Revision of the structure and total synthesis of altenuisol

Article abstract of DOI:10.1002/ejoc.201200506

A total synthesis of the reported structure of altenuisol is described. Comparison of the ¹H NMR spectra of the synthesized compound and of the natural product revealed that the originally proposed structure was not correct. Consequently, two constitutional isomers were synthesized. The spectra of one of these compounds - a structure originally proposed as the structure of altertenuol - matched perfectly with the spectra of the natural product. The total synthesis of altenuisol was thus achieved starting with phloroglucinic acid and protocatechuic aldehyde in 10 steps and in 23% yield, where the longest linear sequence consisted of 6 steps. The key step was a Suzuki coupling with concomitant formation of the lactone ring. Whether altertenuol is identical with altenuisol could not be decided. Total synthesis of altenuisol, a minor toxin in ubiquitous Alternaria spp. revealed that the originally proposed structure was not correct. Altenuisol was proved to have an isomeric structure by total synthesis. Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Full text of DOI:10.1002/ejoc.201200506

Job/Unit: O20506
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Date: 31-05-12 17:21:40
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FULL PAPER
DOI: 10.1002/ejoc.201200506
Revision of the Structure and Total Synthesis of Altenuisol
Gregor Nemecek,[a] Judith Cudaj,[a] and Joachim Podlech*[a]
Keywords: Mycotoxins / Polyketides / Lactones / Total synthesis / Structure elucidation
A total synthesis of the reported structure of altenuisol is de-
scribed. Comparison of the 1H NMR spectra of the synthe-
sized compound and of the natural product revealed that the
originally proposed structure was not correct. Consequently,
two constitutional isomers were synthesized. The spectra of
one of these compounds – a structure originally proposed as
the structure of altertenuol – matched perfectly with the
spectra of the natural product. The total synthesis of altenui-
sol was thus achieved starting with phloroglucinic acid and
protocatechuic aldehyde in 10 steps and in 23% yield, where
the longest linear sequence consisted of 6 steps. The key step
was a Suzuki coupling with concomitant formation of the lac-
tone ring. Whether altertenuol is identical with altenuisol
could not be decided.
Introduction
The resorcylic lactones[1] alternariol and alternariol 9-
methyl ether are important secondary metabolites of toxin-
producing alternaria fungi (Figure 1).[2,3] Although the tox-
icity of these mycotoxins is lower than that of others (e.g.,
aflatoxins),[4] infestation with Alternaria spp. leads to sig-
nificant crop shortfalls by fouling of tomatoes, apples, and
other fruits.[5] Total syntheses of these compounds[6,7] and
of the structurally related toxins altenuene, isoaltenuene,[8]
neoaltenuene,[9] and alterlactone have been reported.[10]
In 1957, altertenuol, a minor toxin produced by Al-
ternaria tenuis, was isolated.[11] Although hardly any evi-
dence was available, the structure given in Figure 1 was as-
signed.[12] In 1973, altenuisol, a toxin with identical molecu-
lar formula (C14H10O6) but slightly different melting point
was isolated from Alternaria tenuis by Pero et al.[13] Al-
1
though the H NMR spectroscopic data were available for
the latter compound,[2] no unambiguous evidence was avail-
able for proposed structure 1 given in Figure 1. Altenuisol is
present in extracts from molds only in very small quantities,
preventing detailed investigations into biological activities.
Nevertheless, significant activity against HeLa cells (8 μg/
mL) and zones of inhibition with Bacillus mycoides were
noted from a 200–5 μg/assay disc.[4a,13] According to these
data, altenuisol should be one of the most toxic alternaria
toxins of those investigated; only altertoxin II, a mycotoxin
with a perylenequinone structure, showed a higher toxicity
against HeLa cells.[4a] Fortunately, most alternaria extracts
seem not to contain altenuisol, although methods for its
Figure 1. Selection of alternaria toxins.
detection and isolation were developed in the decades fol-
lowing its isolation.[14] To supply enough material for a de-
tailed biological investigation and to provide evidence for
the proposed structure, we decided to develop a total syn-
thesis of altenuisol.
[a] Institut für Organische Chemie,
Karlsruher Institut für Technologie (KIT),
Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany
Fax: +49-721-608-47652
Results and Discussion
E-mail: joachim.podlech@kit.edu
The proposed strategy for the total synthesis of altenuisol
(1) had already successfully been applied to the total syn-
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200506.
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G. Nemecek, J. Cudaj, J. Podlech
FULL PAPER
theses of other resorcylic lactones.[8–10,15] The key reaction
would be a Suzuki reaction of a suitably substituted aryl
boronate with a highly oxygenated aryl bromide, allowing
C–C bond formation and generation of the typical lactone
moiety of these metabolites in a single step. Starting with
phloroglucinic acid (2), four steps were needed to obtain
benzyl-protected pinacol-derived boronate 6 (together with
side product 7) according to published procedures
(Scheme 1).[15,16]
Scheme 2. Synthesis of putative altenuisol (1). Reagents and condi-
tions: (e) Br2 (1.02 equiv.), AcOH, 15 °C, 20 min, see ref.[17]
(f) boronate (1.3 equiv.), Cs2CO3 (3 equiv.), Pd(OAc)2
;
6
(0.03 equiv.), SPhos (0.06 equiv.), dioxane/H2O, 80 °C, 2.5 h; (g) H2
(5 bar), Pd/C (10%, 0.2 equiv.), THF, 40 °C, 24 h.
(Figure 2), where compound 12 is identical with the origi-
nally proposed structure of altertenuol (Figure 1) and with
a compound published by Kuramochi et al.[18]
Figure 2. Alternative structures for altenuisol.
Scheme 1. Synthesis of boronate 6. Reagents and conditions:
(a) DMAP (0.05 equiv.), SOCl2 (3.4 equiv.), acetone (2.6 equiv.),
1,2-DME, –15 °C to r.t., 16 h, see ref.[16a]; (b) BnOH (1.1 equiv.),
DIAD (1.1 equiv.), Ph3P (1.1 equiv.), THF, 0 °C to r.t., 4 h, see
Retrosynthetic analysis of compound 11 revealed that a
similar strategy, with Suzuki coupling as the key step, could
be used for its total synthesis. The same boronate 6 could
be used in the coupling, but a different aryl halide was
needed. First, we synthesized aryl bromide 15 starting with
isovanillin (13) in two steps (Scheme 3). The aldehyde moi-
ref.[16b]; (c) Tf2O (1.2 equiv.), pyridine, 0 °C, 3.5 h, see ref.[16b]
;
(d) pinacolborane
(3 equiv.),
Et3N
(3 equiv.),
Pd(PPh3)4
(0.05 equiv.), dioxane, 80 °C, 1.5 h, see ref.[15]
Aryl bromide 9 was prepared from 2-methoxyhydro- ety was directly converted into a hydroxy group (13 Ǟ 14)
quinone (8) in high yield by direct bromination in acetic by using a Dakin reaction with magnesium monoperoxy-
acid.[17] Suzuki coupling with boronate 6 by using a cata- phthalate (MPPA).[19] Subsequent bromination with
lytic amount of Pd(OAc)2 in the presence of SPhos [2-(dicy- N-bromosuccinimide (NBS) at –78 °C led to thermally un-
clohexylphosphanyl)-2Ј,6Ј-dimethoxybiphenyl] as ligand led stable bromide 15. Attempts to synthesize the correspond-
to benzyl-protected resorcylic lactone 10 in a single step. ing iodide or chloride from 14 under similar conditions by
Hydrogenolysis of the benzyl group with Pd/C as catalyst using NIS or NCS, respectively, only led to decomposition
gave target compound 1 in quantitative yield (Scheme 2).
of the substrate.
1
Comparison of the H NMR spectra of synthetic 1 and
We attributed the temperature sensitivity to a possible
the natural product[13] revealed significant deviations, mak- oxidation leading to quinoid structures, and considered it
ing the originally proposed structure of altenuisol very un- likely that this could be reduced, or even avoided, by benzyl
likely (vide infra, Table 1 and Figure 3). Because only a low- ether protection of brominated intermediate 19. Hence, we
1
resolution H NMR spectrum of the natural product had investigated a modified four-step synthesis (Scheme 3), in
been published, a re-examination of the available NMR which isovanillin (13) was benzyl-protected under standard
spectroscopic data was not very promising. A credible mo- conditions[20] and oxidized in a Baeyer–Villiger oxidation
lecular formula (C14H10O6) of the natural product had been by using 3-chloroperbenzoic acid (mCPBA). Crude formate
determined by high-resolution mass spectrometry and all 17 was directly saponified with aqueous sodium hydroxide
functional groups had been assigned by spectroscopic meth- to give phenol 18.[21] Bromination under identical condi-
ods.[13] Because the presence of a resorcylic lactone is very tions to those used earlier furnished bromide 19 in high
likely from the biosynthesis, and is furthermore strongly yield. This compound again turned out to be not very
supported by the spectroscopic data, we considered an in- stable, but it could be significantly stabilized by addition of
terchange of the functional groups in ring C or between a few drops of solvent. We chose ethyl acetate, as this sol-
rings A and C giving rise to isomeric structures 11 and 12 vent was expected to cause no problems in the following
2
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Revision of the Structure and Total Synthesis of Altenuisol
Scheme 3. Synthesis of brominated substrates suitable for Suzuki
couplings. Reagents and conditions: (h) MPPA (0.65 equiv.),
MeOH/H2O, 15 °C to r.t., 24 h, see ref.[18] (i) NBS (1 equiv.), THF,
–78 °C, 35 min; (j) BnBr (1 equiv.), K2CO3 (1.1 equiv.), EtOH, r.t.,
20 h, see ref.[20]; (k) mCPBA (1.5 equiv.), CH2Cl2, r.t., 24 h; (l) aq.
NaOH (6 m), MeOH, r.t., 5 min, see ref.[21]
Scheme 4. Synthesis of alternative structure 11. Reagents and con-
ditions: (m) boronate 6 (1.25 equiv.), Cs2CO3 (3 equiv.), Pd(OAc)2
(0.05 equiv.), SPhos (0.1 equiv.), dioxane/H2O, 80 °C, 2.5 h; (n) H2
(5 bar), Pd/C (10%, 0.2 equiv.), THF, 40 °C, 4 h; (o) boronate 6
(1.35 equiv.), Cs2CO3 (3 equiv.), Pd(OAc)2 (0.05 equiv.), SPhos
(0.1 equiv.), dioxane/H2O, 80 °C, 2.5 h.
palladium-catalyzed cross-coupling reaction. Thus, stabi-
lized compound 19 could be stored at room temperature for
a few hours, and at –18 °C for a few weeks.
Both compounds 15 and 19 were suitable for Suzuki cou-
pling with boronate 6. The benzyl-protected compound
gave significantly better yields and gave rise to smaller
amounts of side products. Both products were deprotected
by hydrogenolysis to yield targeted resorcylic lactone 11
(Scheme 4).
Compound 12 has already been synthesized by Kuramo-
chi et al.[18] Because no detailed spectroscopic data were
given in that publication, which would have allowed an un-
ambiguous comparison with the published spectra of the
natural product, we decided to synthesize compound 12
again, but using a different strategy. Bromide 26 needed for
the synthesis of putative altertenuol structure 12 was syn-
thesized starting with protocatechuic aldehyde (22) by our
well-proven protocol (Scheme 5).
Scheme 5. Synthesis of bromide 26. Reagents and conditions:
(p) BnCl (2.5 equiv.), K2CO3 (3.5 equiv.), DMF, 120 °C, 15 h, see
ref.[22]
Suzuki coupling with methoxy-substituted boronate 27,
which has been used in previous total syntheses of our
group[15,23] and which was synthesized by a strategy analo-
gous to that shown in Scheme 1, could be achieved in 30%
yield. Hydrogenolysis of the benzyl groups led to target
structure 12 in high yield (Scheme 6). This total synthesis
of 12 turned out to be superior to the synthesis published
previously.[18]
The 1H NMR spectroscopic data for the natural product
and for synthesized compounds 1, 11, and 12 are summa-
rized in Table 1. It is evident that the signal pattern (from
high to low field: d, s, d, s) of the aromatic protons in the
spectrum of the natural product does not fit the signal se-
Scheme 6. Synthesis of alternative structure 12. Reagents and con-
ditions: (q) boronate 27 (1.3 equiv.), Cs2CO3 (3 equiv.), Pd(OAc)2
quence of synthesized compound 1 (d, d, s, s), making it (0.05 equiv.), SPhos (0.1 equiv.), dioxane/H2O, 80 °C, 2.5 h.
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G. Nemecek, J. Cudaj, J. Podlech
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1
Table 1. Comparison of H NMR spectroscopic data of the natural product[2] and of synthesized substrates 1, 11, and 12.
Natural product
Signal
Compound 1[b]
Compound 11[b]
Compound 12[b]
δ [ppm][a]
δ [ppm]
Δδ [ppm][c]
δ [ppm]
Δδ [ppm][c]
δ [ppm]
Δδ [ppm][c]
3.89 (s)
6.47 (d)
6.70 (s)
6.92 (d)
7.38 (s)
11.62 (s)
OMe
8-H (or 10-H)
4-H
10-H (or 8-H)
1-H
3.94 (s)
6.32 (d)
6.95 (s)
6.85 (d)
7.36 (s)
11.61 (s)
+0.05
–0.15
+0.25
–0.07
–0.02
–0.01
3.97 (s)
6.30 (d)
6.74 (s)
6.92 (d)
7.44 (s)
11.62 (s)
+0.08
–0.17
+0.04
Ϯ0.00
+0.06
Ϯ0.00
3.92 (s)
6.49 (d)
6.71 (s)
6.95 (d)
7.40 (s)
11.68 (s)
+0.03
+0.02
+0.01
+0.03
+0.02
+0.06
7-OH
[a] In [D8]THF, 100 MHz.[2] [b] In [D8]THF, 500 MHz. [c] Deviation of corresponding signals of the natural product. Major deviations
in boldface.
very unlikely that the natural product has the structure of
To further check the structural identity of the synthe-
compound 1 (Figure 3). The signal patterns of the natural sized material with the natural product we synthesized tri-
product and of compound 11 match more closely. The small acetates 29 and 30 of compounds 11 and 12 (see Scheme 7).
deviations between corresponding signals of the natural In agreement with the limited data published for the per-
1
product and of synthesized compound 11 are generally acetylated natural product,[13] we observed H NMR sig-
within the usual margin of error for measurement, but a nals for the aromatic protons of compound 30 in deuterated
significant deviation exists for protons 8-H (or 10-H), tetrahydrofuran at δ = 8.04 ppm (singlet, ref.[13] 8.01 ppm)
whose signals appear at δ = 6.47 ppm for the natural prod- and 7.24 ppm (singlet, ref.[13] 7.23 ppm). Significant devia-
uct and at δ = 6.30 ppm for synthesized product 11. How- tions were observed for the signals of compound 29 (7.95
ever, the spectrum of compound 12 matches perfectly with and 7.15 ppm, doublets). A thorough comparison of the
all deviations within measurement errors.[2] All other ana- analytical data of the peracetylated compounds was not
lytical data available for the natural product (IR, UV/Vis, possible, as neither a detailed synthetic description nor
MS, m.p., Rf for TLC) perfectly match with the data of comprehensive analytical data of the triacetate of the natu-
compound 12.
ral product were given in the original paper.
Scheme 7. Synthesis of triacetates 29 and 30. Reagents and condi-
tions: (r) Ac2O (8 equiv.), pyridine, r.t., 24 h.
Conclusions
Comparison of the spectra of synthesized compounds 1,
11, and 12 and of their peracetylated derivatives with those
of natural altenuisol and its triacetate unambiguously re-
vealed altenuisol to be identical to compound 12 – the
structure that had originally been proposed as the structure
of altertenuol. Consequently, we can correct the erroneously
given structure of altenuisol. Whether the natural product
altertenuol is identical with altenuisol (12) – as has been
claimed previously without evidence[1] – or with one of the
alternative compounds 1 or 11, is currently not determin-
able from the insufficient data from the original pa-
Figure 3. Sections of 1H NMR spectra of the natural product
(printed with permission, Copyright Elsevier)[2] and of compounds
1, 11, and 12.
4
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Revision of the Structure and Total Synthesis of Altenuisol
pers.[11,12] Thus, we have completed the total synthesis of
altenuisol (12) starting with phloroglucinic acid and proto-
catechuic aldehyde in 10 steps and in 23% yield, where the
longest linear sequence consisted of 6 steps. This total syn-
thesis turned out to be superior to the synthesis published
previously (19% with 12 steps).[18] Isomeric structure 11
was synthesized in 42% yield in 10 steps. A detailed bio-
logical investigation of altenuisol and its isomers is cur-
rently in progress.
washed with THF (30 mL), and concentrated in vacuo to yield an
essentially pure product 1 as a colorless solid (15 mg, 55 μmol,
quant.). M.p. 276–281 °C; Rf = 0.13 (hexanes/EtOAc, 2:1); Rf =
0.33 (benzene/THF, 4:1). 1H NMR (500 MHz, [D8]THF): δ = 11.61
(s, 1 H, OH), 9.59 (br. s, 1 H, OH), 8.13 (br. s, 1 H, OH), 7.36 (s,
1 H, 1-H), 6.95 (s, 1 H, 4-H), 6.86 (d, 4J = 2.5 Hz, 1 H, 10-H), 6.32
(d, 4J = 2.5 Hz, 1 H, 8-H), 3.94 (s, 3 H, OMe) ppm. 1H NMR
(400 MHz, [D6]DMSO): δ = 11.14 (s, 1 H, OH), 10.98 (br. s, 1 H,
OH), 9.46 (br. s, 1 H, OH), 7.35 (s, 1 H, 1-H), 7.05 (s, 1 H, 4-H),
6.86 (d, J = 2.3 Hz, 1 H, 10-H), 6.34 (d, J = 2.3 Hz, 1 H, 8-H),
3.86 (s, 3 H, OMe) ppm. 13C NMR (100 MHz, [D6]DMSO): δ =
165.8 (C), 164.7 (C), 163.6 (C), 150.6 (C), 144.0 (C), 139.9 (C),
137.1 (C), 109.7 (C), 107.8 (CH), 101.5 (CH), 100.8 (CH), 99.3
4
4
(CH), 97.4 (C), 56.0 (CH ) ppm. IR (DRIFT): ν = 3182, 1666,
˜
3
Experimental Section
1582, 1489, 1434, 1280, 1235, 1180, 1160, 1089, 1022, 981, 855,
824, 789, 635 cm–1. MS (FAB): m/z (%) = 275 (100) [M + H]+.
HRMS (FAB): calcd. for C14H11O6 275.0556; found 275.0554.
General: Tetrahydrofuran (THF) and dioxane were distilled from
sodium with benzophenone ketyl radical as indicator, and CH2Cl2
was distilled from CaH2. All moisture-sensitive reactions were car-
ried out under an oxygen-free argon atmosphere by using oven-
dried glassware and a vacuum line. Flash column chromatog-
raphy[24] was carried out by using Merck SiO2 60 (230–400 mesh),
and thin-layer chromatography (TLC) was carried out by using
commercially available Merck F254 precoated sheets. 1H and 13C
NMR spectra were recorded with a Bruker Cryospek WM-250
(only literature-known compounds), an AM-400, or a DRX Av-
ance 500. Chemical shifts are given in ppm and were referenced
using residual signals of the solvent as internal standard (1H:
CHCl3, 7.26 ppm; [D5]DMSO, 2.50 ppm; [D7]THF, 1.73 and
3.58 ppm; CD2HOD, 3.31 ppm. 13C: CDCl3, 77.0 ppm; [D6]-
DMSO, 39.5 ppm; [D8]THF, 25.4 and 67.6 ppm). IR spectra were
recorded with a Bruker IFS-88 spectrometer. Mass spectra were
recorded with a Finnigan MAT-90 mass spectrometer. UV/Vis
spectra were recorded with a Perkin–Elmer Lambda 2 spectrome-
ter. Melting points were determined by using an OptiMelt MPA100
device from Stanford Research Systems.
4-Bromo-6-methoxybenzene-1,3-diol (15): NBS (2.86 g, 16.1 mmol)
was added in small portions at –78 °C over 10 min to a solution
of compound 14 (2.25 g, 16.1 mmol) in THF (60 mL) under an
atmosphere of argon. The mixture was stirred at that temperature
for 35 min, and then the reaction was quenched by the addition of
brine (80 mL). The aqueous layer was extracted with EtOAc (3ϫ
50 mL), and the combined organic layers were dried (Na2SO4) and
concentrated. The residue was purified by column chromatography
(1st chromatography: silica gel; hexanes/EtOAc, 4:1, 2nd
chromatography: silica gel, CH2Cl2), where concentration of prod-
uct-containing fractions was carried out at room temperature or
below. Product 15 was obtained as a yellow, temperature-sensitive
oil (2.35 g, 10.7 mmol, 67%). Rf = 0.30 (CH2Cl2). 1H NMR
(400 MHz, CDCl3): δ = 6.90 (s, 1 H, 5-H), 6.67 (s, 1 H, 2-H), 5.65
(br. s, 1 H, OH), 5.15 (br. s, 1 H, OH), 3.83 (s, 3 H, OMe) ppm.
13C NMR (100 MHz, CDCl3): δ = 147.0 (C), 146.4 (C), 141.3 (C),
113.7 (CH), 103.0 (CH), 98.2 (C), 56.68 (CH3) ppm. IR (DRIFT):
ν = 3403, 1498, 1439, 1301, 1239, 1142, 1028, 994, 850, 793 cm–1.
˜
MS (EI): m/z (%) = 218 (100) [M]+, 203 (85), 175 (33), 95 (28).
9-Benzyloxy-2,7-dihydroxy-3-methoxy-6H-benzo[c]chromen-6-one
(10): A solution of bromide 9 (173 mg, 0.79 mmol), boronate 6
(421 mg, 1.03 mmol), Pd(OAc)2 (5 mg, 24 μmol), SPhos (20 mg,
47 μmol), and Cs2CO3 (772 mg, 2.37 mmol) in dioxane/H2O (6:1,
10 mL) was stirred at 80 °C for 2.5 h under an atmosphere of ar-
gon. The mixture was poured into satd. aq. solution of NH4Cl
(20 mL) and extracted with EtOAc (4ϫ 40 mL). The combined or-
ganic layers were washed with brine (30 mL), dried (Na2SO4), and
concentrated. The residue was purified by chromatography (silica
gel; cyclohexane/EtOAc, 5:1) to yield a pale yellow solid. Macera-
tion with CH2Cl2 furnished 10 as a pure colorless solid (90 mg,
0.25 mmol, 31%). M.p. 230–235 °C; Rf = 0.22 (hexanes/EtOAc,
2:1). 1H NMR (400 MHz, [D6]DMSO): δ = 11.47 (s, 1 H, OH),
8.96 (br. s, 1 H, OH), 7.67 (s, 1 H, 1-H), 7.26–7.41 (m, 5 H, OBn),
HRMS (EI): calcd. for C7H7BrO3 217.9579 found 217.9578.
5-Benzyloxy-2-bromo-4-methoxyphenol (19): NBS (772 mg,
4.34 mmol) was added in small portions at –78 °C over 10 min to
a solution of compound 18 (1.00 g, 4.34 mmol) in THF (30 mL)
under an atmosphere of argon. The mixture was stirred at that
temperature for 35 min and quenched by addition of brine (60 mL).
The aqueous layer was extracted with CH2Cl2 (3ϫ 50 mL), and
the combined organic layers were dried (Na2SO4) and concentrated
(keeping the temperature below r.t.). The residue was purified by
column chromatography (silica gel, CH2Cl2), where concentration
of product-containing fractions was carried out at room tempera-
ture or below. Product 19 was obtained as a reddish, temperature-
sensitive oil (1.23 g, 3.98 mmol, 92%), which crystallized at –18 °C
after some days. The product could be stabilized for a prolonged
storage at –18 °C by adding some drops of EtOAc. Rf = 0.63
(CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 7.31–7.42 (m, 5 H,
OBn), 6.94, (s, 1 H, 3-H), 6.64 (s, 1 H, 6-H), 5.16 (br. s, 1 H, OH),
5.10 (s, 2 H, OBn), 3.82 (s, 3 H, OMe) ppm. 13C NMR (100 MHz,
CDCl3): δ = 149.0 (C), 146.6 (C), 144.3 (C), 136.4 (C), 128.6 (CH),
128.0 (CH), 127.3 (CH), 115.3 (CH), 102.6 (CH), 99.2 (C), 71.1
4
4
6.89 (d, J = 2.3 Hz, 1 H, 10-H), 6.77 (s, 1 H, 4-H), 6.48 (d, J =
2.3 Hz, 1 H, 8-H), 5.15 (s, 2 H, OBn), 3.86 (s, 3 H, OMe) ppm. 13
C
NMR (100 MHz, [D6]DMSO/CDCl3): δ = 165.2 (C), 164.7 (C),
163.7 (C), 150.0 (C), 143.9 (C), 143.7 (C), 136.6 (C), 135.3 (C),
128.0 (CH), 127.7 (CH), 127.0 (CH), 109.8 (C), 107.5 (CH), 100.1
(C), 99.7 (CH), 98.6 (CH), 98.5 (CH), 69.6 (CH2), 55.5 (CH3) ppm.
IR (DRIFT): ν = 3183, 1666, 1581 cm–1. MS (FAB): m/z (%) = 365
˜
(100) [M + H]+. HRMS (FAB): calcd. for C21H17O6 365.1025;
found 365.1023.
(CH ), 56.9 (CH ) ppm. IR (DRIFT): ν = 3502, 1507, 1397, 1159,
˜
2
3
1026, 983, 855, 800 cm–1. MS (EI): m/z (%) = 308 (18) [M]+, 91
(100). HRMS (EI): calcd. for C14H13BrO3 308.0048; found
308.0045.
2,7,9-Trihydroxy-3-methoxy-6H-benzo[c]chromen-6-one, Originally
Proposed Structure of Altenuisol (1): Pd/C (10%, 12 mg, 11 μmol)
was added to a solution of benzyl-protected compound 10 (20 mg,
55 μmol) in THF (4 mL) and stirred under an H2 atmosphere
(5 bar) for 24 h at 40 °C. The mixture was filtered through Celite,
9-Benzyloxy-3,7-dihydroxy-2-methoxy-6H-benzo[c]chromen-6-one
(20): Bromide 15 (72 mg, 0.33 mmol), boronate
6
(168 mg,
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/KAP1
Date: 31-05-12 17:21:40
Pages: 9
G. Nemecek, J. Cudaj, J. Podlech
FULL PAPER
0.41 mmol), Pd(OAc)2 (4 mg, 17 μmol), SPhos (14 mg, 34 μmol), solid (239 mg, 0.872 mmol, 90%). M.p. 279–281 °C; Rf = 0.33
and Cs2CO3 (323 mg, 0.99 mmol) were dissolved in dioxane/H2O
(6:1, 3 mL) and stirred at 80 °C for 2.5 h under an atmosphere of
argon. The mixture was poured into satd. aq. NH4Cl (20 mL) and
extracted with EtOAc (3ϫ 20 mL). The combined organic layers
were washed with brine (30 mL), dried (Na2SO4) and concentrated.
The residue was purified by column chromatography (silica gel;
hexanes/EtOAc, 6:1 Ǟ 4:1 Ǟ 2:1) to yield product 20 as a pale
yellow solid containing minor amounts of non-identified by-prod-
ucts (19 mg, 52 μmol, 16%). Rf = 0.34 (hexanes/EtOAc, 2:1). 1H
(benzene/THF, 4:1). UV (EtOH): λ = 214, 255, 277 (sh.) nm. 1H
NMR (500 MHz, [D8]THF): δ = 11.62 (s, 1 H, OH), 9.45 (br. s, 1
H, OH), 8.77 (br. s, 1 H, OH), 7.44 (s, 1 H, 1-H), 6.92 (d, 4J =
4
2.0 Hz, 1 H, 10-H), 6.74 (s, 1 H, 4-H), 6.30 (d, J = 2.0 Hz, 1 H,
8-H), 3.97 (s, 3 H, OMe) ppm. 13C NMR (125 MHz, [D8]THF): δ
= 166.6 (C), 166.2 (C), 165.9 (C), 151.2 (C), 147.2 (C), 146.7 (C),
138.9 (C), 110.4 (C), 105.6 (CH), 104.6 (CH), 102.1 (CH), 100.0
(CH), 99.2 (C), 56.7 (CH ) ppm. IR (DRIFT): ν = 3387, 3247,
˜
3
1632, 1615, 1587, 1501, 1442, 1286, 1207, 1171, 1100, 1016, 966,
NMR (400 MHz, CDCl3): δ = 11.61 (s, 1 H, OH), 7.28–7.48 (m, 5 922, 843, 824, 773 cm–1. MS (EI): m/z (%) = 274 (100) [M]+, 259
4
H, OBn), 7.23 (s, 1 H, 1-H), 6.95 (d, J = 2.4 Hz, 1 H, 10-H), 6.92 (52), 245 (20), 203 (65). HRMS (EI): calcd. for C14H10O6 274.0477;
(s, 1 H, 4-H), 6.60 (d, 4J = 2.4 Hz, 1 H, 8-H), 6.02 (br. s, 1 H, OH),
5.18 (s, 2 H, OBn), 3.99 (s, 3 H, OMe) ppm. 13C NMR (100 MHz,
CDCl3): δ = 165.9 (C), 165.4 (C), 165.0 (C), 148.4 (C), 146.0 (C),
144.5 (C), 137.0 (C), 135.7 (C), 128.8 (CH), 128.5 (CH), 127.7
(CH), 110.1 (C), 103.7 (CH), 103.5 (CH), 100.1 (CH), 99.7 (CH),
found 274.0475.
3,7,9-Triacetoxy-2-methoxy-6-oxo-6H-benzo[c]chromene (29): Com-
pound 11 (30 mg, 110 μmol) was dissolved in anhydrous pyridine
(1 mL) under an atmosphere of argon. Ac2O (90 mg, 880 μmol)
was added, and the mixture was stirred for 24 h at room tempera-
ture. The mixture was then poured into 1 m HCl (20 mL) and ex-
tracted with EtOAc (4ϫ 20 mL). The combined organic layers were
dried (Na2SO4) and concentrated. The residue was purified by
recrystallization (THF/hexanes) to yield triacetate 29 (38 mg,
95 μmol, 86%) as a colorless solid. M.p. 246–249 °C; Rf = 0.28
(hexanes/EtOAc, 1:1). 1H NMR (500 MHz, [D8]THF): δ = 7.95 (d,
99.4 (CH), 70.6 (CH ), 56.4 (CH ) ppm. IR (DRIFT): ν = 3324,
˜
2
3
2916, 1666, 1615, 1568, 1501, 1384, 1151, 1024, 830 cm–1. MS (EI):
m/z (%) = 364 (12) [M]+, 140 (29), 125 (32), 97 (22), 91 (100).
HRMS (EI): calcd. for C21H16O6 364.0947; found 364.0945.
3,9-Bis(benzyloxy)-7-hydroxy-2-methoxy-6H-benzo[c]chromen-6-one
(21): Bromide 19 (405 mg, 1.31 mmol), boronate 6 (717 mg,
1.75 mmol), Pd(OAc)2 (15 mg, 66 μmol), SPhos (53 mg, 130 μmol)
and Cs2CO3 (1.28 g, 3.93 mmol) were dissolved in dioxane/H2O
(6:1, 14 mL) and stirred at 80 °C for 2.5 h under an atmosphere of
argon. The mixture was poured into a satd. aq. solution of NH4Cl
(60 mL) and extracted with EtOAc (3ϫ 40 mL). The combined or-
ganic layers were washed with brine (50 mL), dried (Na2SO4), and
concentrated. The residue was purified by column chromatography
(silica gel, CH2Cl2) to yield product 21 as a colorless solid (456 mg,
1.00 mmol, 77%). M.p. 178–180 °C; Rf = 0.74 (CH2Cl2). 1H NMR
(400 MHz, CDCl3): δ = 11.56 (s, 1 H, OH), 7.33–7.48 (m, 10 H,
4J = 2.0 Hz, 1 H, 10-H), 6.70 (s, 1 H, 1-H), 7.15 (d, J = 2.0 Hz, 1
H, 8-H), 7.10 (s, 1 H, 4-H), 3.92 (s, 3 H, OMe), 2.31 (s, 6 H, 2
4
1
OAc), 2.25 (s, 3 H, OAc) ppm. H NMR (400 MHz, [D6]DMSO):
4
4
δ = 8.31 (d, J = 2.0 Hz, 1 H, 10-H), 7.93 (s, 1 H, 1-H), 7.35 (d, J
= 2.0 Hz, 1 H, 8-H), 7.32 (s, 1 H, 4-H), 3.93 (s, 3 H, OMe), 2.38
(s, 3 H, OAc), 2.35 (s, 3 H, OAc), 2.31 (s, 3 H, OAc) ppm. 13C
NMR (100 MHz, [D6]DMSO): δ = 168.7 (C), 168.3 (C), 168.1 (C),
156.2 (C), 155.9 (C), 153.0 (C), 148.4 (C), 144.5 (C), 141.8 (C),
137.5 (C), 118.4 (CH), 114.8 (C), 114.2 (CH), 112.0 (CH), 110.9
(C), 106.9 (CH), 56.7 (CH3), 20.8 (CH3), 20.7 (CH3), 20.3 (CH3)
4
ppm. IR (DRIFT): ν = 1770, 1759, 1730, 1190, 1152, 1133, 1056,
˜
OBn), 7.22 (s, 1 H, 1-H), 6.93 (d, J = 2.4 Hz, 1 H, 10-H), 6.83 (s,
1025, 894 cm–1. MS (EI): m/z (%) = 400 (22) [M]+, 358 (32), 316
(100), 274 (65), 259 (20), 245 (20). HRMS (EI): calcd. for C20H16O9
400.0794; found 400.0792.
1 H, 4-H), 6.57 (d, 4J = 2.4 Hz, 1 H, 8-H), 5.20 (s, 2 H, OBn), 5.16
(s, 2 H, OBn), 3.96 (s, 3 H, OMe) ppm. 13C NMR (100 MHz,
CDCl3): δ = 165.9 (C), 165.3 (C), 164.9 (C), 150.7 (C), 147.2 (C),
145.5 (C), 136.9 (C), 135.8 (C), 135.7 (C), 128.8 (CH), 128.7 (CH),
128.5 (CH), 128.3 (CH), 127.7 (CH), 127.3 (CH), 110.4 (C), 104.6
(CH), 102.6 (CH), 100.3 (CH), 99.7 (CH), 99.4 (C), 71.1 (CH2),
4,5-Bis(benzyloxy)-2-bromophenol (26): NBS (755 mg, 4.24 mmol)
was added in small portions at –78 °C over 10 min to a solution
of compound 25 (1.30 g, 4.24 mmol) in THF (30 mL) under an
atmosphere of argon. The mixture was stirred at that temperature
for 35 min, and then the reaction was quenched by the addition of
brine (60 mL). The aqueous layer was extracted with CH2Cl2 (3ϫ
50 mL), and the combined organic layers were dried (Na2SO4) and
concentrated (keeping the temperature below r.t.). The residue was
purified by column chromatography (silica gel, CH2Cl2), where
concentration of product-containing fractions was carried out at
room temperature or below. Compound 26 was obtained as a red-
dish, temperature-sensitive oil (1.44 g, 3.74 mmol, 88%) containing
minor amounts of unidentified byproducts. Rf = 0.69 (CH2Cl2). 1H
NMR (400 MHz, CDCl3): δ = 7.31–7.42 (m, 10 H, 2 OBn), 7.03
(s, 1 H, 3-H), 6.68 (s, 1 H, 6-H), 5.19 (br. s, 1 H, OH), 5.11 (s, 2
H, OBn), 5.05 (s, 2 H, OBn) ppm. 13C NMR (100 MHz, CDCl3):
δ = 150.2 (C), 147.5 (C), 143.2 (C), 136.9 (C), 136.5 (C), 128.6
(CH), 128.5 (CH), 128.0 (CH), 127.9 (CH), 127.6 (CH), 127.3
(CH), 119.4 (CH), 103.0 (CH), 99.4 (C), 72.9 (CH2), 71.2 (CH2)
70.5 (CH ), 56.5 (CH ) ppm. IR (DRIFT): ν = 3086, 1665, 1615,
˜
2
3
1570, 1515, 1257 cm–1. C28H22O6 (454.47): calcd. C 74.00, H 4.88;
found C 73.50, H 4.86. MS (EI) m/z (%): = 454 (10) [M]+, 230
(24), 91 (100). HRMS (EI): calcd. for C28H22O6 454.1416; found
454.1412.
3,7,9-Trihydroxy-2-methoxy-6H-benzo[c]chromen-6-one (11)
Method A: Pd/C (10%, 36 mg, 32 μmol) was added to a solution
of benzyl-protected compound 20 (64 mg, 158 μmol) in THF
(12 mL), and the mixture was stirred under an H2 atmosphere
(5 bar) for 4 h at 40 °C, then filtered through Celite, washed with
THF (60 mL), and concentrated. The residue was dissolved in a
small amount of THF and purified by column chromatography
(silica gel; hexanes/EtOAc, 1:1) to yield product 11 as a colorless
solid (37 mg, 135 μmol, 85%).
Method B: Pd/C (10%, 207 mg, 0.194 mmol) was added to a solu-
tion of benzyl-protected compound 21 (441 mg, 0.970 mmol) in
THF (50 mL), and the mixture was stirred under an H2 atmosphere
(5 bar) for 4 h at 40 °C, then filtered through Celite, washed with
THF (120 mL), and concentrated. The residue was dissolved in a
small amount of THF and purified by column chromatography
(silica gel; hexanes/EtOAc, 1:1) to yield product 11 as a colorless
ppm. IR (DRIFT): ν = 3440, 1585, 1503, 1454, 1257, 1193, 1026,
˜
736 cm–1. MS (EI): m/z (%) = 384 (28) [M]+, 294 (100). HRMS
(EI): calcd. for C20H17BrO3 384.0361; found 384.0363.
2,3-Bis(benzyloxy)-7-hydroxy-9-methoxy-6H-benzo[c]chromen-6-one
(28): Bromide 26 (478 mg, 1.24 mmol), boronate 27 (538 mg,
1.61 mmol), Pd(OAc)2 (14 mg, 62 μmol), SPhos (51 mg, 120 μmol),
6
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/KAP1
Date: 31-05-12 17:21:41
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Revision of the Structure and Total Synthesis of Altenuisol
and Cs2CO3 (1.22 g, 3.72 mmol) were dissolved in dioxane/H2O
(6:1, 14 mL) and stirred at 80 °C for 2.5 h under an atmosphere of
argon. The mixture was poured into a satd. aq. solution of NH4Cl
(50 mL) and extracted with EtOAc (3ϫ 40 mL). The combined or-
ganic layers were washed with brine (40 mL), dried (Na2SO4), and
concentrated. The residue was purified by column chromatography
(silica gel, CH2Cl2) to yield product 28 as a colorless solid (169 mg,
0.370 mmol, 30%). M.p. 199–201 °C; Rf = 0.71 (CH2Cl2). 1H NMR
(400 MHz, CDCl3): δ = 11.53 (s, 1 H, OH), 7.32–7.49 (m, 11 H, 2
OBn, 1-H), 6.87 (s, 1 H, 4-H), 6.75 (d, 4J = 2.4 Hz, 1 H, 10-H),
Supporting Information (see footnote on the first page of this arti-
cle): Spectra of compounds 1, 10, 11, 15, 19–21, 26, and 28–30.
Acknowledgments
This work was supported by the Landesgraduiertenförderung Ba-
den-Württemberg (grant for G. N.). J. C. is grateful for a grant from
the Karlsruhe House of Young Scientists (KHYS), which allowed
for a stay abroad.
4
6.50 (d, J = 2.4 Hz, 1 H, 8-H), 5.22 (s, 4 H, 2 OBn), 3.91 (s, 3 H,
OMe) ppm. 13C NMR (100 MHz, CDCl3): δ = 166.8 (C), 165.3
(C), 164.8 (C), 151.7 (C), 146.2 (C), 146.1 (C), 136.8 (C), 136.7 (C),
135.9 (C), 128.7 (CH), 128.7 (CH), 128.2 (CH), 128.1 (CH), 127.5
(CH), 127.2 (CH), 110.6 (C), 109.0 (CH), 103.0 (CH), 99.8 (CH),
99.2 (C), 98.7 (CH), 72.4 (CH2), 71.1 (CH2), 55.7 (CH3) ppm. IR
[1] G. Bringmann, C. Günther, M. Ochse, O. Schupp, S. Tasler in
Fortschritte der Chemie organischer Naturstoffe (Eds.: W. Herz,
H. Falk, G. W. Kirby, R. E. Moore), Springer, Vienna, 2001,
vol. 82, pp. 1–249.
(DRIFT): ν = 2943, 1674, 1615, 1567, 1510, 1267, 1195, 1156, 830,
[2] R. J. Cole, R. H. Cox (Eds.), Handbook of Toxic Fungal Metab-
olites, Academic Press, New York, 1981, pp. 614–645.
[3] a) E. E. Stinson, J. Food Prot. 1985, 48, 80–91; b) D. J. Harvan,
R. W. Pero in Mycotoxins and Other Fungal Related Food Prob-
lems (Ed.: J. V. Rodricks), American Chemical Society, Wash-
ington, D. C., 1976, vol. 149, pp. 344–355.
[4] a) R. W. Pero, H. Posner, M. Blois, D. Harvan, J. W. Spalding,
Environ. Health Perspect. 1973, 4, 87–94; b) V. M. Davis, M. E.
Stack, Appl. Environ. Microbiol. 1994, 60, 3901–3902.
[5] a) M. Combina, A. Dalcero, E. Varsavsky, A. Torres, M. Etch-
everry, M. Rodriguez, H. Gonzalez Quintana, Mycotoxin Res.
1999, 15, 33–38; b) V. H. Tournas, M. E. Stack, J. Food Prot.
2001, 64, 528–532.
˜
691 cm–1. MS (EI): m/z (%) = 454 (32) [M]+, 91 (100). HRMS (EI):
calcd. for C28H22O6 454.1416; found 454.1415.
2,3,7-Trihydroxy-9-methoxy-6H-benzo[c]chromen-6-one,
Revised
Structure of Altenuisol (12): Pd/C (10%, 62 mg, 59 μmol) was added
to a solution of benzyl-protected compound 28 (133 mg, 293 μmol)
in THF (15 mL), and the mixture was stirred under an H2 atmo-
sphere (5 bar) for 4 h at 40 °C, filtered through Celite, washed with
THF (60 mL), and concentrated. The residue was recrystallized
(acetic acid) to yield product 12 as a colorless solid (76 mg,
277 μmol, 95%). M.p. 277–280 °C; Rf = 0.33 (benzene/THF, 4:1).
UV (EtOH): λ = 217, 255, 276 (sh.) nm. 1H NMR (500 MHz, [D8]-
THF): δ = 11.68 (s, 1 H, OH), 9.13 (br. s, 1 H, OH), 8.30 (br. s, 1
[6] a) T. M. Harris, J. V. Hay, J. Am. Chem. Soc. 1977, 99, 1631–
1637; b) C. C. Kanakam, N. S. Mani, G. S. R. Subba Rao, J.
Chem. Soc. Perkin Trans. 1 1990, 2233–2237; c) B. I. Alo, A.
Kandil, P. A. Patil, M. J. Sharp, M. A. Siddiqui, V. Snieckus,
P. D. Josephy, J. Org. Chem. 1991, 56, 3763–3768.
[7] K. Koch, J. Podlech, E. Pfeiffer, M. Metzler, J. Org. Chem.
2005, 70, 3275–3276.
4
H, OH), 7.40 (s, 1 H, 1-H), 6.95 (d, J = 2.0 Hz, 1 H, 10-H), 6.71
4
(s, 1 H, 4-H), 6.49 (d, J = 2.0 Hz, 1 H, 8-H), 3.92 (s, 3 H, OMe)
1
ppm. H NMR (250 MHz, CD3OD, cf. ref.[18]): δ = 7.39 (s, 1 H, 1-
4
4
H), 6.95 (d, J = 2.2 Hz, 1 H, 10-H), 6.75 (s, 1 H, 4-H), 6.50 (d, J
= 2.2 Hz, 1 H, 8-H), 3.94 (s, 3 H, OMe) ppm. 13C NMR (125 MHz,
[D8]THF): δ = 168.0 (C), 166.3 (C), 165.9 (C), 149.8 (C), 146.1 (C),
144.7 (C), 138.6 (C), 110.9 (C), 109.2 (CH), 104.2 (CH), 100.4
[8] M. Altemöller, J. Podlech, D. Fenske, Eur. J. Org. Chem. 2006,
1678–1684.
[9] M. Altemöller, J. Podlech, Eur. J. Org. Chem. 2009, 2275–2282.
[10] J. Cudaj, J. Podlech, Synlett 2012, 371–374.
[11] T. Rosett, R. H. Sankhala, C. E. Stickings, M. E. U. Taylor, R.
Thomas, Biochem. J. 1957, 67, 390–400.
[12] R. Thomas, Biochem. J. 1961, 80, 234–240.
[13] R. W. Pero, D. Harvan, M. C. Blois, Tetrahedron Lett. 1973,
14, 945–948.
(CH), 100.1 (C), 98.8 (CH), 56.1 (CH ) ppm. IR (DRIFT): ν =
˜
3
3533, 3277, 1643, 1597, 1566, 1544, 1441, 1272, 1225, 1161, 1097,
979, 849, 787, 629 cm–1. MS (EI): m/z (%) = 274 (100) [M]+, 91
(30). HRMS (EI): calcd. for C14H10O6 274.0477; found 274.0476.
The data match with those of the natural product.[13]
[14] a) F. S. Chu, J. Am. Oil Chem. Soc. 1981, 58, 1006A–1008A;
b) G. F. Griffin, C. Bennett, F. S. Chu, J. Chromatogr. 1983,
280, 363–369; c) T. Rotunno, Chromatographia 1992, 34, 56–
62.
[15] M. Altemöller, T. Gehring, J. Cudaj, J. Podlech, H. Goesmann,
C. Feldmann, A. Rothenberger, Eur. J. Org. Chem. 2009, 2130–
2140.
[16] a) S. Kamisuki, S. Takahashi, Y. Mizushina, S. Hanashima, K.
Kuramochi, S. Kobayashi, K. Sakaguchi, T. Nakata, F. Suga-
wara, Tetrahedron 2004, 60, 5695–5700; b) R. G. Dushin, S. J.
Danishefsky, J. Am. Chem. Soc. 1992, 114, 655–659.
[17] A. P. Guzikowski, S. X. Cai, S. A. Espitia, J. E. Hawkinson,
J. E. Huettner, D. F. Nogales, M. Tran, R. M. Woodward, E.
Weber, J. F. W. Keana, J. Med. Chem. 1996, 39, 4643–4653.
[18] K. Kuramochi, K. Fukudome, I. Kuriyama, T. Takeuchi, Y.
Sato, S. Kamisuki, K. Tsubaki, F. Sugawara, H. Yoshida, Y.
Mizushina, Bioorg. Med. Chem. 2009, 17, 7227–7238.
[19] H. Hauer, T. Ritter, G. Grotemeier, Arch. Pharmacal. Res.
1995, 328, 737–738.
2,3,7-Tris(acetoxy)-9-methoxy-6-oxo-6H-benzo[c]chromen-6-one
(30): Compound 12 (15 mg, 55 μmol) was dissolved in anhydrous
pyridine (0.5 mL) under an atmosphere of argon. Ac2O (45 mg,
440 μmol) was added, and the mixture was stirred for 24 h at room
temperature. The mixture was then poured into 1 m HCl (10 mL)
and extracted with EtOAc (4ϫ 10 mL). The combined organic lay-
ers were dried (Na2SO4) and concentrated. The residue was purified
by recrystallization (THF/hexanes) to yield triacetate 30 (20 mg,
50 μmol, 91%) as a colorless solid. M.p. 234–236 °C; Rf = 0.27
(hexanes/EtOAc, 1:1), 1H NMR (500 MHz, [D8]THF): δ = 8.04 (s,
1 H, 1-H), 7.54 (d, 4J = 2.4 Hz, 1 H, 10-H), 7.24 (s, 1 H, 4-H), 6.86
4
(d, J = 2.4 Hz, 1 H, 8-H), 3.97 (s, 3 H, OMe), 2.31 (s, 3 H, OAc),
2.28 (s, 3 H, OAc), 2.26 (s, 3 H, OAc) ppm. 13C NMR (125 MHz,
[D8]THF): δ = 169.1 (C), 168.4 (C), 167.9 (C), 166.3 (C), 157.0 (C),
156.0 (C), 150.3 (C), 145.5 (C), 140.2 (C), 138.6 (C), 119.1 (CH),
116.7 (C), 113.1 (CH), 112.1 (CH), 108.1 (C), 105.1 (CH), 56.6
(CH ), 21.0 (CH ), 20.4 (CH ), 20.2 (CH ) ppm. IR (DRIFT): ν =
˜
3
3
3
3
[20] J. H. Schrittwieser, V. Resch, S. Wallner, W.-D. Lienhart, J. H.
Sattler, J. Resch, P. Macheroux, W. Kroutil, J. Org. Chem. 2011,
76, 6703–6714.
[21] E. S. C. Pôças, D. V. S. Lopes, A. J. M. da Silva, P. H. C. Pi-
menta, F. B. Leitão, C. D. Netto, C. D. Buarque, F. V. Brito,
3079, 1762, 1730, 1617, 1274, 1191, 1166, 1135, 1054, 1031, 1008,
897, 801 cm–1. MS (EI): m/z (%) = 400 (24) [M]+, 358 (47), 316
(77), 274 (100), 175 (23). HRMS (EI): calcd. for C20H16O9
400.0794; found 400.0786.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Job/Unit: O20506
/KAP1
Date: 31-05-12 17:21:41
Pages: 9
G. Nemecek, J. Cudaj, J. Podlech
FULL PAPER
P. R. R. Costa, F. Noël, Bioorg. Med. Chem. 2006, 14, 7962–
7966.
[22] S. P. H. Mee, V. Lee, J. E. Baldwin, A. Cowley, Tetrahedron
2004, 60, 3695–3712.
[23] J. Cudaj, J. Podlech, Tetrahedron Lett. 2010, 51, 3092–3094.
[24]
W. C. Still, M. Kahn, A. Mitra, J. Org. Chem. 1978, 43, 2923–
2925.
Received: April 18, 2012
Published Online: ᭿
8
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20506
/KAP1
Date: 31-05-12 17:21:41
Pages: 9
Revision of the Structure and Total Synthesis of Altenuisol
Alternaria Toxins
G. Nemecek, J. Cudaj, J. Podlech* ... 1–9
Revision of the Structure and Total Syn-
thesis of Altenuisol
Keywords: Mycotoxins
Lactones Total synthesis
elucidation
/
Polyketides
/
Total synthesis of altenuisol, a minor toxin
in ubiquitous Alternaria spp. revealed that
the originally proposed structure was not
correct. Altenuisol was proved to have an
isomeric structure by total synthesis.
/
/
Structure
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