (3×10 mL), washed with brine (1×2 mL) and
1 H, 2-H), 9.01 (s, 1 H, OH) ppm. 13C NMR (50.3 MHz, CDCl3): δ the combined organic fractions dried (MgSO4), filtered and con-
= 13.7, 25.7, 60.4, 66.0, 67.7, 98.8, 122.5, 127.6, 128.2, 128.6, 134.7,
136.9, 152.9 ppm. MS (EI, 70 eV): m/z (%) = 333.1 (5) [M]+, 316.1
(20) [M – OH]+, 91.1 (100). C13H17BrO5 (333.18). HRMS: calcd.
333.1751; found 333.1751.
centrated under reduced pressure to afford a clear yellow oil. Sub-
jection of the resulting crude oil to flash chromatography (9:1 pen-
tane/EtOAc) and concentration of the appropriate fractions af-
forded diphenylcarbinol 12 (190 mg, 0.34 mmol, 39%) as a colour-
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Intramolecular Heck Reactions for the Synthesis of the Novel Antibiotic Mensacarcin
FULL PAPER
less solid; R = 0.4. IR (KBr): ν = 3560 cm–1, 2838, 1572. UV
3.87 (s, 3 H, OCH3), 4.03 (d, J = 11.2 Hz, 1 H, CH2Ph), 4.55 (d, J
˜
f
(CH3CN): λmax (lg ε) = 203.5 nm (4.6397), 292.0 (3.5932). 1H NMR = 11.2 Hz, 1 H, CH2Ph), 5.16 (dd, J = 12.4, 1.6 Hz, 1 H, 2ЈЈ-H),
(300 MHz, CDCl3): δ = 1.20–1.24 (m, 1 H, 5Ј-H), 1.29–1.37 (m, 1
H, 5Ј-H), 2.60 (s, 3 H, CH3), 3.52 (s, 3 H, OCH3), 3.74 (s, 3 H,
5.41 (dd, J = 12.4, 1.6 Hz, 1 H, 2ЈЈ-H), 6.25 (s, 1 H, 1Ј-H), 6.89 (d,
J = 8.2 Hz, 1 H, Ar-H), 7.10–7.25 (m, 3 H, Ar-H), 7.25–7.37 (m,
OCH3), 3.62–3.82 (m, 2 H, 4Ј-H/6Ј-H), 4.01–4.21 (m, 2 H, 4Ј-H/ 4 H, Ar-H), 7.66 (d, J = 9.2 Hz, 1 H, 1ЈЈ-H), 10.16 (s, 1 H, CHO)
6Ј-H), 4.41 (d, J = 12.0 Hz, 1 H, CH2Ph), 4.81 (d, J = 12.0 Hz, 1
H, CH2Ph), 5.15 (dd, J = 12.7, 1.6 Hz, 1 H, 2ЈЈ-H), 5.21 (dd, J =
12.7, 1.6 Hz, 1 H, 2ЈЈ-H), 5.45 (d, J = 7.2 Hz, 1 H, 1Ј-H), 5.93 (s,
1 H, 2Ј-H), 6.54 (d, J = 9.2 Hz, 1 H, 1ЈЈ-H), 6.64 (d, J = 8.2 Hz, 1
H, Ar-H), 6.95–7.09 (m, 3 H, Ar-H), 7.25–7.37 (m, 4 H, Ar-H)
ppm. 13C NMR (75.5 MHz, CDCl3): δ = 14.1, 55.3, 55.8, 59.2,
65.0, 80.4, 109.7, 118.6, 119.7, 124.2, 127.6, 128.6, 128.9, 129.1,
129.5, 129.9, 130.1, 130.2, 130.4, 136.4, 136.6, 137.8, 141.3, 152.3,
158.5, 158.2, 194.1 ppm. MS (EI, 70 eV): m/z (%) = 512.2 (38),
510.2 (42) [M]+, 433.1 (12) [M – Br]+. C27H27BrO5 (511.40).
ppm. 13C NMR (75.5 MHz, CDCl3): δ = 12.5, 14.1, 20.9, 25.8, HRMS: calcd. 510.1042; found 510.1042.
55.5, 55.8, 60.3, 67.4, 67.8, 99.1, 110.4, 111.4, 116.7, 119.9, 127.1,
6,11,12-Trimethoxy-2,2,5-trimethyl-7-methylene-7,12-dihydro-4H-
127.6, 127.8, 127.9, 128.2, 128.3, 128.4, 130.6, 133.5, 135.2, 137.6,
138.6, 148.6, 154.6, 157.4 ppm. MS (EI, 70 eV): m/z (%) = 556.1
(5), 554.1 (4) [M]+, 465.1 (43), 463.1 (42) [M – C7H7]+, 417.1 (11),
415.1 (10). C29H31BrO6 (555.46) HRMS: calcd. 554.1304; found
554.1304.
1,3-dioxabenzo[a]anthracene (rac-3). Procedure I: A magnetically
stirred solution of rac-2 (70 mg, 0.15 mmol) and nBu4NOAc
(46 mg, 0.15 mmol), in a degassed mixture of DMF/CH3CN/H2O
(2 mL of a 5:5:1 solution) at 60 °C was treated in one portion with
trans-{di(μ-acetato)-bis[ortho-(di-ortho-tolylphosphanyl)benzyl]di-
palladium(ii)} (4; 14 mg, 0.015 mmol). The resulting suspension
was heated to 120 °C for 4 h with stirring. The ensuing brown mix-
ture was cooled, diluted with diethyl ether (20 mL) and washed
with water (3×3 mL). The organic layer was dried (MgSO4), fil-
tered and concentrated under reduced pressure to afford a crude
brown solid. Subjection of this material to flash chromatography
(19:1 pentane/EtOAc) and concentration of the appropriate frac-
tions afforded the dihydroanthracene rac-3 (14 mg, 0.004 mmol,
24%) as a yellow solid along with starting material rac-2 (40 mg,
0.086 mmol, 57%). Rf = 0.2. UV/Vis: λmax (lg ε) = 201.5 (4.4756),
2-{(2-Benzyloxy-4-bromo-5-methoxy)-(3RS)-[methoxy-(2-methoxy-
6-vinylphenyl)methyl]-6-methylphenyl}-1,3-dioxane (rac-13): A mag-
netically stirred solution of diphenylcarbinol 12 (150 mg,
0.27 mmol) in THF (5 mL) was treated in one portion with KH
(22 mg, 0.54 mmol) at 0 °C. Stirring was continued for 40 min be-
fore the reaction mixture was treated dropwise with MeI (34 μL,
0.54 mmol). The ensuing solution was warmed to 20 °C and stirred
for a further 1 h before being treated with water (2 mL) and ex-
tracted with diethyl ether (3×5 mL). The combined organic frac-
tions were dried (MgSO4), filtered and concentrated under reduced
pressure to afford a colourless solid. Subjection of this material to
flash chromatography (19:1 pentane/EtOAc) and concentration of
the appropriate fractions afforded methyl ether 13 (148 mg,
290.5 (4.5398), 306.0 (3.5456) nm. IR (KBr): ν = 2929, 1456 cm–1.
˜
1H NMR (300 MHz, CDCl3): δ = 1.57 (s, 3 H, CH3), 1.61 (s, 3 H,
CH3), 2.11 (s, 3 H, CH3), 3.30 (s, 3 H, OCH3), 3.57 (s, 3 H, OCH3),
9.92 (s, 3 H, OCH3), 4.77 (s, 2 H, 4-H), 5.95 (d, J = 1.2 Hz, 1 H,
1Ј-H), 6.16 (s, 1 H, 12-H), 6.34 (d, J = 1.2 Hz, 1 H, 1Ј-H), 6.85–
6.89 (m, 1 H, Ar-H), 7.26–7.30 (m, 2 H, Ar-H) ppm. 13C NMR
(75.5 MHz, CDCl3): δ = 10.7, 24.5, 25.0, 55.7, 56.3, 59.7, 60.2, 64.0,
98.9, 109.5, 116.6, 117.2, 117.8, 122.2, 123.4, 127.0, 128.8, 129.2,
137.9, 140.8, 145.1, 148.9, 157.0 ppm. MS (EI, 70 eV): m/z (%) =
382 (32) [M+], 324 (100) [M – C3H6O]+, 293 (86) [M – C3H6O –
CH3O]+, 278 (65) [M – C3H6O – CH3O – CH3]+, 265 (29). HRMS:
calcd. for C23H26O5: 382.1780; found 382.1780. Procedure II:
Cy2NMe (12.5 μL, 59.3 μmol) in degassed dioxane (0.5 mL) and
P(tBu)3 (5.2 μL, 2.58 μmol of a 0.5 m solution in hexane) were
added, in a glovebox, to a magnetically stirred mixture of [Pd2-
(dba)3] (1.18 mg, 1.29 μmol) and rac-2 (20 mg, 43.0 μmol) at 20 °C.
The resulting suspension was heated to 120 °C for 5 h with stirring.
Work up was performed as described previously. Flash chromatog-
raphy (19:1 pentane/EtOAc) of the crude product afforded dihy-
droanthracene rac-3 (15.5 mg, 40.5 μmol, 94%) as a yellow solid
along with starting material rac-2 (1.1 mg, 2.4 μmol, 5 %). Pro-
0.26 mmol, 91 %) as a colourless oil; R = 0.2. IR (KBr): ν =
˜
f
3543 cm–1, 2812, 1589. UV (CH3CN): λmax (lg ε) = 209.0 nm
(4.7395), 294.5 (3.4654). 1H NMR (300 MHz, CDCl3): δ = 1.20–
1.24 (m, 1 H, 5Ј-H), 1.29–1.37 (m, 1 H, 5Ј-H), 2.60 (s, 3 H, CH3),
3.32 (s, 3 H, OCH3), 3.59 (s, 3 H, OCH3), 3.78 (s, 3 H, OCH3),
3.62–3.82 (m, 2 H, 4Ј-H/6Ј-H), 4.01- 4.21 (m, 2 H, 4Ј-H/6Ј-H), 4.41
(d, J = 12.4 Hz, 1 H, CH2Ph), 4.81 (d, J = 12.4 Hz, 1 H, CH2Ph),
5.15 (dd, J = 12.4, 1.6 Hz, 1 H, 2ЈЈ-H), 5.21 (dd, J = 12.4, 1.6 Hz,
1 H, 2ЈЈ-H), 5.74 (s, 1 H, 2Ј-H), 6.25 (s, 1 H, 1Ј-H) 6.54 (d, J =
9.2 Hz, 1 H, 1ЈЈ-H), 6.64 (d, J = 8.2 Hz, 1 H, Ar-H), 6.95–7.09 (m,
3 H, Ar-H), 7.25–7.37 (m, 4 H, Ar-H) ppm. 13C NMR (75.5 MHz,
CDCl3): δ = 13.7, 25.7, 55.4, 55.8, 57.4, 60.0, 67.62, 67.64, 80.2,
80.79, 80.80, 98.8, 109.6, 113.4, 120.8, 126.1, 126.2, 127.1, 127.6,
127.9, 130.6, 131.2, 132.6, 133.6, 137.9, 138.6, 139.9, 152.8, 153.1,
157.2 ppm. MS (EI, 70 eV): m/z (%) = 570.3 (20), 568.2 (19) [M]+,
479.2 (30), 477.2 (28), [M – CH2Ph]+, 447.2 (25), 445.2 (26), 91
(100). C30H33BrO6 (569.48) HRMS: calcd. 568.1461; found
568.1461.
2-Benzyloxy-4-bromo-5-methoxy-(3RS)-[methoxy-(2-methoxy-6-vi- cedure III: [Pd2(dba)3] (1.45 mg, 1.62 μmol) and HP(tBu)3BF4
nylphenyl)methyl]-6-methylbenzaldehyde (rac-6): A magnetically
stirred solution of acetal 13 (100 mg, 0.18 mmol) in a water/acetone
mixture (2.5:5 mL) was treated in one portion with a few crystals
of pyridinium p-toluenesulfonate at 20 °C. The resulting suspension
was heated at reflux for 12 h before being extracted with diethyl
(0.94 mg, 3.23 μmol) were transferred into a flask containing a
magnetic stirrer bar, which was then evacuated and refilled with
argon. A solution of rac-2 (25 mg, 53.9 μmol) and Cy2NMe
(12.5 μL, 59.3 μmol) in degassed dioxane (0.5 mL) was then added
in one portion at 20 °C. The resulting suspension was heated to
ether (3 ×15 mL). The combined organic fractions were washed 120 °C for 5 h with stirring. Work up was performed as described
with brine (1×2 mL), dried (MgSO4), filtered and concentrated un-
der reduced pressure to afford a crude solid. Subjection of this
material to flash chromatography (19:1 pentane/EtOAc) and con-
centration of the appropriate fractions afforded the corresponding
aldehyde 6 (65 mg, 0.13 mmol, 71%) as a colourless solid; Rf = 0.3.
previously. Flash chromatography (19:1 pentane/EtOAc) of the
crude product afforded dihydroanthracene rac-3 (18.8 mg,
49.3 μmol, 92%) as a yellow solid along with starting material rac-
2 (1.5 mg, 3.2 μmol, 6 %). Procedure IV: A magnetically stirred
solution of rac-2 (25 mg, 53.9 μmol), nBu4NOAc (29.5 mg,
107.8 μmol) and K2CO3 (14.9 mg, 107.8 μmol) in degassed DMF
IR (KBr): ν = 2941 cm–1, 1710, 1597. UV (CH CN): λ
(lg ε) =
˜
3
max
1
205.0 nm (4.6429), 292.0 (4.0995). H NMR (300 MHz, CDCl3): δ (0.5 mL) at 20 °C was treated with Pd(OAc)2 (1.21 mg, 5.39 μmol).
= 2.63 (s, 3 H, CH3), 3.34 (s, 3 H, OCH3), 3.56 (s, 3 H, OCH3), The resulting suspension was heated to 90 °C for 5 h with stirring.
Eur. J. Org. Chem. 2005, 1752–1759
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1757

L. F. Tietze, S. G. Stewart, M. E. Polomska
FULL PAPER
Work up was performed as described previously. Flash chromatog-
raphy (19:1 pentane/EtOAc) of the crude product afforded dihy-
droanthracene rac-3 (2.3 mg, 5.9 μmol, 11 %) as a yellow solid
along with starting material rac-2 (10 mg, 21.6 μmol, 40%). Pro-
cedure V: A magnetically stirred solution of rac-2 (25 mg,
53.9 μmol) and NaOAc (9.0 mg, 107.8 μmol) in degassed CH3CN
NOAc (23.6 mg, 78.2 μmol) in a degassed mixture of DMF/
CH3CN/H2O (2 mL of a 5:5:1 solution) at 60 °C was treated in one
portion with 4 (7.3 mg, 7.82 μmol). The resulting suspension was
heated at 120 °C for 5 h with stirring. Work up was performed as
described previously. Flash chromatography (9:1 pentane/EtOAc)
of the crude product afforded dihydroanthracene rac-15 (13.8 mg,
(0.5 mL) at 20 °C was treated with [PdCl2(PPh3)2] (4.48 mg, 32.1 μmol, 82%) as a yellow solid along with starting material rac-
5.39 μmol). The resulting suspension was heated to 90 °C for 5 h
with stirring. Work up was performed as described previously.
Flash chromatography (19:1 pentane/EtOAc) of the crude product
afforded dihydroanthracene rac-3 (1.2 mg, 3.23 μmol, 6%) as a yel-
low solid along with starting material rac-2 (14.5 mg, 31.3 μmol,
58%).
6 (5.9 mg, 1.17 μmol, 3 %). Rf = 0.8 (9:1 pentane/EtOAc). IR
(KBr): ν = 2932 cm–1, 1687, 1584. UV (CH CN): λ
(lg ε) =
˜
3
max
1
206.5 nm (4.6564), 283.0 (4.0785). H NMR (300 MHz, CDCl3): δ
= 2.53 (s, 3 H, CH3), 3.21 (s, 3 H, OCH3), 3.61 (s, 3 H, OCH3),
3.89 (s, 3 H, OCH3), 4.92 (d, J = 10.8 Hz, 1 H, CH2Ph), 5.20 (d, J
= 10.8 Hz, 1 H, CH2Ph), 6.08 (s, 1 H, 1Ј-H), 6.31 (s, 1 H, 9-H),
6.46 (s, 1 H, 1Ј-H), 6.89 (dd, J = 9 Hz, 1.2 Hz, 1 H, Ar-H), 7.24–
7.53 (m, 6 H, Ar-H), 7.55 (d, J = 1.5 Hz, 1 H, Ar-H), 10.50 (s, 1
H, CHO) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 13.0, 55.7, 55.8,
59.7, 64.6, 80.1, 109.6, 117.6, 118.9, 122.2, 127.2, 127.7, 128.4,
128.5, 128.5, 128.6, 128.7, 128.8, 129.0, 129.5, 136.3, 136.6, 137.8,
140.5, 152.7, 157.2, 192.2 ppm. MS (EI, 70 eV): m/z (%) = 430.2
(20) [M]+, 308.1 (58), 280.1 (100). C27H26O5 (430.49) HRMS: calcd.
430.1780; found 430.1780. Procedure II: [Pd2(dba)3] (1.00 mg,
1.17 μmol) and HP(tBu)3BF4 (0.68 mg, 2.34 μmol) were transferred
to a flask containing a magnetic stirrer bar, which was evacuated
and then refilled with argon. A solution of compound rac-6 (20 mg,
39.1 μmol) and Cy2NMe (9.0 μL, 43.0 μmol) in degassed dioxane
(0.5 mL) was then added in one portion at 20 °C. The resulting
suspension was heated to 120 °C for 5 h with stirring. Work up
was performed as described previously. Flash chromatography (9:1
pentane/EtOAc) of the crude product afforded dihydroanthracene
rac-15 (13 mg, 30.2 μmol, 77%) as a yellow solid along with start-
ing material rac-6 (3.5 mg, 6.8 μmol, 18%). Procedure III: A mag-
netically stirred solution of rac-6 (20 mg, 39.1 μmol), nBu4NOAc
(22 mg, 78.2 μmol) and K2CO3 (10.5 mg, 78.2 μmol) in degassed
DMF (0.5 mL) at 20 °C was treated with Pd(OAc)2 (1.2 mg,
5.4 μmol). The resulting suspension was heated to 90 °C for 5 h
with stirring. Work up was performed as described previously.
Flash chromatography (9:1 pentane/EtOAc) of the crude product
afforded dihydroanthracene rac-15 (5.7 mg, 13.3 μmol, 34%) as a
yellow solid along with starting material rac-6 (10.5 mg, 20.4 μmol,
52 %). Procedure IV: A magnetically stirred solution of rac-6
(20 mg, 31.1 μmol) and NaOAc (6.4 mg, 78.2 μmol) in degassed
CH3CN (0.5 mL) at 20 °C was treated with [PdCl2(PPh3)2] (4.4 mg,
5.40 μmol). The resulting suspension was heated to 90 °C for 5 h
with stirring. Work up was performed as described previously.
Flash chromatography (9:1 pentane/EtOAc) of the crude product
afforded dihydroanthracene rac-15 (1.6 mg, 4.73 μmol, 12%) as a
yellow solid along with starting material rac-6 (13.4 mg, 26.4 μmol,
84%).
6,11-Dimethoxy-2,2,5-trimethyl-7-methylene-4,7-dihydro-1,3-dioxa-
benzo[a]anthracen-12-one (14). Procedure I: A magnetically stirred
solution of benzophenone (5; 25 mg, 55.9 μmol) and nBu4NOAc
(34 mg, 111.8 μmol) in a degassed mixture of DMF/CH3CN/H2O
(0.5 mL of a 5:5:1 solution) at 60 °C was treated with 4 (10.4 mg,
11.2 μmol). The resulting suspension was heated at 110 °C for 5 h
with stirring. Work up was performed as described previously.
Flash chromatography (19:1 pentane/EtOAc) of the crude product
afforded anthracenone 14 (15 mg, 40.8 μmol, 73%) along with
starting material 3 (1.5 mg, 3.6 μmol, 6%) as a yellow solid. Rf =
0.3. UV/Vis λmax (lg ε) = 194.0 nm (4.6834), 229.0 (4.6089). IR
1
(KBr): ν = 1672 cm–1, 1456, 1273. H NMR (300 MHz, CDCl ): δ
˜
3
= 1.60 (s, 6 H, 2×CH3), 2.14 (s, 3 H, CH3), 3.61 (s, 3 H, OCH3),
3.94 (s, 3 H, OCH3), 4.77 (s, 2 H, CH2), 6.07 (s, 1 H, 1Ј-H), 6.53
(s, 1 H, 1Ј-H), 6.95 (d, J = 8.2 Hz, 1 H, Ar-H), 7.31–7.44 (m, 2 H,
Ar-H) ppm. 13C NMR (150.8 MHz, CDCl3): δ = 11.3, 24.7, 56.2,
59.8, 60.1, 67.0, 99.2, 111.2, 116.0, 119.3, 120.0, 121.7, 122.4, 129.3,
131.9, 132.5, 136.2, 141.1, 146.6, 147.9, 158.3, 183.5 ppm. MS (EI,
70 eV): m/z (%) = 366.2 (10) [M]+, 308.1 (23) [M – C3H6O]+, 293.1
(100) [M – C3H6O – CH3]+, 265.1 (6). C22H22O5 (366.41). HRMS:
calcd. 366.1467; found 366.1467. Procedure II: [Pd2(dba)3]
(1.53 mg, 1.68 μmol) and HP(tBu)3BF4 (0.97 mg, 3.35 μmol) were
transferred into a flask containing a magnetic stirrer bar, which was
then evacuated and refilled with argon. A solution of compound 5
(25 mg, 55.9 μmol) and Cy2NMe (13.0 μL, 61.0 μmol) in degassed
dioxane (0.5 mL) was then added in one portion at 20 °C. The re-
sulting suspension was heated to 120 °C for 5 h with stirring. Work
up was performed as described previously. Flash chromatography
(19:1 pentane/EtOAc) of the crude product afforded anthracenone
14 (15.9 mg, 43.6 μmol, 78%) as a yellow solid along with starting
material 5 (1.2 mg, 2.7 μmol, 5%). Procedure III: A magnetically
stirred solution of 5 (25 mg, 55.9 μmol), nBu4NOAc (31.0 mg,
111.8 μmol) and K2CO3 (15.0 mg, 111.8 μmol) in degassed DMF
(0.5 mL) at 20 °C was treated with Pd(OAc)2 (1.25 mg, 5.59 μmol).
The resulting suspension was heated to 90 °C for 5 h with stirring.
Work up was performed as described previously. Flash chromatog-
raphy (19:1 pentane/EtOAc) of the crude product afforded anthra-
cenone 14 (4.2 mg, 11.5 μmol, 22%) as a yellow solid along with
starting material 5 (15.3 mg, 34.2 μmol, 61 %). Procedure IV: A
magnetically stirred solution of 5 (25 mg, 55.9 μmol) and NaOAc
(9.1 mg, 111.8 μmol) in degassed CH3CN (0.5 mL) at 20 °C was
treated with [PdCl2(PPh3)2] (4.60 mg, 5.59 μmol). The resulting sus-
pension was heated to 90 °C for 5 h with stirring. Work up was
performed as described previously. Flash chromatography (19:1
pentane/EtOAc) of the crude product afforded anthracenone 14
(1.4 mg, 4.17 μmol, 7%) as a yellow solid along with starting mate-
rial 5 (17.4 mg, 38.9 μmol, 70%).
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1758
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 1752–1759

Intramolecular Heck Reactions for the Synthesis of the Novel Antibiotic Mensacarcin
FULL PAPER
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Received: November 2, 2004
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