Synthesis of the altertoxin III framework

Article abstract of DOI:10.1016/j.tet.2013.03.013

The framework of altertoxin III, a mycotoxin produced by Alternaria fungi investing food and feed, has been synthesised for the first time. Synthetic schemes including Diels-Alder reactions of anthracene derivatives turned out to be not successful due to

Full text of DOI:10.1016/j.tet.2013.03.013

Tetrahedron 69 (2013) 3683e3689
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of the altertoxin III framework
Oliver Geiseler, Monika M u€ ller, Joachim Podlech *
Institut f u€ r Organische Chemie, Karlsruher Institut f u€ r Technologie (KIT), Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
The framework of altertoxin III, a mycotoxin produced by Alternaria fungi investing food and feed, has
been synthesised for the first time. Synthetic schemes including DielseAlder reactions of anthracene
derivatives turned out to be not successful due to an aromatisation of key intermediates. This aroma-
tisation was further investigated by DFT calculations, which showed that the aromatisation tendency is
dependant from the electronic characteristics of attached substituents. A FriedeleCrafts-type hafnium
triflate-catalysed dimerisation of dihydroxytetralins with subsequent benzylic oxidation furnished the
target compound, which should be a suitable precursor for the synthesis of altertoxin III and related
natural products.
Received 10 January 2013
Accepted 4 March 2013
Available online 13 March 2013
Keywords:
Total synthesis
Mycotoxins
FriedeleCrafts acylation
DielseAlder reaction
Perylene quinones
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
Altertoxins IeIII (ATX IeIII), mycotoxins1 produced by ubiqui-
tous Alternaria sp. investing food and feed, are derivatives of per-
ylene quinone. Altertoxins I and II are oxygenated derivatives of
framework A and altertoxin III is derived from framework B (Fig. 1),
where frameworks A and B are hexahydroperylene quinones.
2
Further similar compounds are the alterlosins I and II, altei-
chin,3 the stemphyltoxins IeIV,
4,5
stemphyperylenol
3,4,6
and
stemphytriol. Altertoxins IeIII are mutagenic and phytotoxic,3
6a
7
altertoxin I is furthermore antifungal and antibacterial and shows
8
3
toxicity against HeLa cells. Alteichin is phytotoxic and antifungal
9
and was identified to be a human telomerase inhibitor; alterlosins
I and II are phytotoxic. Stemphyltoxins I, III, IV and stemphyper-
ylenol were isolated from Stemphylium botryosum,
phyltoxin III furthermore from Alternaria alternata. Stemphyltoxin
II turned out to be identical with altertoxin II. Altertoxin III, alter-
losin II and stemphyperylenol are derivatives of framework B, while
the other perylene quinone-derived toxins are related to frame-
work A.
2
4
a,10
stem-
10
While total syntheses of similar compounds with intact per-
1
1
12e14
ylene quinone framework,
like the calphostins,
cerco-
sporin,13 hypocrellin A and pleichrom,
15
12,14
and of Alternaria toxins
16
with resorcylic lactone structure have been published, no total
syntheses of natural products with framework A or B have been
reported. In this manuscript, we report on our efforts towards the
synthesis of natural products derived from framework B. The only
*
Corresponding author. Tel.: þ49 721 608 43209; fax: þ49 721 608 47652; e-mail
Fig. 1. Perylene quinone-derived natural products (selection) and the parent ring
systems.
address: joachim.podlech@kit.edu (J. Podlech).
0
040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.03.013

3684
O. Geiseler et al. / Tetrahedron 69 (2013) 3683e3689
prior efforts in this direction were not successful, and seem to have
not been continued.17
2
. Retrosynthesis
The altertoxins and the related compounds are not stable
against elimination of water with formation of fully aromatic
compounds.7 This should be similarly true for possible in-
termediates in a total synthesis of these. A further problem is the
flat structure of these natural products and especially of synthetic
precursors, resulting in a putative poor solubility due to aggrega-
tion phenomena. Consequently, we planned a synthetic strategy
with mild reaction steps hopefully avoiding eliminations and
aromatisations (key intermediates are given in Scheme 1). A ret-
rosynthetic analysis includes a DielseAlder addition to 2,6-
dihydroxyanthracene 2a (or a protected derivative, e.g., 2b) with
subsequent degradation to a dialdehyde 4. Olefination and elec-
trophilic acylation should lead to an intermediate 6, which can be
used for the synthesis of natural products derived from framework
B, e.g., altertoxin III.17 An alternative approach would start with
c
Fig. 2. Dienophiles for DielseAlder reaction and adducts from anthracenes.
20
the dimethoxyanthracene 2b could be synthesised with 95% yield.
21
22
PSNE (11) is an electron-deficient dienophile, where the sulfonyl
and the nitro groups have been degradated in similar reactions
with formation of a double bond. Addition of PSNE to unprotected
anthracene-2,6-diol (2a) in a mixture of toluene and acetone at
(
protected) 1,5-dihydroxytetralin 8, which would upon oxidative
dimerisation and oxidation furnish framework B. Dehydrogenation
and epoxidation would similarly supply altertoxin III.
Scheme 1. Retrosynthetic analysis for natural products derived from framework B.
3
. The anthracene route
elevated temperature could be achieved with 59% yield, but a sub-
sequent radicalic degradation with tributyl tinhydride and a radical
starter (AIBN) towards the etheno derivative 17 turned out to be not
successful in our hands. The addition of DMAD (12) to unprotected
2,6-dihydroxyanthracene 1a yielded the corresponding DielseAlder
A suitable intermediate for the synthesis of framework B, the
ethenoanthracene 17, would arise from a DielseAlder cycloaddition
of acetylene to the respective anthracene, but is actually not pos-
sible with unsubstituted acetylene. Various DielseAlder adducts
from anthracenes can be transformed into ethenoanthracenes
2
3
adduct 16, which was decarboxylated to alkene 17 by saponifica-
2
4
tion and subsequent thermal degradation (Scheme 2). Oxidative
cleavage of the double bond was tested with various reaction con-
(
Fig. 2),18 which were expected to be cleavable into the respective
2
5
dialdehydes. We tested the addition of (E)-1-nitro-2-(phenyl-
sulfonyl)ethene (PSNE, 11), of dimethyl acetylene dicarboxylate
ditions, but a fully aromatic product was obtained in all cases.
Ozonolysis with subsequent addition of dimethyl sulfide led to the
2,6-dihydroxyanthracene-9,10-dicarbaldehyde 20a, while reductive
workup with sodium borohydrate led to the non-aromatised bis(h-
ydroxymethyl) derivative 18 with poor yield (20%). This compound
aromatised within few hours with formation of diol 19 and turned
out to be not suitable for further reactions. Nevertheless, these
(
DMAD, 12) and of vinylene carbonate (13).
Suitable diene precursors for a DielseAlder reaction were acces-
sible by reduction of anthraflavic acid (2,6-dihydroxyanthraquinone,
a) and its O,O-dimethyl derivative 1b, respectively, with sodium
1
19
borohydrate. Anthracene-2,6-diol (2a) was obtained with 86%, and

O. Geiseler et al. / Tetrahedron 69 (2013) 3683e3689
3685
23. Meinwald rearrangement of the respective anthracene (without
methoxy groups) derivative in the presence of boron trifluoride
diethyl etherate as Lewis acid was reported to lead to a dia-
31
ldehyde. When we applied this method to the dimethoxy de-
rivative 23, the fully aromatic compound 22b was obtained. These
intermediates seem to be similarly unstable as the natural prod-
ucts. Already Stack et al. noted that ATX III tends to the formation of
fully aromatic substrates; a DMSO solution of ATX II is turning
7
c
purple, when oxygen is not strictly excluded.
Scheme 4. Rearrangement of a bis(epoxide). a Me
quant.).
3 3 2
SI, NaH, DMSO (91%); b F B$OEt
(
DFT calculations showed that anthracene derivative 22 is not
necessarily more stable than the isomeric dibenzo derivative 4
Fig. 3). While the dimethoxy derivative 22b is more stable than
(
isomer 4b by 3.8 kJ/mol, the stabilities of these compounds are
successively inverted with more electron-withdrawing sub-
stituents. The dinitro and the bis(trifluoroacetyl) derivatives 4e and
4
f are 2.1 and 3.1 kJ/mol more stable than the respective anthracene
Scheme 2. Attempted synthesis of
a NaBH , Na CO ; b DMAD, dioxane, acetone,
O, , 4 h; d Cu, quinoline, 230 C, 1 h (41%, two steps); e O
then NaBH (20%); f fast aromatisation within few hours.
a 9,10-dihydroanthracene-9,10-dicarbaldehyde.
derivatives 22e and 22f. A trifluoroacetyl group can putatively be
converted into a hydroxy substituent by a Dakin reaction, though
we are not very confident, that the reaction conditions necessary
4
2
3
D (24e31%, two steps); c NaOH, MeOH/
3
2
ꢀ
, ꢁ78 ꢀC,
H
2
D
3 2 2
, MeOH, CH Cl
4
2 2
for this transformation (NaOH, H O ) would be compatible with the
functional groups present in molecules like ATX III.
aromatised compounds might be suitable precursors for, e.g., the
2
6
27
synthesis of antitumour agents and of fluorescent sensors.
A ring-opening metathesis of 17 with methyl acrylate in the
2
8
presence of the GrubbseHoveyda catalyst was not successful and
an ozonolysis of the diester 16 could not be achieved neither.
2
6
The addition of vinylene carbonate (13)
to 2,6-
dimethoxyanthracene (2b) yielded adduct 15 (38%), which was
saponified quantitatively to a diol 21 (Scheme 3). Oxidative cleav-
age using sodium periodate or lead tetraacetate did not deliver
the dialdehyde 4b but quantitatively furnished a fully aromatic
10-(hydroxymethyl)-anthracene-9-carbaldehyde 22b.
2
Fig. 3. Relative calculated energies of isomers 4 and 22 (B3LYP/6-31G**; cpcm, H O//
B3LYP/6-311G**).
The general tendency of these intermediates towards aromati-
sation tempted us to consider an alternative approach with oxi-
dative dimerisation of 1,5-dihydroxytetralins.
4. The tetralin route
For this route we started with methoxytetralone (7b), which
was reduced with sodium borohydrate with quantitative yield
Scheme 5). The resulting alcohol 8b has been dimerised by Negrete
et al. with catalytic amounts of toluenesulfonic acid obtaining 9b
(
3
3
with 9% yield. We tested hafnium triflate, which has been found
3
4
to be a very efficient catalyst in FriedeleCrafts reactions, and
obtained the dimerisation product 9b with 60% yield, even when
catalytic amounts of the Lewis acid were applied. The product
turned out to be hardly soluble in all common solvents. Hexyloxy
groups in 9c were expected to lead to an increased solubility.
Alkylation of 5-hydroxytetralone (7a) with hexyl bromide and
potassium carbonate was achieved with quantitative yield and the
further sequence to the previously unknown dimer 9c with better
solubility was accomplished accordingly.
Scheme 3. Attempted synthesis via a diol. a; b NaBH
carbonate, toluene, 200 C, 5 bar (autoclave), 8 days (38%); d 4 N NaOH, dioxane (72%);
e NaIO or Pb(OAc) , quantitative formation of 22b.
4 4
4
, then HCl (95%);29 c vinylene
ꢀ
In an alternative approach we started with dimethylated
anthraflavic acid 1b and prepared a bis(epoxide) 23 using a Cor-
3
0
eyeChaykovsky reaction (Scheme 4). Reaction of the carbonyl
functions with a sulfur ylide prepared by deprotonation of trime-
thylsulfonium iodide with sodium hydride furnished bis(epoxide)

3686
O. Geiseler et al. / Tetrahedron 69 (2013) 3683e3689
5.3. The anthracene route
5
5
.3.1. Anthracene-2,6-diol (2a). Anthraflavic acid (1a, 12.0 g,
0.0 mmol) was added in five portions to a suspension of Na CO
(28.4 g, 750 mmol) in H O (600 mL)
2
3
(63.6 g, 600 mmol) and NaBH
4
2
and the mixture was stirred at rt over night, poured on ice-cold 6 N
HCl (50 mL), which was covered with a layer of EtOAc (50 mL). The
aqueous layer was extracted with EtOAc (3ꢂ30 mL) and the com-
3
bined organic layers were washed with satd NaHCO soln (50 mL),
2 4
dried (Na SO ) and concentrated to yield crude 2a (0.338 g), which
Scheme 5. Dimerisation of tetralin derivatives. a R¼Hexyl: HexylBr, K
4 h (99%); b NaBH
, EtOH, rt, (R¼Me: quant.; R¼Hexyl: 92%); c Hf(OTf)
MeCN, rt, 10e30 min (R¼Me: 59%; R¼Hexyl: 60%).
2
CO
3
, acetone, rt,
(5e7 mol %),
was used without purification. Spectroscopic data are in full
1
4
4
19
agreement with published data.
5
.3.2. trans-9,10-Dihydro-2,6-dihydroxy-9,10-ethano-12-nitro-11-
Benzylic oxidation of methyl-protected pentacycle 9b was ach-
ieved with chromium(VI) oxide in the presence of acidic acid,
yielding the diketone 10b with 84% yield (Scheme 6). Other oxi-
3
5
phenylsulfonylanthracene (14). Anthracene 2a (0.210 g, 1.00 mmol)
and PSNE (11, 0.213 g, 1.00 mmol) were dissolved in a mixture of
toluene (5 mL) and acetone (2 mL acetone), heated for 3 h with
reflux and concentrated to yield a crude product (0.491 g), which
was purified by column chromatography (silica gel, cyclohexane/
dation methods based on tert-butyl hydroperoxide turned out to be
not successful.36 The poor solubility of 9b in diluted acidic acid was
obviously sufficient for a clean, albeit slow reaction. Nevertheless,
no reaction was observed, when hexyl-protected compound 9c was
subjected to these reaction condition.
EtOAc, 5:1/1:1) to yield 14 as a brownish foam (0.316 mg,
ꢀ
0
1
5
.746 mmol, 75%). Mp: 148e154 C. R
f
¼0.5 (cyclohexane/EtOAc,
(ppm)¼4.21 (ddd, J¼2.2, 5.0,
.2 Hz, 1H), 4.70 (m, 1H), 4.90 (dd, J¼2.8, 14.0 Hz, 1H), 5.17 (ddd,
1
3
:2). H NMR (400 MHz, CDCl ): d
J¼3.0, 4.7, 7.6 Hz, 1H), 6.42e6.53 (m, 2H), 6.64e6.89 (m, 2H),
.39e7.20 (m, 2H), 7.47e7.55 (m, 2H, HAr), 7.59e7.66 (m, 1H, HAr),
7
13
7
(
1
1
.75e7.82 (m, 2H, HAr). C NMR (100 MHz, CDCl
CH), 44.9 (CH), 50.6 (CH), 50.7 (CH), 68.9 (CH), 69.2 (CH), 87.6 (CH),
26.8 (CH), 127.5 (CH), 128.3 (CH), 128.6 (CH), 130.5 (CH), 131.5 (CH),
33.6 (C), 136.2 (CH), 136.5 (CH), 140.6 (C), 140.6 (C), 141.8 (C), 142.1
C), 143.0 (C), 145.0 (C).
3
): d (ppm) 31.3
(
ꢀ
Scheme 6. Oxidation to framework B. a CrO
3
, HOAc/H
2
O, 0 C, 48 h (84%).
5.3.3. Dimethyl 9,10-dihydro-2,6-dihydroxy-9,10-ethenoanthracene-
1
1,12-dicarboxylate (16). Crude anthracene 2a (12.0 g, 50.0 mmol)
With this, the first synthesis of framework B, the skeleton
of altertoxin III and related perylene quinone mycotoxins, was
achieved. Further work aiming for the total synthesis of these
compounds is currently ongoing in our laboratories.
and DMAD (12, 30.6 mL, 250.0 mmol) were dissolved in dioxane/
acetone (2:1, 300 mL) and the mixture was heated with reflux for
14 days and concentrated. The residue was purified by column
chromatography (silica gel, cyclohexane/EtOAc, 5:1/2:1) to yield
ꢀ
1
6 (12.8 g, 36.2 mmol, 72%) as a yellowish solid. Mp: 95e103 C.
5
5
. Experimental and calculations
.1. General
ꢁ1
R
1
f
¼0.68 (cyclohexane/EtOAc, 1:1). IR (DRIFT): ~
697 (s), 1613 (m), 1435 (s), 1214 (s), 1131 (s), 1057 (m). H NMR
400 MHz, CDCl ): ), 5.44 (s, 2H, H-9), 6.49
(ppm)¼3.74 (s, 6H, CH
n
¼3365 (br) cm
,
1
(
(
3
d
3
3
3
dd, 2H, J¼7.9, 2.4 Hz, H-3), 7.02 (d, 2H, J¼2.4 Hz, H-1), 7.25 (d, 2H,
Abbreviations: AIBN, azobis(isobutyronitrile); ATX, altertoxin;
3
13
J¼7.9 Hz, H-4), 8.32 (s, 2H, OH). C NMR (100 MHz, CDCl
3
):
DMAD, dimethyl acetylene dicarboxylate; PSNE, (E)-1-nitro-2-
phenylsulfonyl)ethene. Anhydrous solvents were used as pur-
chased. All moisture-sensitive reactions were carried out under
oxygen-free argon or N using oven-dried glassware and a vacuum
d
(ppm)¼53.2 (CH), 53.5 (CH
3
), 112.3 (CH), 113.6 (CH), 126.0 (CH),
(
ꢀ
36.8 (C), 148.4 (C), 149.2 (C), 156.8 (C), 187.6 (C). MS (EI, 150 C):
1
þ
þ
þ
m/z (%)¼353 (16) [(Mþ1) ], 352 (86) [M ], 294 (18) ½C18H14O4 ꢃ;
þ
þ
4
2
2
2
93 (100) ½C
H
13
O
ꢃ; 292 (99) ½C
H
O
ꢃ; 272 (14), 265 (17),
1
8
4
18 12
37
line. Flash column chromatography was carried out using Merck
silica gel 60 (230e400 mesh) and thin layer chromatography (TLC)
was carried out using commercially available Merck F254 pre-coated
þ
61 (21), 249 (15), 241 (15), 235 (18) ½C
H
O
2
ꢃ; 234 (67)
1
6
11
þ
þ
O
2
þ
½
C
H
10
O
ꢃ; 233 (15), 210 (49) ½C
H
ꢃ; 205 (30) ½C16H13 ꢃ;
1
6
2
14 10
181 (32), 177 (13), 167 (15), 166 (19), 152 (11), 89 (17).
1
13
sheets. H and C NMR spectra were recorded on a Bruker Cryospek
WM-250, an AM-400 or a DRX 500. Chemical shifts are given in
5
.3.4. 9,10-Dihydro-2,6-dihydroxy-9,10-ethenoanthracene-11,12-
13
parts per million downfield of tetramethylsilane. C NMR spectra
were recorded with broad band proton decoupling and were
assigned using DEPT 135 and DEPT 90 experiments. Melting points
were measured on a B u€ chi apparatus. IR spectra were recorded on
a Bruker IFS-88 spectrometer. Electrical ionisation and high reso-
lution mass spectra were recorded on a Finnigan MAT-90.
dicarboxylic acid (17). Diester 16 (0.164 g, 0.460 mmol) was added
to a soln of NaOH (0.280 g, 7.00 mmol) in MeOH/H O (2:3, 5 mL)
and the mixture was heated for 4 h with reflux. It was cooled to rt,
2
brought to pH 2 with concd HCl and extracted with EtOAc
(
4ꢂ20 mL). The combined organic layers were washed with aq
NaHCO soln (20 mL) and brine, dried (Na SO ) and concentrated to
3
2
4
yield the crude dicarboxylate. It was mixed with freshly distilled
5
.2. Calculations
quinoline (5 mL) and Cu powder (0.127 g, 2 mmol) and heated to
ꢀ
230 C until the evolution of gas ceased (w45 min). After cooling to
All structures were fully optimised at the B3LYP38/6-31G (d,p)39
rt, 10% HCl (5 mL) was added and the mixture was extracted with
a mixture of EtOAc and acetone. Column chromatography (silica
4
0
level using the Gaussian 03 program package. Energies were
calculated by single point calculations at the B3LYP/6-311G (d,p)
level, where water as a virtual solvent was modelled with the
41
gel, cyclohexane/EtOAc, 7:1) yielded 17 (0.022 g, 931
a slightly brownish solid. R
¼0.68 (cyclohexane/EtOAc, 1:1).
NMR (400 MHz, CDCl ):
(ppm)¼5.00 (dd, J¼4.3, 3.2 Hz, 2H, H-9,
mmol, 20%) as
1
f
H
42
CPCM-SCRF method.
3
d

O. Geiseler et al. / Tetrahedron 69 (2013) 3683e3689
3687
H-10), 6.38 (dd, J¼7.8, 2.4 Hz, 2H, H-3, H-7), 6.86 (d, J¼2.4 Hz, 2H,
H-1, H-5), 6.94 (dd, J¼4.3, 3.2 Hz, 2H, H-11, H-12), 7.06 (d, J¼7.8 Hz,
(m, 2H, Har), 6.93 (d, J¼2.2 Hz, 2H, Har), 7.13e7.29 (m, 2H, Har). MS
þ
(FAB): m/z (%)¼325 (100) [(MþH) ], 238 (81), 136 (96).
13
2
3
H, H-4, H-8), 8.05 (s, 2H, OH). C NMR (100 MHz, CDCl ):
d
(ppm)¼52.1 (CH),111.1 (CH),113.0 (CH),124.9 (CH),139.4 (C),141.3
5.3.9. 2,6-Dimethoxy-9,10-dihydro-9,10-ethanoanthracene-11,12-
diol (21). 4 M NaOH (10 mL) was added to a soln of 15 (458 mg,
(
CH), 150.7 (C), 156.1 (C).
1.41 mmol) in dioxane (20 mL) and the mixture was heated to
5
.3.5. 9,10-Bis(hydroxymethyl)-9,10-dihydroanthracene-2,6-diol
reflux for 2 h. The mixture was cooled to rt, extracted with CHCl
(4ꢂ50 mL), dried (Na SO
foam (421 mg, 1.41 mmol, quant.). IR (DRIFT): ~
3
ꢀ
(
1
18). Ozone was passed for 3 min through a cooled (ꢁ78 C) soln of
2
4
) and concentrated to yield 21 as a yellow
ꢁ
1
7 (47.3 mg, 0.200 mmol) in MeOH (5 mL). The solution was purged
n
¼ 3378 cm
;
for 15 min with oxygen, NaBH (151 mg, 4.00 mmol) was added,
stirring was continued for 1 h, 10% HCl was added and the mixture
4
2997, 2942, 2833, 2055, 1868, 1749, 1615, 1584, 1480, 1283, 1245,
1220, 1181, 1141, 1118, 1067, 1033, 1009, 939, 873, 823, 803, 757,
1
was extracted with EtOAc (3ꢂ20 mL). The combined organic layers
725, 699, 667, 599, 542, 511, 482, 440, 419. H NMR (250 MHz,
were washed with NaHCO
3
soln (15 mL), dried (Na
2
SO
4
),
CDCl
3
):
d
¼2.68 (br, 2H, 2ꢂ OH), 3.76 (s, 6H, 2ꢂ OMe), 3.98 (m, 2ꢂ
concentrated and purified by column chromatography (silica gel,
CH
0
CH), 4.27 (d, J¼4.7 Hz, 2H, 2ꢂ CH), 6.64e6.72 (m, 2H, Har), 6.91 (dd,
13
2
Cl
2
/MeOH, 10:1) to yield 18 as a colourless solid (41.9 mg,
J¼2.4, 15.7 Hz, 2H, Har), 7.18e7.26 (m, 2H, Har). C NMR (100 MHz,
CDCl ): ), 55.4 (OCH ), 68.1 (CH),
ꢀ
.55 mmol, 78%). Mp: 145e152 C. R
f
¼0.28 (CH
2
Cl
2
/MeOH, 10:1). IR
3
d¼50.7 (CH), 50.8 (CH), 55.3 (OCH
3
3
ꢁ1
(
DRIFT): ~
n
¼3254 cm (br), 1610 (m), 1350 (s), 1228 (m), 1148 (w),
68.3 (CH), 111.0 (CH), 111.3 (CH), 112.9 (CH), 125.5 (CH), 127.1 (CH),
129.7 (C), 130.2 (C), 131.8 (C), 140.6 (C), 141.8 (C), 158.6 (C), 158.6
1
1125 (w), 1043 (s). H NMR (400 MHz, CDCl
3
):
d
(ppm)¼3.70 (m, 4H,
þ
H-11), 3.92 (t, 2H, J¼6.6 Hz, H-10), 4.14 (m, 2H, OH), 6.70 (dd, 2H,
J¼8.2, 2.6 Hz, H-3), 6.85 (d, 2H, J¼2.5 Hz, H-1), 7.18 (d, 2H, J¼8.3 Hz,
(C). MS (EI): m/z (%)¼298 (4) [M ], 238 (94), 195 (58), 152 (45), 43
þ
1
2
1
16
(100). HRMS ð
C
H
O
4
; EIÞ: calcd 298.1205 amu; found
1
8
18
13
H-4), 8.31 (s, 2H, OH). C NMR (100 MHz, CDCl
3
):
d
(ppm)¼49.8
298.1204.
(
(
2
CH), 72.1 (CH ), 115.5 (CH), 117.3 (CH), 129.5 (C), 131.8 (CH), 140.3
C), 157.5 (C). MS (EI, 70 C): m/z (%)¼270 (100) [M ], 256 (24)
ꢀ
þ
þ
0
0
0
00
5.3.10. 2,6-Dimethoxydispiro[oxirane-2,9 (10 H)-anthracene-10 ,2 -
oxirane] (23). NaH (50% in petroleum, 217 mg, 4.53 mmol) was
added under Ar and with exclusion of light within 5 min to a sus-
pension of anthraquinone 1b (540 mg, 2.01 mmol) in anhyd DMSO
þ
þ
½
C16H16
O
ꢃ; 242 (26) ½C
H
O
2
ꢃ; 194 (26) ½C
H
15 14
ꢃ; 192 (24)
4
16 18
þ
þ
½
C15H12 ꢃ; 177 (21),166 (16),155 (57),150 (22) [C10
H14O ],138 (38),
þ
1
39 (62), 134 (66) ½C
H
14
ꢃ; 132 (25), 110 (31), 108 (45), 106 (36).
10
3
(15 mL). A soln of Me SI (924 mg, 4.53 mmol) in anhyd DMSO
5
5
.3.6. 2,6-Dimethoxyanthracene-9,10-dione (1b). Me
2.0 g, 408 mmol) was added within 5 min to a suspension of
CO (36.7 g,
65 mmol) in anhyd acetone (200 mL) and the mixture was heated
2
SO
4
(39.0 mL,
(10 mL) was added within 30 min and the mixture was filtered
through sintered glass and poured on ice. After standing for 30 min
a fluffy yellow solid precipitated, which was separated by filtration,
anthraflavic acid (1a, 5.45 g, 20.4 mmol) and K
2
to reflux for 8 h and cooled to rt. H
2
3
thoroughly rinsed with H O (6ꢂ50 mL), dissolved in CH
2
2 2
Cl
2
O (200 mL) was added and
(3ꢂ100 mL), dried (Na
2
SO ) and concentrated to yield 23 as an
4
stirring was continued for 2 h. The aqueous layer was extracted
with CHCl
(5ꢂ150 mL). The organic layers were washed with H
2ꢂ50 mL), dried (Na SO ), concentrated and recrystallised from
toluene to yield 1b as yellow needles (4.33 g, 16.1 mmol, 79%).
orange solid (542 mg, 1.83 mmol, 91%). Due to the instability of
3
2
O
the compound, it was immediately reacted without extensive de-
1
(
2
4
termination of spectroscopic data. H NMR (250 MHz, CDCl
3
):
d
¼3.21 (d, J¼1.7 Hz, 4H, 2ꢂ CH
2
), 3.82 (s, 6H, 2ꢂ CH
3
), 6.89e6.93
2
9 1
Spectroscopic data are in full agreement with published data.
NMR (300 MHz, CDCl ):
H, Har), 7.73 (s, 2H, Har), 8.24 (d, J¼8.7 Hz, 2H, Har).
H
(m, 4H, Har), 7.26e7.30 (m, 2H, Har).
3
d¼3.99 (s, 6H, 2ꢂ OMe), 7.24 (d, J¼8.7 Hz,
2
5.3.11. 10-(Hydroxymethyl)-2,6,dimethoxyanthracene-9-
carbaldehyde (22b). Method A: NaIO (25.1 mg, 117 mol) was
added to a suspension of diol 21 (73, 35.0 mg, 117 mol) in a mix-
ture of EtOH (500 L) and H O (10 mL). After stirring at rt for 2 h
a fluffy red solid precipitated. The mixture was extracted with
CHCl SO ) and concentrated to yield 22b as
(3ꢂ25 mL), dried (Na
a red solid (34.7 mg, 117 mol, quant.).
Method B: F B$OEt (46% soln, 100
an ice-cooled suspension of K CO (500 mg, 3.62 mmol) in anhyd
Et O (10 mL). The mixture was stirred for 5 min, a soln of 23 (50 mg,
169
continued for 15 min. Satd aq NaHCO
the organic layer was dried (Na SO ) and concentrated to yield 22b
as red solid (50 mg, 169 mol, quant.). IR (DRIFT):
4
m
5.3.7. 2,6-Dimethoxyanthracene (2b). NaBH (1.89 g, 49.8 mmol)
4
m
was added under Ar portionwise within 15 min to a soln of an-
thraquinone 1b (1.34 g, 4.98 mmol) in anhyd i-PrOH (70 mL). The
m
2
ꢀ
mixture was heated to reflux over night, cooled to ꢁ15 C, and the
3
2
4
excess NaBH
4
was hydrolysed by careful addition of 1 M HCl until
m
evolution of gas ceased. The mixture was extracted with hot CHCl
3ꢂ100 mL) and the organic layers were dried (Na SO ) and con-
centrated to yield 2b as a yellow solid (1.13 g, 4.74 mmol, 95%).
Spectroscopic data are in full agreement with published data.20 1
NMR (250 MHz, CDCl ):
¼3.96 (s, 6H, 2ꢂ OMe), 7.12e7.18 (m, 4H,
ar), 7.84 (d, J¼8.9 Hz, 2H, Har), 8.20 (s, 2H, Har).
3
3
2
mL, 363 mmol) was added to
(
2
4
2
3
2
ꢀ
H
mmol) in anhyd Et
2
O (10 mL) was added and stirring at 0 C was
soln (5 mL) was added and
3
d
3
H
2
4
a
m
ꢁ
1
5
.3.8. 2,6-Dimethoxy-9,10,11,15-tetrahydro-9,10-[4,5]epidioxoloan-
~
n
¼ 3487 cm ; 3051, 2913, 2845, 2632, 2432, 2046, 1912, 1669,
thracene-13-one (15). A soln of anthracene 2b (976 mg, 4.10 mmol)
and vinylene carbonate (13, 705 mg, 8.19 mmol) in anhyd toluene
1620, 1570, 1496, 1479, 1436, 1328, 1282, 1218, 1173, 1075, 1017, 989,
1
922, 881, 827, 784, 719, 679, 631, 580, 548, 526, 457, 436, 418. H
(
2
50 mL) under Ar (5 bar) was heated in an autoclave for 8 days at
00 C. The solution was concentrated and purified by column
NMR (250 MHz, DMSO-d
6
):
d
¼3.95 (s, 3H, OMe), 3.96 (s, 3H, OMe),
ꢀ
5.36 (d, J¼5.2 Hz, 2H, CH ), 5.56 (t, J¼5.2 Hz, 1H, OH), 7.30 (dd,
2
chromatography (silica gel, hexane/EtOAc, 10:1/1:1) to yield 15 as
a slightly yellow solid (505 mg, 1.56 mmol, 38%). Due to the in-
stability of the compound, it was immediately reacted without
comprehensive determination of spectroscopic data. IR (DRIFT):
J¼9.6, 2.4 Hz, 1H, Har), 7.37 (dd, J¼9.6, 2.3 Hz, 1H, Har), 7.71 (d,
J¼2.4 Hz, 1H, Har), 8.31 (d, J¼2.4 Hz, 1H, Har), 8.43 (d, J¼9.6 Hz, 1H,
13
H
ar), 8.90 (d, J¼9.6 Hz, 1H, Har), 11.3 (s, 1H, CHO). C NMR (63 MHz,
DMSO-d
6
):
d
¼55.1 (CH
3 3 2
), 55.3 (CH ), 55.9 (CH ), 100.3 (CH), 102.5
ꢁ1
~
n
¼ 3558 cm ; 2976, 2837, 2248, 1977, 1852, 1789, 1620, 1584,
484, 1445, 1364, 1335, 1317, 1289, 1266, 1244, 1215, 1165, 1116,
077, 1053, 1022, 933, 905, 838, 795, 765, 733, 677, 651, 605, 571,
(CH), 120.3 (CH), 122.5 (CH), 123.0 (CH), 125.0 (CH), 126.4 (C), 127.3
(C), 128.3 (C), 129.4 (C), 131.5 (C), 139.6 (C), 156.0 (C), 158.5 (C), 194.3
1
1
5
þ
(CHO). MS (EI): m/z (%)¼296 (66) [M ], 283 (62), 217 (49), 136 (95),
1
12
1
16
þ
40, 475, 434, 411. H NMR (250 MHz, CDCl
3
):
d¼3.78 (s, 6H, 2ꢂ
81 (100). HRMS ð
C
H
O
4
; EIÞ: calcd 296.1049 amu; found
1
8
16
OMe), 4.57 (br, 2H, 2ꢂ CH), 4.85e4.86 (m, 2H, 2ꢂ CH), 6.71e6.78
296.1050.

3688
O. Geiseler et al. / Tetrahedron 69 (2013) 3683e3689
5
.4. The tetralone route
3.85 (s, 6H, 2OMe), 6.84 (d, J¼8.5 Hz, 2H,
d, J¼8.5 Hz, 2Har).
Har), 7.27
(
5.4.1. 5-Methoxy-1,2,3,4-tetrahydronaphthalen-1-ol
(8b). NaBH
4
(
859 mg, 22.7 mmol) and tetralone 7b (1.00 g, 5.67 mmol) were
suspended in anhyd EtOH (20 mL) and stirred at rt for 14 h. After
careful hydrolysation of the excess NaBH with 1 M HCl, the re-
action mixture was extracted with CH Cl
(3ꢂ50 mL), dried
) and concentrated to yield 8b as a yellowish solid (1.01 g,
.67 mmol, quant.). Spectroscopic data are in full agreement with
5.4.5. 4,10-Bis(hexyloxy)-1,2,3,6b,7,8,9,12b-octahydroperylene
(9c). Alcohol 8c (652 mg, 2.62 mmol) was dissolved in anhyd MeCN
4
(5 mL) under Ar atmosphere and Hf(OTf)
4
(5 mol %, 102 mg,
2
2
131 mol) was added. The colourless solution turned bright yellow
m
(
Na
2
SO
4
and a fluffy solid precipitated. After 10 min, the solid was removed
by filtration and washed excessively with MeCN (at least 3ꢂ10 mL).
5
33 1
published data.
H NMR (300 MHz, CDCl
3
):
d¼1.72e1.98 (m, 5H),
Pentacycle 9c was obtained as a yellow solid (361 mg, 784 mmol,
ꢁ
1
2
(
7
.49e2.60 (m, 1H), 2.72e2.81 (m, 1H), 3.83 (s, 3H, OMe), 4.77
br, 1H, OH), 6.76 (d, J¼7.8 Hz, 1H, Har), 7.06 (d, J¼7.8 Hz, 1H, Har),
.20 (t, J¼7.8 Hz, 1H, Har).
60%). IR (ATR): ~
n
¼ 2917 cm ; 2862, 1845, 1600, 1579, 1488, 1467,
1390, 1345, 1301, 1258, 1127, 1077, 1034, 996, 936, 888, 795, 766,
725, 669, 620, 560, 497, 445, 424. H NMR (400 MHz, CDCl ):
3
1
d
¼0.92 (t, J¼6.9 Hz, 6H), 1.33e1.56 (m, 12H), 1.69e1.86 (m, 8H),
5
(
1
.4.2. 5-(Hexyloxy)-3,4-dihydronaphthalen-1(2H)-one (7c). K
4.26 g, 30.8 mmol), tetralone 7a (500 mg, 3.08 mmol) and
-bromohexane (4.33 mL, 5.09 g, 30.8 mmol) were suspended in
2
CO
3
2.00e2.11 (m, 2H), 2.47e2.59 (m, 4H), 3.12 (qd, J¼6.9, 5.2 Hz, 2H),
3.73 (dd, J¼11.5, 4.1 Hz, 2H), 3.98 (td, J¼6.5, 2.4 Hz, 4H), 6.82 (d,
13
J¼8.5 Hz, 2H, 2Har), 7.24 (d, J¼8.5 Hz, 2H, 2Har). C NMR (100 MHz,
acetone (50 mL) and heated to reflux for 14 h. After cooling to rt, the
solution was concentrated to ca. 20 mL and the residue was diluted
CDCl
29.5 (CH
3
):
d
¼14.0 (CH
3
), 20.9 (CH ), 21.1 (CH
2
2
), 22.6 (CH
2
), 25.9 (CH
2
),
2
), 29.9 (CH
2
), 31.6 (CH ), 36.0 (CH), 68.4 (CH
2
2
), 109.7 (CH),
with CH
Na SO ) and removal of the solvent under reduced pressure yiel-
ded 7c as a yellowish oil (753 mg, 3.06 mmol, 99%). IR (KBr):
2
Cl
2
(80 mL). Washing with H
2
O (2ꢂ25 mL), drying
124.5 (CH),126.5 (C), 127.8 (C), 136.8 (C),154.0 (C). MS (EI): m/z (%)¼
þ
12
1
16
þ
(
2
4
460 (100) [M ], 359 (29). HRMS
ð
C
H
O
2
; EIÞ:
3
2
44
calcd 460.3341 amu; found 460.3336.
ꢁ1
~
n
¼ 3383 cm ; 2931, 2872, 1686, 1597, 1582, 1464, 1433, 1380,
1
345, 1326, 1308, 1280, 1263, 1246, 1183, 1116, 1085, 1049, 902, 880,
5.4.6. 4,10-Dimethoxy-1,7,8,12b-tetrahydroperylene-3,9(2H,6bH)-di-
1
7
(
(
CH
7
97, 785, 726, 680, 561. H NMR (400 MHz, CDCl
t, J¼7.2 Hz, 3H, Me), 1.27e1.53 (m, 6H), 1.78e1.87 (m, 2H, CH
quint, J¼6.5 Hz, 2H, CH ), 2.61e2.64 (m, 2H), 2.91 (t, J¼6.2 Hz, 2H,
), 3.98 (t, J¼6.5 Hz, 2H, CH ), 7.00 (dd, J¼8.0, 0.9 Hz, 1H, Har),
.24 (t, J¼8.0 Hz, 1H, Har), 7.63 (dd, J¼8.0, 0.9 Hz, 1H, Har). C NMR
100 MHz, CDCl ): ), 22.6 (CH ), 22.6 (CH ), 22.9 (CH ),
¼14.0 (CH
5.8 (CH ), 29.2 (CH ) 31.5 (CH ), 38.9 (CH ), 68.4 (CH ), 115.2 (CH),
3
):
d
¼0.91
one (10b). Pentacycle 9b (41.8 mg, 130
mmol) was suspended in
2
), 2.11
HOAc (100%, 3 mL) and a solution of CrO
3
(196 mg, 1.96 mmol) in
ꢀ
2
2
H O (2 mL) und HOAc (100%, 5 mL) was added dropwise at 0 C and
2
2
the mixture was stirred for 48 h at rt. The freshly precipitated solid
was filtrated, washed with H
O (3ꢂ5 mL) and lyophilised. The
product 10b was obtained as a yellow solid (38.2 mg, 110 mol,
84%), which was insoluble in all common solvents. IR (ATR):
13
2
(
2
3
d
3
2
2
2
m
2
2
2
2
2
ꢁ
1
1
18.5 (CH), 126.6 (CH), 133.6 (C), 133.7 (C), 156.3 (C), 198.7 (C). MS
~
n
¼ 2921 cm ; 2857, 1699 (C]O), 1655, 1602, 1573, 1487, 1468,
þ
(
(
EI): m/z (%)¼246 (71) [M ], 162 (77), 133 (49), 105 (92), 77 (78), 43
1444, 1427, 1403, 1334, 1292, 1263, 1217, 1180, 1093, 1029, 996, 925,
þ
12
1
16
100). HRMS ð
C
H
O
2
; EIÞ: calcd 246.1619 amu; found
842, 797, 764, 744, 716, 682, 551, 453. MS (ESI): m/z (%)¼387 (2)
16
22
þ
þ
4þ
2
46.1621.
[(MþK) ], 348 (2) [M ], 126 (100) [(Mþ4K) ].
5
.4.3. 5-Hexyloxy-1,2,3,4-tetrahydronaphthalen-1-ol
(8c). NaBH
4
Acknowledgements
(
578 mg, 15.3 mmol) and tetralone 7c (753 mg, 3.06 mmol) were
suspended in anhyd EtOH (10 mL) and stirred at rt for 14 h. After
careful hydrolysation of the excess NaBH using 1 M HCl, the re-
action mixture was extracted with CH Cl
(3ꢂ20 mL), dried
Na SO ) and concentrated to yield 8c as a yellowish solid (697 mg,
.81 mmol, 92%). IR (ATR): ~
431, 1392, 1345, 1308, 1262, 1248, 1173, 1101, 1078, 1040, 1018, 996,
This work was supported by the Deutsche Forschungsgemein-
schaft (DFG). We thank Daniel Weingand for performing pre-
liminary calculations.
4
2
2
(
2
1
2
4
ꢁ1
n
¼ 3383 cm ; 3354, 2937, 2851, 1461,
References and notes
1
9
22, 896, 873, 851, 781, 727, 691, 644, 508, 423. H NMR (400 MHz,
CDCl ):
¼0.93 (t, J¼7.1 Hz, 3H, Me), 1.27e1.53 (m, 7H), 1.76e1.98
m, 6H), 2.53e2.61 (m, 1H), 2.78 (td, J¼17.6, 5.5 Hz, 1H), 3.96
t, J¼6.4 Hz, 2H, CH ), 4.76 (br, 1H, OH), 6.74 (d, J¼7.8 Hz, 1H, Har),
1
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3
d
2
(
(
1
2
4
13
7
.04 (d, J¼7.8 Hz, 1H, Har), 7.17 (t, J¼7.8 Hz, 1H, Har). C NMR
1
(
100 MHz, CDCl
3
):
d
¼14.0 (CH
3
), 18.1 (CH
2
), 22.6 (CH
2
), 23.0 (CH
2
),
),
Nasini, G. Phytochemistry 1988, 27, 1669e1674.
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6
. Davis, V. M.; Stack, M. E. Appl. Environ. Microbiol. 1991, 57, 180e182.
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5.8 (CH ), 29.3 (CH
2
2
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2
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2
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2
109.5 (CH), 120.2 (CH), 126.2 (C), 126.4 (CH), 140.0 (C), 156.5 (C).
þ
MS (EI): m/z (%)¼248 (89) [M ], 146 (100). HRMS
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1
2
C161H2416O ; EIÞ: calcd 248.1776 amu; found 248.1774.
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ð
2
5
.4.4. 4,10-Dimethoxy-1,2,3,6b,7,8,9,12b-octahydroperylene
(
9b). Alcohol 8b (890 mg, 4.99 mmol) was dissolved in anhyd
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Perspect. 1973, 4, 87e94.
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1
m
bright yellow and a fluffy solid precipitated. After 30 min, the solid
was removed by filtration and washed excessively with MeCN (at
least 3ꢂ20 mL). Pentacycle 9b was obtained as a yellow solid
1
1
0. Stack, M. E.; Mazzola, E. P. J. Nat. Prod. 1989, 52, 426e427.
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(
472 mg, 1.47 mmol, 59%). Spectroscopic data are in full agreement
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33 1
with published data.
H NMR (300 MHz, CDCl
3
):
d
¼1.44e1.55
(
m, 2H), 1.67e1.81 (m, 2H), 2.03e2.13 (m, 2H), 2.41e2.63 (m, 4H),
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