A New Secondary Metabolite from Alternaria Alternata: Structure Elucidation and Total Synthesis of Altenuic Acid IV

Article abstract of DOI:10.1002/ejoc.201801801

A putative intermediate in the biosynthesis of altenuic acids I–III was isolated from Alternaria alternata in the 1950ies and a sample survived over the decades. This resorcylic lactone named altenuic acid IV is a composite of a resorcylic and a muconic a

Full text of DOI:10.1002/ejoc.201801801

A Journal of
Accepted Article
Title: A New Secondary Metabolite from Alternaria Alternata: Structure
Elucidation and Total Synthesis of Altenuic Acid IV
Authors: Dominik Kohler and Joachim Podlech
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201801801
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10.1002/ejoc.201801801
European Journal of Organic Chemistry
FULL PAPER
A New Secondary Metabolite from Alternaria Alternata: Structure
Elucidation and Total Synthesis of Altenuic Acid IV
Dominik Kohler[a] and Joachim Podlech*[a]
To the memory of Robert Thomas
Abstract: A putative intermediate in the biosynthesis of altenuic acids
I–III was isolated from Alternaria alternata in the 1950ies and a
sample survived over the decades. This resorcylic lactone named
altenuic acid IV is a composite of a resorcylic and a muconic acid. Its
structure was confirmed by NMR spectroscopy and by total synthesis.
Altenuic acid IV was here obtained starting with 2-bromo-4,6-
dimethoxybenzene and 4-methylbenzene-1,2-diol with a total yield of
20%. The synthesis was achieved in ten steps where the longest
sequence consists of seven steps. Key steps were an oxidative ring
opening of a bromocresol furnishing a bromomuconate and its Suzuki
coupling with a resorcylate-derived boronate.
structure could then unambiguously be elucidated by NMR
spectroscopy and by total synthesis.[9] Unfortunately, no sample
of AA I survived over the decades. Its structure is still unknown,
but R. Thomas made a suggestion in a personal correspondence
for its constitution (Figure 1) which is based on the structural and
chemical features elucidated in the original publication[7] and on
the catalytic mechanism of 4-methylmuconolactone methyl-
isomerase.[10] In the last years the isolation of AA II from A.
alternata could be repeated[11] and methods for the
chromatographic separation[12] and the analysis[12,13] of AA III
have furthermore been developed.
OH
O
OH
O
Introduction
O
O
OH
OH
Mycotoxins, i.e. toxins produced by fungal molds,[1] are a serious
health problem for humans and cattle. Alternariol (ALT),
alternariol 9-methyl ether (AME),[2] and further resorcylic lactones
or resorcylic acids are major secondary metabolites of Alternaria
fungi (Figure 1).[3] Although the toxicity of these mycotoxins is
lower than others (e.g., aflatoxins or ochratoxins),[4] infestation
with Alternaria spp. leads to significant crop shortfalls by fouling
of fruits, vegetables, juices, and other products[5] and can lead to
intoxications and deseases.[6] The altenuic acids (AA I‒III) are
known since 1957 when they were isolated by Rosett et al. from
Alternaria tenuis (obsolete synonym of A. alternata) together with
altenusin.[7] The altenuic acids have identical molecular formula
and are not optically active, but show different melting points,
differ in the number of acidic functionalities, and give specific color
reactions, e.g., in the reaction with ferric chloride. It turned out that
AA I and AA II are converted into AA III when dissolved in mild
alkali (NaOH) and subsequently re-acidified. Unambiguous
information on the structure of AA II became available through a
crystallographic analysis; it shows a unique spirocyclic structure
and is present in nature as racemate (a mixture of the R,R and
the S,S enantiomers).[8] Further structural information on the other
altenuic acids was not accessible until 2013 when our group
acquired original samples from the 1950ies, stored by the late
Robert Thomas, who obtained these from the heritage of the late
C. Ewart Stickings. Among these was a sample of AA III whose
MeO
RO
OH
3-hydroxy-alternariol
9-methyl ether
R = H: alternariol (ALT)
R = Me: alternariol 9-methyl ether (AME)
OH
OH
3'
CO2H
CO2H
2'
4'
2
1'
5'
1
OH
3
MeO
MeO
CO2H
6'
CO2H
4
OH
6
5
altenusin
proposed name:
altenuic acid IV (AA IV)
OH
OH
O
CO2H
O
CO2H
MeO
MeO
O
CO2H
O
O
altenuic acid III
(AA III)
altenuic acid II
(AA II)
O
OH
CO2H
O
structure proposed by
R. Thomas for
altenuic acid I (AA I)
(not unambiguously proven)
O
MeO
O
O
Figure 1. Selected Alternaria toxins.
[a]
Dr. D. Kohler, Prof. Dr. J. Podlech
Karlsruher Institut für Technologie (KIT)
Institut für Organische Chemie
Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany
E-mail: joachim.podlech@kit.edu
http://www.ioc.kit.edu/podlech/
Although the biosynthesis of the altenuic acids has never been
investigated in detail, some proposals have been made over the
years: AME is oxidized to 3-hydroxy-alternariol 9-methyl ether,[14]
which has been isolated from Alternaria spp. and other fungi[14,15]
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201801801
European Journal of Organic Chemistry
FULL PAPER
and was observed in the human metabolization of ALT and
AME.[16] Reductive cleavage should in the further course lead to
altenusin.[14,17] Among the above mentioned samples was a vial
with about 25 milligrams of a compound which had been isolated
from A. tenuis (A. alternata) together with the altenuic acids I‒III.
Robert Thomas suggested in a personal conversation the
constitution given in Figure 1 (altenuic acid IV) and suspected it
to be the biosynthetic successor of altenusin and a precursor of
the altenuic acids I‒III. We propose the name altenuic acid IV (AA
IV) for this natural product. This compound has not been
published by the original investigators since it was only obtained
in small amounts not sufficient for further investigations at that
time. AA IV might be biosynthesized in the fungi by oxidative
cleavage of the catechol moiety in altenusin.[18] The absence of
optical activity in altenuic acids I‒III supports the possibility that
their chiral centers might be built up by oxidation with a
peroxidase[10] to free radical intermediates, which can undergo
spontaneous radical coupling or cyclisation without accumulation
of an excess of one enantiomer. Herein, we present the structure
elucidation of AA IV and its total synthesis.
most promising for this key reaction. We envisaged the pinacol-
derived boronate 7 which was easily obtained from 2-bromo-4,6-
dimethoxybenzene 3 by Vilsmeyer-Haack formylation (→4),
oxidation (→5),[22] esterification (→6)[23] and subsequent
palladium-catalyzed
Miyaura
boronylation
with
bis(pinacolato)diboron (9).[24] Boronate 7 was thus accessible in
95% yield over two steps from the known resorcylic acid 5
(Scheme 2). An alternative approach using a metal-halogen
interchange with butyl lithium followed by transmetalation with 2-
isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (10) was
unsuccessful and led to the formation of significant amounts of
defunctionalized substrate 8.[25]
OMe
OMe
5
Ref. 22
78%
3
c, d
CO2H
MeO
Br
MeO
Br
OMe
OMe
8
CO2Me
CO2Me
O
B
MeO
MeO
O
7
O
O
O
O
O
O
Results and Discussion
B
B
B OiPr
Inspired by the putative biosynthesis of the altenuic acids, we at
first tried a biomimetic approach featuring an oxidative ring
opening of the catechol moiety in altenusin. For this we tested a
published method developed by Kaschabek et al. who
transformed catechols into the corresponding muconates.[19]
According to this protocol, altenusin[20] was oxidized with sodium
periodate under phase transfer catalytic conditions to ortho-
quinone 1, which was not isolated but immediately reacted with
lead(IV) acetate (Scheme 1). Nevertheless, these conditions led
to unspecific decomposition of the substrate; the expected
muconate 2 could not be detected in the complex product mixture.
9
10
Scheme 2. Synthesis of a boronate 7 suitable for Suzuki coupling. Reagents
and conditions: (c) K2CO3, MeI, DMF, 85 °C, 45 min (99%); (d) B2Pin2 (9)
Pd(dppf)Cl2·CH2Cl2 (cat.), KOAc, dioxane, 80 °C, 20 h (96%).
A general approach to simple muconates was established via the
protocol, which has already been applied by us in the
unsuccessful oxidative transformation of altenusin (Scheme 3).[19]
A suitable building block 13 was obtained by bromination of 4-
methylcatechol (11) with N-bromosuccinimide (NBS).[26]
Performing the bromination with elemental bromine led to
considerable amounts (20%) of the hardly separable 3,5-
dibrominated catechol side product.[27] Using the above
mentioned two-step protocol with sodium periodate and lead(IV)
acetate in methanol furnished the corresponding brominated
dimethyl muconate 13 with 64% yield (Scheme 3).[19]
Unfortunately, the analogous reaction in tert-butanol did not
supply the respective di-tert-butyl muconate which could have
been useful in the final liberation of the carboxylic acids with
alternative reaction conditions. However, the thus obtained
methyl ester groups in the resorcylic ester and in the muconate
part of the aimed coupled substrate should be cleavable with base,
i. e., with conditions which were expected to not harm the final
altenuic acid IV.
OH
OH
CO2H
CO2H
a
b
OH
OH
O
O
MeO
MeO
1
altenusin
OH
CO2H
MeO
CO2Me
CO2Me
2
Scheme 1. Intended two-step oxidation of altenusin to altenuic acid IV.
Reagents and conditions: (a) NaIO4, Bu4NBr (cat.), CH2Cl2/H2O, rt, 10 min
(36%); b) Pb(OAc)4, MeOH, 0 °C, 1 h.
Br
OH
OH
Br
OH
OH
f, g
e
CO2R
CO2R
Due to the laborious synthesis of altenusin[20] used as starting
material, we abandoned this approach and aimed for a different
strategy, in which suitable resorcylic acid and muconic acid
derivatives should be connected in a cross coupling reaction.
Bases on our prior work[21] we considered a Suzuki coupling to be
11
12
R = Me: 13
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10.1002/ejoc.201801801
European Journal of Organic Chemistry
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Scheme 3. Synthesis of a bromo muconate 13. Reagents and conditions: (e)
NBS, MeCN, 0 °C → rt (quant.); (f) NaIO4, Bu4NBr (cat.), CH2Cl2/H2O, rt, 20 min;
g) Pb(OAc)4, ROH, 0 °C, 1 h (R = Me: 64%, 2 steps; R = tBu: 0%).
for the replacement of the bromine in 13 with a boronate group
turned out to be successful.[33]
Three methyl esters and one methyl ether had finally to be
cleaved in the coupled product 14 to obtain altenuic acid IV
(Scheme 5). Especially the high polarities of the natural product
and of possible intermediates made this endeavor more
challenging than expected. An attempt for simultaneous cleavage
of all four protecting groups in 14 with nine equivalents of boron
tribromide lead to a statistical cleavage of the methyl groups,
which could not be improved with more harsh conditions or longer
reaction times.[34] When the methyl ether was initially deprotected
with boron tribromide (2.2 equivalents), it turned out that the
subsequent trial for the complete saponification of the ester
groups in phenol 15 was not successful:[35] Either the mono
methyl ester 17 or a decarboxylated product 16 was observed
when methanolic sodium or potassium hydroxide, respectively,
were used as reagents. A completion of the reaction by further
application of saponification conditions to mono methyl ester 17
failed – most probably due to a poor reactivity of deprotonated
carboxylate 17, a trianion. To avoid the observed decarboxylation,
we decided to at first perform the threefold saponification (→18)
followed by ether cleavage. This sequence could be performed
successfully with standard conditions and yielded the deprotected
tricarboxylic acid, albeit with a poor 28% yield over two steps.
Nevertheless, altenuic acid IV was finally obtained by
To achieve the cross coupling of boronate 7 and bromomuconate
13, we tested a method which had been successfully applied in
the total synthesis of altenusin.[20] Nevertheless, utilization of
palladium acetate as
a
catalyst with the ligand 2-
dicyclohexylphosphino-2’,6’-dimethoxybiphenyl (SPhos) and
cesium carbonate as a base did not yield the coupled product 14
but furnished debrominated product 8. Only a poor 6% yield was
obtained with potassium phosphate as a base[28] and the catalysts
1,1’-bis(diphenylphosphino)ferrocene-palladium(II)dichloride,[29]
bis(triphenylphosphine)palladium(II)
dichloride,[30]
or
tris(dibenzylideneacetone)dipalladium(0)[31] gave either no
conversion or a poor yield not exceeding 12 % (Scheme 4 and
Table 1). An acceptable yield of 36% could only be achieved when
the boronate 7 was transferred into the respective trifluoroborate.
Palladium(II) acetate was utilized as a catalyst in this protocol.[32]
OMe
CO2Me
OMe
O
CO2Me
CO2Me
MeO
B
Table 1
7
O
saponification of phenol 15 with 6N aqueous sodium hydroxide,
where this final step was now achieved with an excellent 92%
yield.
MeO
+
14
CO2Me
Br
13
CO2Me
CO2Me
OH
Scheme 4. Cross coupling to protected altenuic acid IV.
16
OH
15
i
CO2Me
MeO
CO2H
CO2H
MeO
CO2Me
CO2Me
j
h
Table 1. Conditions used in the intended cross coupling.
OH
17
CO2Me
OMe
#
1
Conditions
Yield [%]
Ref.
14
CO2Me
MeO
CO2H
CO2H
Pd(OAc)2, SPhos,[a] Cs2CO3, dioxane/H2O,
80 °C, 20 h
‒
[b]
[20]
MeO
CO2Me
CO2Me
l
[28]
[29]
[30]
[31]
[32]
2
3
4
5
6
Pd(OAc)2, SPhos, K3PO4, THF, 80 °C, 72 h
Pd(dppf)Cl2·CH2Cl2, NEt3, THF/H2O, 60 °C, 18 h
PdCl2(PPh3)2, Na2CO3, THF/H2O, 80 °C, 72 h
Pd2(dba)3, K2CO3, toluene, 80 °C, 72 h
Pd(OAc)2, KF, dioxane, 80 °C, 72 h
6
k
traces
‒
OMe
OH
18
CO2H
CO2H
h
MeO
CO2H
CO2H
MeO
CO2H
CO2H
12
36
altenuic acid IV
[a] SPhos: 2-Dicyclohexylphosphino-2’,6’-dimethoxybiphenyl; [b] Only
defunctionalized product 8 was obtained.
Scheme 5. Liberation of altenuic acid IV. Reagents and conditions: (h) BBr3,
CH2Cl2, ‒78 °C → rt, 75 min (15: 82%, AA IV: 33%); (i) KOH, MeOH, 50 °C, 18
h, then 90 °C, 24 h (52%); (j) NaOH, MeOH, 50 °C, 18 h, then 90 °C, 24 h
(quant.); (k) NaOH, MeOH, 50 °C, 24 h (86%); (l) 5M NaOH, 55 °C, 15 h (92%).
We further considered a vice versa approach in which bromide 5
should be cross coupled with a boronate accessible from
bromomuconate 13 by boronylation. Nevertheless, no attempts
Altenuic acid IV was thus obtained starting with commercially
available 2-bromo-4,6-dimethoxybenzene and 4-methylbenzene-
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10.1002/ejoc.201801801
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FULL PAPER
1,2-diol with a total yield of 20%. The total synthesis was achieved Conclusions
in ten steps while the longest sequence has consisted of seven
steps.
The structure of an authentic sample of a fungal metabolite called
altenuic acid IV (AA IV) was elucidated by NMR spectroscopy and
by total synthesis. It seems quite obvious (albeit not proven) that
AA IV is a metabolic intermediate resulting from oxidative
cleavage of altenusin. Intramolecular oxy-Michael-type additions
would further lead to altenuic acids I‒III.
The target compound synthesized turned out to be identical with
the isolated natural product altenuic acid IV, which could be
proven by comparison of the NMR spectra and by measurement
of a 1:1 mixture of synthesized material and the natural product.
The NMR-spectroscopic data are given in Table 2. The 13C signal
of the quaternary C-2’ carbon was not detected in standard NMR
experiments, obviously due to a prolonged relaxation time T1.
Nevertheless, the signal could be exposed as cross peak in an
HMBC experiment with higher relaxation delay d1 and
suppression of 1J couplings.[36] While the constitution of the
Experimental Section
2-Bromo-4,6-dimethoxybenzaldehyde (4).[22] Freshly distilled POCl3
(3.15 mL, 5.29 g, 34.5 mmol) was added dropwise at 0 °C under Ar to a
solution of 2-bromo-4,6-dimethoxybenzene (3, 3.00 g, 13.8 mmol) in
anhydrous DMF (8 mL). The mixture was stirred for 4 h at 100 °C, poured
on ice water (500 mL), and left for 16 h. The precipitate was collected by
filtration, washed with H2O (50 mL) and dried in high vacuum. The crude
product was recrystallized (hexane/EtOAc, 2:1) to yield 4 (2.26 g, 9.22
mmol, 67%) as a colorless solid; Rf 0.40 (hexane/EtOAc, 2:1); 1H NMR
compound is unambiguously derived after evaluation of H, 13C,
1
1H-13C HSQC, and 1H-13C HMBC spectra, the double bonds’
configuration kept inconclusive. If the atom’s positions are
maintained during the oxidation process (Scheme 3), altenuic
acid IV should have a 2E,4Z configuration, which admittedly could
be foiled by concomitant or subsequent double bond
isomerizations, where this must have similarly happened during
the synthesis and the biosynthesis. Nevertheless, Kaschabek et
al. clearly showed that the oxidation of the catechols is obtained
with preservation of the configuration.[17] An nOe from 4-CH3 to
the vicinal proton 5-H gave further evidence at least for the
preservation of the 4Z configuration.
(300 MHz, CDCl3):
δ (ppm) = 3.87 (s, 3 H, Me), 3.89 (s, 3 H, Me), 6.43 (d,
4J = 2.1 Hz, 1 H, Ar-H), 6.78 (d, 4J = 2.1 Hz, 1 H, Ar-H), 10.31 (s, 1 H,
CHO).
2-Bromo-4,6-dimethoxybenzoic Acid (5).[22] A solution of KMnO4 (1.42
g, 8.99 mmol) in H2O (75 mL) was added at 75 °C within 40 min to an
emulsion of carbaldehyde 4 (1.37 g, 5.59 mmol) in H2O (50 mL). The
mixture was stirred for 2 h at that temperature and the pH was raised to 13
by slow addition of aqueous KOH solution (20%). The mixture was filtered
Table 2. NMR data of altenuic acid IV.[a]
(Celite), the filtrate was acidified with 2N HCl and extracted with CH2Cl2
(3×100 mL). The combined organic layers were dried (Na2SO4) and
concentrated under reduced pressure to yield 5 (1.16 g, 4.44 mmol, 79%)
as a colorless solid; Rf 0.59 (CH2Cl2/MeOH/AcOH, 100:10:1); 1H NMR
Position[b]
δ
[ppm] [c,d]
δ
[ppm][c,e]
Position[b]
δ
[ppm][c,e]
4-CH3
OCH3
5-H
2.32 (d, 4J = 0.9)
3.78 (s)
C-6’
C-2
109.1
119.8
121.8
142.1
152.8
155.3
162.9
164.9
166.7
167.4
171.9
(300 MHz, CDCl3):
δ (ppm) = 3.82 (s, 3 H, OMe), 3.86 (s, 3 H, OMe), 6.44
(d, 4J = 2.1 Hz, 1 H, Ar-H), 6.74 (d, 4J = 2.1 Hz, 1 H, Ar-H).
5.29 (d, 4J = 0.9)
6.03 (d, 4J = 2.5)
6.18 (s)
C-5
Methyl 2-Bromo-4,6-dimethoxybenzoate (6).[23] A solution of benzoic
acid 5 (420 mg, 1.61 mmol), K2CO3 (334 mg, 2.42 mmol), and MeI (0.150
6’-H
C-1’
C-3
mL, 342 mg, 2.41 mmol) in DMF (5 mL) was stirred for 45 min at 85 °C. 1
N
HCl (10 mL) was added and the organic layer was separated and the
aqueous layer was extracted with EtOAc (3×10 mL). The combined
organic layers were dried (Na2SO4) and concentrated under reduced
pressure to yield 6 (438 mg, 1.59 mmol, 99%) as a dark red oil; Rf 0.18
2-H
4’-H
6.47 (d, 4J = 2.5)
C-4
(hexane/EtOAc, 2:1); 1H NMR (300 MHz, CDCl3):
δ (ppm) = 3.79 (s, 6 H,
C-5’
C-3’
C-1
2×OMe), 3.91 (s, 3 H, CO2Me), 6.40 (d, 4J = 2.1 Hz, 1 H, Ar-H), 6.68 (d, 4J
4-CH3
OCH3
C-4’
15.4
= 2.1 Hz, 1 H, Ar-H).
55.5
Methyl
2,4-Dimethoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)benzoate (7). Benzoate 6 (304 mg, 1.11 mmol), KOAc (271 mg, 2.76
mmol), and bis(pinacolato)diboron (9, 309 mg, 1.21 mmol) were dissolved
under argon in anhydrous and degassed dioxane (6 mL).
Pd(dppf)Cl2·CH2Cl2 (39 mg, 0.048 mmol) was added under an argon flow.
The mixture was stirred at 80 °C for 20 h, filtered (Celite), and purified by
column chromatography (silica gel, hexane/EtOAc, 4:1) to yield 7 (345 mg,
1.07 mmol, 96%) as a yellow oil which contained traces of pinacol; Rf 0.54
100.0
106.9[f]
C-6
C-2’
2’-CO2H
[a] Assignment was made according to 1H, 13C, 1H-13C HSQC, and 1H-13
C
HMBC spectra. [b] Numbering see Figure 1. [c] Signals are given in
increasing order. [d] 1H NMR (400 MHz, DMSO-d6); multiplicities and
coupling constants [Hz] are given in parentheses. [e] 13C NMR (100 MHz,
DMSO-d6). [f] Signal is not detected in standard experiments due to a high
T1 relaxation time. It was visible as cross peak in an HMBC experiment with
higher relaxation delay d1 and suppression of 1J couplings.
(hexane/EtOAc, 2:1); 1H NMR (400 MHz, CDCl3):
δ (ppm) = 1.33 (s, 12 H,
Me2CCMe2), 3.81 (s, 3 H, OMe), 3.83 (s, 3 H, OMe), 3.86 (s, 3 H, OMe),
6.49 (d, 4J = 2.2 Hz, 1 H, Ar-H), 6.71 (d, 4J = 2.3 Hz, 1 H, Ar-H); 13C NMR
(100 MHz, CDCl3):
δ (ppm) = 24.9 (Me2CCMe2), 52.4 (OMe), 55.6 (OMe),
56.1 (OMe), 84.1 (Me2CCMe2), 101.0 (CH), 109.2 (CH), 119.1 (C), 158.8
(C), 162.4 (C), 169.2 (C); IR (ATR): \tilde{\nu } (cm‒1) = 2977 (w), 1735 (w),
1591 (w), 1452 (w), 1422 (w), 1356 (m), 1325 (w), 1296 (w), 1265 (w),
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10.1002/ejoc.201801801
European Journal of Organic Chemistry
FULL PAPER
1215 (w), 1191 (w), 1145 (m), 1098 (w), 1050 (w), 850 (w); MS (ESI, pos.):
(2E,4Z)-3-(2-Carboxy-3,5-dimethoxyphenyl)-4-methylhexa-2,4-
m/z (%) = 345 (100) [M++Na], 344 (24), 340 (21), 339 (87), 245 (38).
dienoic Acid (18). 1
triester 14 (55.6 mg, 0.147 mmol) in MeOH (5 mL) and the mixture was
stirred at 50 °C for 24 h, acidified (pH 1) by addition of 1 HCl, and diluted
N NaOH (1.47 mL) was added to a solution of the
N
4-Bromo-5-methylbenzene-1,2-diol (12). A solution of NBS (7.16 g, 40.2
mmol) in MeCN (100 mL) was added slowly at 0 °C to a solution of 4-
methylbenzene-1,2-diol (11, 5.00 g, 40.3 mmol) in MeCN (200 mL). The
with H2O to a total of 10 mL. The aqueous layer was extracted with EtOAc
(3×10 mL) and the combined organic layers were dried (Na2SO4) and
concentrated under reduced pressure. The remnant was dissolved in 2.5
N
mixture was warmed to room temperature overnight and poured in 1N HCl
NaOH (1.6 mL), stirred at 90 °C for 24 h, cooled to room temperature,
diluted with H2O to a total of 15 mL, and washed with EtOAc (2×15 mL).
The aqueous layer was acidified with 6N HCl and extracted with EtOAc
(200 mL). The aqueous layer was extracted with EtOAc (3×200 mL) and
the combined organic layers were dried (Na2SO4) and concentrated under
reduced pressure to yield 12 (8.18 g, 40.3 mmol, quant.) as a brownish
solid; Rf 0.64 (hexane/EtOAc, 1:1); 1H NMR (300 MHz, acetone-d6):
δ
(3×20 mL). The combined organic layers were dried (Na2SO4) and
concentrated under reduced pressure to yield 18 (42.5 mg (0.126 mmol,
(ppm) = 2.19 (s, 3 H, Me), 6.79 (s, 1 H, Ar-H), 6.99 (s, 1 H, Ar-H).
1
86%) as a light brown solid; Rf 0.11 (CH2Cl2/MeOH/AcOH, 100:10:1); H
NMR (400 MHz, methanol-d4):
δ
(ppm) = 2.37 (d, 4J = 1.1 Hz, 3 H, Me),
Dimethyl (2E,4Z)-3-Bromo-4-methylhexa-2,4-dienedioate (13).
A
3.83 (s, 3 H, OMe), 3.89 (s, 3 H, OMe), 5.58 (d, 4J = 1.1 Hz, 1 H, C = CH),
6.27 (d, 4J = 2.2 Hz, 1 H, Ar-H), 6.39 (s, 1 H, C = CH), 6.27 (d, 4J = 2.2 Hz,
solution of NaIO4 (3.32 g, 15.5 mmol) in H2O (150 mL) was added to a
solution of cresol 12 (2.72 g, 13.4 mmol) and Bu4NBr (TBAB, a spatula tip)
in CH2Cl2 (100 mL). The mixture was stirred vigorously for 20 min, the
phases were separated and the organic layer was dried (MgSO4). The
ortho-quinone (still dissolved in CH2Cl2) was added immediately at 0 °C to
a solution of Pb(OAc)4 (7.30 g, 16.5 mmol) in anhydrous MeOH (150 mL)
and the mixture was stirred for 1 h in the dark. The solvents were removed
under reduced pressure and the remnant was extracted with
hexane/EtOAc (1:1, 4×100 mL). The combined organic layers were stirred
with an excess of a saturated NaHCO3 solution (evolution of CO2), washed
with H2O, dried (MgSO4), and concentrated under reduced pressure to
yield 13 (2.27 g, 8.63 mmol, 64%) as a red oil; Rf 0.65 (hexane/EtOAc,
1 H, Ar-H); 13C NMR (100 MHz, methanol-d6):
δ (ppm) = 15.8 (4-Me), 56.1
(Me), 56.6 (Me), 99.1 (CH), 108.2 (CH), 122.2 (CH), 124.6 (CH), 141.4 (C),
153.8 (C), 156.5 (C), 160.6 (C), 164.5 (C), 169.0 (C), 169.7 (C), 169.8 (C);
IR (ATR): \tilde{\nu } (cm‒1) = 2919 (w), 2849 (w), 1681 (w), 1593 (m), 1459
(w), 1425 (w), 1363 (w), 1334 (w), 1286 (w), 1216 (w), 1157 (w), 1088 (w),
1034 (w), 867 (w), 838 (w), 819 (w), 426 (w); MS (ESI, neg.): m/z (%) =
335 (27) [M‒‒H], 291 (42) [C15H15O6‒], 248 (15), 247 (100) [C14H15O4‒],
203 (8) [C13H15O2‒]; HMRS (ESI, neg.): M‒‒H, found 335.0771.
12
C
16
1H1516O8 requires 335.0767.
2:1); 1H NMR (400 MHz, CDCl3):
3.67 (s, 3 H, CO2Me), 3.69 (s, 3 H, CO2Me), 5.72 (d, 3J = 1.4 Hz, 1 H, CH),
6.35 (s, 1 H, CH); 13C NMR (400 MHz, CDCl3):
(ppm) = 22.3 (4-Me), 51.2
δ
(ppm) = 2.10 (d, 3J = 1.5 Hz, 3 H, Me),
Dimethyl
(methoxycarbonyl)phenyl]-4-methylhexa-2,4-dienedioate (15). BBr3
(1 in CH2Cl2, 1.04 mL, 1.04 mmol) was added under argon at ‒78 °C to
(2E,4Z)-3-[3-Hydroxy-5-methoxy-2-
M
δ
a solution of triester 14 (17.9 mg, 47.3 µmol) in anhydrous CH2Cl2 (4 mL).
The mixture was stirred for 30 min at ‒78 °C and 45 min at room
temperature and poured into saturated aqueous NH4Cl solution (5 mL).
The aqueous layer was extracted with CH2Cl2 (3×5 mL) and the combined
organic layers were dried (Na2SO4) and concentrated under reduced
pressure to yield 15 (14.1 mg, 38.7 µmol, 82%) as a light brown solid; Rf
(OMe), 51.5 (OMe), 117.5 (CH), 122.0 (CH), 140.0 (C), 152.6 (C), 163.7
(C), 164.6 (C); IR (ATR): \tilde{\nu } (cm‒1) = 3278 (w), 2951 (w), 1724 (m),
1656 (m), 1609 (m), 1487 (w), 1431 (m), 1367(w), 1280 (m), 1223 (m),
1191 (m), 1168 (s), 1131 (m), 1065 (m), 1042 (m), 1005 (m), 954 (m), 918
(m), 865 (m), 806 (w), 759 (m), 699 (w), 666 (m), 605 (w), 539 (w), 453
(w); MS (EI, 20 °C): m/z (%) = 263 (1) [M+(81Br)], 262 (1) [M+(80Br)], 261
(1) [M+(79Br)], 233 (10), 206 (6), 205 (73), 203 (76), 183 (100) [C9H11O4+],
151 (12) [C8H7O3+], 137 (22) [C8H9O2+], 95 (11), 93 (14) [C6H5O+], 69 (14),
0.43 (hexane/EtOAc, 2:1); 1H NMR (400 MHz, acetone-d6):
δ (ppm) = 2.49
(d, 4J = 1.1 Hz, 3 H, 4-Me), 3.52 (s, 3 H, OMe), 3.60 (s, 3 H, OMe), 3.76
(s, 3 H, OMe), 3.87 (s, 3 H, OMe), 5.48 (d, 4J = 1.1 Hz, 1 H, 2-H or 4-H),
6.16 (d, 4J = 2.5 Hz, 1 H, Ar-H), 6.33 (s, 1 H, 4-H or 2-H), 6.53 (d, 4J = 2.5
1
59 (13); HMRS (EI, 20 °C): M+, found 261.9836. 12C9 H1116O479Br requires
261.9835.
Hz, 1 H, Ar-H); 13C NMR (100 MHz, acetone-d6):
δ (ppm) = 15.6 (4-Me),
51.4 (OMe), 51.5 (OMe), 56.1 (OMe), 101.0 (CH), 110.9 (CH), 119.7 (CH),
122.6 (CH), 142.7 (C), 154.1 (C), 157.7 (C), 165.2 (C), 165.8 (C), 166.1
(C), 167.1 (C), 171.2 (C); IR (ATR): \tilde{\nu } (cm‒1) = 2951 (w), 1710 (w),
1652 (w), 1604 (w), 1572 (w), 1433 (w), 1377 (w), 1331 (w), 1248 (w), 1193
(m), 1153 (m), 1037 (w), 1011 (w), 994 (w), 953 (w), 861 (w), 804 (w), 757
(w), 712 (w), 626 (w); MS (ESI, pos.): m/z (%) 365 (20) [M++H], 364 (3)
Dimethyl
(2E,4Z)-3-(3,5-Dimethoxy-2-(methoxycarbonyl)phenyl)-4-
methylhexa-2,4-dienedioate (14). KF (83.1 mg, 1.43 mmol) was added
to boronate 7 (154 mg, 0.478 mmol) dissolved in anhydrous dioxane (1
mL) in a pyrex tube and the mixture was stirred for 10 min at room
temperature. A solution of muconate 13 (83.3 mg, 0.317 mmol) and
Pd(OAc)2 (1.7 mg, 7.6 µmol) in anhydrous dioxane (1 mL) was added and
the transfer was completed by rinsing with further anhydrous dioxane (0.5
mL). The mixture was stirred at 80 °C for 72 h, filtered (Celite) and rinsed
with EtOAc (7.5 mL). The filtrate was concentrated under reduced
pressure and purified by column chromatography (hexane/EtOAc, 2:1) to
[M+], 351 (11) 334 (18), 333 (100) [C17H17O7+], 319 (22) [C16H15O7+], 221
(19); HMRS (ESI, pos.): M+, found 364.1143.
364.1158.
C
18
1H2016O8 requires
12
(2E,4Z)-3-(2-Carboxy-3-hydroxy-5-methoxyphenyl)-4-methylhexa-
2,4-dienoic Acid, Altenuic Acid IV. A solution of phenol 15 (13.3 mg,
yield 14 (42.7 mg, 0.113 mmol, 36%) as
a
yellow oil; Rf 0.23
(ppm) = 2.39 (d,
(hexane/EtOAc, 2:1); 1H NMR (400 MHz, acetone-d6):
δ
4J = 1.2 Hz, 3 H, Me), 3.54 (s, 3 H, CO2Me), 3.61 (s, 3 H, CO2Me), 3.63 (s,
3 H, CO2Me), 3.84 (s, 3 H, OMe), 3.85 (s, 3 H, OMe), 5.63 (d, 4J = 1.2 Hz,
1 H, C = CH), 6.29 (d, 4J = 2.2 Hz, 1 H, Ar-H), 6.33 (s, 1 H, C = CH), 6.64
36.5 µmol) in 5
mixture was carefully acidified with 6
M
aqueous NaOH (3 mL) was stirred for 15 h at 55 °C. The
HCl (5 mL) and extracted with
M
EtOAc (3×10 mL). The combined organic layers were dried (Na2SO4) and
concentrated under reduced pressure to yield AA IV (10.8 mg, 33.5 µmol,
(d, 4J = 2.2 Hz, 1 H, Ar-H); 13C NMR (100 MHz, acetone-d6):
δ (ppm) =
92%) as a brown solid; 1H NMR (400 MHz, DMSO-d6)
δ (ppm) = 2.32 (d,
15.5 (Me), 51.4 (Me), 51.5 (Me), 51.8 (Me), 55.9 (Me), 56.3 (Me), 98.7
(CH), 107.3 (CH), 121.8 (CH), 123.8 (CH), 139.8 (C), 153.6 (C), 155.2 (C),
159.6 (C), 162.5 (C), 165.8 (C), 167.1 (C), 167.3 (C); IR (ATR): \tilde{\nu }
(cm‒1) = 2950 (w), 1715 (s), 1597 (m), 1431 (m), 1366 (w), 1342 (w), 1264
(m), 1195 (s), 1156 (s), 1097 (m), 1044 (m), 945 (w), 865 (w), 836 (w), 599
(w); m/z (%) = 378 (4) [M+], 377 (7) [M+‒H], 359 (26), 348 (19), 347 (100)
4J = 0.9 Hz, 3 H, 4-Me), 3.78 (s, 3 H, OMe), 5.29 (d, 4J = 0.9 Hz, 1 H, 5-H),
6.03 (d, 4J = 2.5 Hz, 1 H, 6’-H), 6.18 (s, 1 H, 2-H), 6.47 (d, 4J = 2.5 Hz, 1
H, 4’-H), 12.7 (br s, 3 H, 3 CO2H); 13C NMR (100 MHz, DMSO-d6)
δ (ppm)
= 15.4 (4-Me), 55.5 (OMe), 100.0 (CH), 109.0 (CH), 119.8 (CH), 121.8
(CH), 142.1 (C), 152.8 (C), 155.3 (C),162.9 (C), 164.9 (C), 166.7 (C), 167.4
(C), 171.9 (C); IR (ATR): \tilde{\nu } (cm‒1) = 2945 (w), 1685 (w), 1602 (m),
1442 (w), 1365 (w), 1231 (m), 1200 (m), 1158 (m), 1074 (w), 1037 (m),
[C18H19O7+], 221 (12); HRMS (ESI, pos.): M+, found 378.1299.
12
C
19
1H2216O8 requires 378.1309.
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10.1002/ejoc.201801801
European Journal of Organic Chemistry
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867 (w), 838 (w), 704 (w), 606 (w), 427 (w); MS (EI, 220 °C): m/z (%) 322
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2007, 51, 307–316; b) E. Pfeiffer, B. Burkhardt, M. Altemöller, J. Podlech,
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(20) [M+], 278 (52) [C14H14O6+], 192 (100) [C10H8O4+]; HMRS (EI, 220 °C):
1
M+, found 322.0684. 12C15 H1416O8 requires 322.0683.
Acknowledgements
We are extremely grateful to the late Prof. Robert Thomas for
donating the sample collection inter alia containing altenuic acid
IV and to Dr. Gregor Nemecek for his help in its acquisition. We
are greatly indebted to Miriam Himmelsbach, Prof. Dr. Burkhard
Luy, and Dr. Andreas Rapp for measuring special NMR spectra
and for helpful discussions.
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Keywords: mycotoxins • resorcylic acids • fungal metabolites •
Suzuki coupling • catechols
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Entry for the Table of Contents
Layout 2:
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Mycotoxins
Dominik Kohler, Joachim Podlech*
Page No. – Page No.
A New Secondary Metabolite from
Alternaria Alternata: Structure
Elucidation and Total Synthesis of
Altenuic Acid IV
A missing link in the putative biosynthesis of the altenuic acids I‒III has been
identified and its structure was confirmed by total synthesis. It could be produced in
the fungus Alternaria alternata by oxidative ring opening of altenusin.
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