Zearalenone mimics: Synthesis of (E)-6-(1-Alkenyl)-substituted β-resorcylic acid esters

Article abstract of DOI:10.1080/00397911.2012.681827

Two versatile strategies for the synthesis of mimics of the Fusarium mycotoxin zearalenone (1) have been developed. Optimized preparation of (E)-6-(1-alkenyl) substituted β-resorcylic acid esters was realized via ortho-directed lithiation of variable substrates combined with allylation/isomerization or via formylation/Schlosser-Wittig olefination using different protective group patterns. Spontaneous decarboxylation of (E)-6-(1-alkenyl) substituted β-resorcylic acids indicated the influence of this substituent on the chemical behavior of these compounds. These mimics were already used for the development of optimized standard protocols for the synthesis of phase II metabolites of ZEN (glucosides, glucuronides), and further applications (i.e., sulfate conjugates) are still under investigation. Supplemental materials are available for this article. Go to the publisher's online edition of Synthetic Communications to view the free supplemental file.

Full text of DOI:10.1080/00397911.2012.681827

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Zearalenone Mimics: Synthesis of (E)-6-
(1-Alkenyl)-substituted β-Resorcylic Acid
Esters
Hannes Mikula a , Christian Hametner a & Johannes Fröhlich a
a Institute of Applied Synthetic Chemistry, Vienna University of
Technology, Vienna, Austria
Accepted author version posted online: 10 Jan 2013.Version of
record first published: 10 Jan 2013.
To cite this article: Hannes Mikula , Christian Hametner & Johannes Fröhlich (2013): Zearalenone
Mimics: Synthesis of (E)-6-(1-Alkenyl)-substituted β-Resorcylic Acid Esters, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry, 43:14, 1939-1946
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Synthetic Communications1, 43: 1939–1946, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2012.681827
ZEARALENONE MIMICS: SYNTHESIS OF
(E)-6-(1-ALKENYL)-SUBSTITUTED
b-RESORCYLIC ACID ESTERS
¨
Hannes Mikula, Christian Hametner, and Johannes Frohlich
Institute of Applied Synthetic Chemistry, Vienna University of Technology,
Vienna, Austria
GRAPHICAL ABSTRACT
Abstract Two versatile strategies for the synthesis of mimics of the Fusarium mycotoxin
zearalenone (1) have been developed. Optimized preparation of (E)-6-(1-alkenyl)
substituted b-resorcylic acid esters was realized via ortho-directed lithiation of variable
substrates combined with allylation/isomerization or via formylation/Schlosser–Wittig
olefination using different protective group patterns. Spontaneous decarboxylation of
(E)-6-(1-alkenyl) substituted b-resorcylic acids indicated the influence of this substituent
on the chemical behavior of these compounds. These mimics were already used for the
development of optimized standard protocols for the synthesis of phase II metabolites
of ZEN (glucosides, glucuronides), and further applications (i.e., sulfate conjugates)
are still under investigation.
Supplemental materials are available for this article. Go to the publisher’s online edition
of Synthetic Communications1 to view the free supplemental file.
Keywords Mycotoxin; ortho-directed lithiation; b-resorcylic acid ester; Schlosser–Wittig
olefination; zearalenone
INTRODUCTION
The rapid global re-emergence of Fusarium head blight disease of wheat and
barley in the last 30 years along with contamination of grains with mycotoxins have
spurred basic research on the fungal causal agent. Therefore Fusarium graminearum
quickly has become one of the most intensively studied fungal plant pathogens.[1]
One of the mycotoxins formed from this organism is the macrolide zearalenone
(1) (Fig. 1). This toxin acts as an estrogenic substance and is responsible for many
Received February 13, 2012.
Address correspondence to Hannes Mikula, Institute of Applied Synthetic Chemistry, Vienna
University of Technology, Getreidemarkt 9=163-OC, Vienna 1060, Austria. E-mail: hannes.mikula@
tuwien.ac.at
1939

¨
H. MIKULA, C. HAMETNER, AND J. FROHLICH
1940
Figure 1. Structure of zearalenone and substituted b-resorcylic acid esters as mimics for conjugations at
the reactive site of zearalenone.
breeding problems, especially infertility in swine.[2] Modern analytical methods made
the detection of even small amounts of zearalenone (ZEN) possible and therefore
safety values in food and feed were introduced.[3] One problem remaining is the
occurrence of so- called masked mycotoxins, which are formed during phase II
detoxification in plants, animals, and humans by conjugation of the toxin with
hydrophilic moieties such as sugars, amino acids, or sulfate. These metabolites are
usually not detected by using standard protocols and quantification is not possible
because of lack of reference materials.[4] Glucuronides formed during xenobiotic
metabolism are also considered to serve as possible biomarkers for daily uptake
measurements.[5,6]
In the course of our research to synthesize zearalenone conjugates as reference
materials for bioanalytical studies as well as potential biomarkers, we became very
interested in the design and synthesis of (E)-6-(1-alkenyl)-substituted b-resorcylic
acid esters as mimics for this mycotoxin (Fig. 1) in the development of synthetic stra-
tegies toward such conjugates. These mimics may also be used instead of expensively
isolated and purified mycotoxin in metabolization or chemical reaction studies, for
example, the decarboxylation of ZEN after hydrolysis of the lactone moiety as
described first by Shipchandler[7] or recently by Utermark and coworkers.[8]
In this article we report different strategies for the synthesis of (E)-6-(1-
alkenyl)-substituted b-resorcylic acid esters as mimics for zearalenone.
RESULTS AND DISCUSSION
The site of conjugation of ZEN, therefore responsible for most metabolization
reactions, is basically a b-resorcylic acid ester substituted in position 6.
Simple mimics were obtained by esterification of 2,4-dihydroxybenzoic acid (2),
yielding the corresponding methyl ester (3)[9] and isopropyl ester (4). A second
approach led us to 6-methyl substituted resorcylic acid esters. After condensation
of ethyl acetoacetate and ethyl crotonate,[10] the formed intermediate was aromatized
by bromination and elimination of hydrogen bromide following a known pro-
cedure[11] to afford the ethyl ester 5 in 56% overall yield (data identical with those
reported in the literature.[12]) Basic transesterification using a method described
by Kumar et al.[13] yielded 2,4-dihydroxy-6-methylbenzoic acid isopropyl ester (6)
(Scheme 1).

SYNTHESIS OF ZEARALENONE MIMICS
1941
Scheme 1. Reagents and conditions: (a) cat. H2SO4, MeOH, reflux, 96 h, 89%; (b) NaH, 2-bromopropane,
DMF, 80 ꢁC, 12 h, 74%; (c) NaOEt, EtOH, reflux, 2 h; (d) Ac2O, Br2, reflux, 2 h then HBr, H2O, reflux, 2 h,
56% over two steps); and (e) Na, isopropanol, reflux, 24 h, 81%.
Because many 6-alkyl substituted resorcylic acids and 2,4,6-trihydroxybenzoic
acid are stable compounds and often described in literature, we thought about the
influence of an (E)-6-(1-alkenyl) substituent, such as that present in zearalenone,
which undergoes spontaneous decarboxylation after ester hydrolysis. Excluding
enzymatic reactions, we assume that the substituent in position 6 is crucial for the
decarboxylation step and therefore important for the reactivity and the structure
of ZEN mimics. Thus different strategies, all containing an ortho-directed lithiation
as key step, were applied to prepare (E)-6-(1-alkenyl) substituted b-resorcylic acid
esters (Scheme 2).
Scheme 2. Reagents and conditions: (a) TMEDA, s-BuLi, THF, 30 min, ꢀ90 ꢁC then allyl bromide, 2 h,
ꢀ80 ꢁC, 44%; (b) (CH3CN)2PdCl2, CH2Cl2, 24 h, room temperature (rt); (c) NaH, THF, 0 ꢁC, 1 h then
2-bromopropane, 12 h, rt, 73% (over two steps); (d) BBr3, CH2Cl2, 24 h, ꢀ15 ꢁC, 59 %; (e) SOCl2, 3 h,
reflux then HNEt2, 15 h, rt; (f) NaH, THF, 1 h, 0 ꢁC then TBDMS-Cl, 1 h, rt, 94%; (g) AlMe3, HNR2,
50 min, rt then 12, 20 h, reflux, 72% (14), 76% (15); (h) t-BuLi, THF, 1 h, ꢀ80 ꢁC then CuBr . Me2S,
30 min, ꢀ15 ꢁC then allyl bromide, ꢀ80 ꢁC to rt, 56% (16), 71% (17), 82% (18); (i) (CH3CN)2PdCl2, EtOH,
24 h, rt, 89% (19), 83% (20), 88% (21); (j) BBr3, CH2Cl2, 15 h, ꢀ80 ꢁC to rt; (k) Me3O(BF4), CH2Cl2, 15 h,
rt then Na2CO3, H2O, MeOH, 6 h, rt, 87% (from 20), 86% (from 21), 69% (over two steps from 19); (l) Na,
isopropanol, reflux, 24 h, 90%.

¨
H. MIKULA, C. HAMETNER, AND J. FROHLICH
1942
As first starting material for the lithiation, commercially available 2,4-
dimethoxybenzoic acid (7) seemed to be applicable as it was used and described
by Vintonyak et al.[14] Metalation with s-BuLi=tetramethylenediamine (TMEDA)
and reaction with allyl bromide yielded only 44% of compound 8. After changing
different reaction parameters (temperature, reaction time, and number of equivalents
of s-BuLi), the yield of this reaction was not improved and still far from values
described in the original procedure (79% crude and 51% after subsequent methyl
esterification). Stereoselective double-bond isomerization was achieved using cata-
lytic amounts of bis(acetonitrile)palladium(II) dichloride in dichloromethane. The
crude product 9 was converted to isopropyl ester 10 (73% over two steps) and methyl
protective groups were then cleaved by reaction with BBr3 to yield the first (E)-6-
1
(1-alkenyl) substituted ZEN mimic 11, which was characterized by H NMR to
confirm the E configuration of the conjugated double bond (JCH¼CH ¼ 15.5 Hz).
To optimize the lithiation step, compound 7 was converted to N,N-diethyl-
2,4-dimethoxybenzamide (13) following an already reported procedure,[15] and methyl
ester 12[16] was reacted with AlMe3/HNMe2 or AlMe3/HNEt2 to yield the tert-
butyldimethylsilyl (TBDMS)–protected benzamides 14 and 15,[16] respectively. After
lithiation, transmetalation, and alkylation, yielding 16, 17, and 18 in yields up to 82%
(for 18), the allyl substituent in position 6 was isomerized using again (CH3CN)2PdCl2
as catalyst to afford 19, 20, and 21 in good yields (83–89%). In this case, no conversion
was observed using CH2Cl2 as solvent as used before for the synthesis of 9 and described
in literature.[17,18] Thus different protic solvents were screened to accelerate proton trans-
fer, and dry ethanol gave the best results. After demethylation of (E)-N,N-diethyl-6-(1-
propenyl)benzamide (19) using BBr3 to yield compound 22, the corresponding methyl
ester 23 was prepared by reaction with trimethyloxonium tetrafluoroborate (69% over
two steps). Using these reaction conditions the TBDMS–protected benzamides 20 and
21 could be directly converted to 23 in good yields (>85%). Basic transesterification
was achieved using sodium isopropoxide to yield 11 (90%).
After basic hydrolysis of compounds 11 and 23 we observed spontaneous
decarboxylation to 24, which was identified by comparison of spectral data with
those reported in the literature.[19] As already mentioned, this reaction also occurs
after ZEN hydrolysis (Scheme 3), which indicates the influence of an (E)-6-(1-
alkenyl) substituent on the chemical behavior of b-resorcylic acid esters.
Scheme 3. Spontaneous decarboxylation after basic hydrolysis of (E)-6-(1-alkenyl) substituted b-resorcylic
acid esters 11, 23, and zearalenone (1).

SYNTHESIS OF ZEARALENONE MIMICS
1943
Scheme 4. Reagents and conditions: (a) t-BuLi, THF, 2 h, ꢀ80 ꢁC then DMF, 2 h, ꢀ80 ꢁC to 0 ꢁC, 73%;
(b) EtPh3PþBrꢀ (for 21) or PrPh3PþBrꢀ (for 26), LiBr, PhLi, THF, ꢀ75 ꢁC to 20 ꢁC then 25, PhLi, 90 min,
ꢀ75 ꢁC to rt to ꢀ75 ꢁC then HCl/Et2O and KOtBu, 1 h, rt, 74% (21), 71% (26); (c) Me3O(BF4), CH2Cl2,
15 h, rt then Na2CO3, H2O, MeOH, 6 h, rt, 81% (23), 85% (27); (d) Na, 2-butanol, 24 h, reflux, 66%.
Another versatile strategy using a Schlosser–Wittig olefination[20] as key step
was developed for the synthesis of (E)-6-(1-alkenyl)-substituted ZEN mimics
(Scheme 4). Benzamide 15 was formylated by quenching with dimethylformamide
after t-BuLi lithiation without transmetalation to yield compound 25 (73%). Stereo-
selective olefination [E=Z ratio of 8=1 as determined by gas chromatography–mass
spectrometric (GC=MS] analysis) afforded the desired products 21 (in comparison
to the allylation=isomerization approach described previosly) and 26 in 74% and
71% yields, respectively. After TBDMS deprotection and simultaneous conversion
of the diethylamide to the corresponding methyl ester using trimethyloxonium
tetrafluoroborate, basic transesterification of 27 was achieved using sodium in
2-butanol to yield the ZEN mimic 28 (29% overall yield starting from 15).
In conclusion, different approaches to the synthesis of unsaturated substituted
b-resorcylic acid esters as mimics for the mycotoxin zearalenone and other natural
products were demonstrated and used to prove spontaneous decarboxylation of
(E)-6-(1-alkenyl)-b-resorcylic acids.
Ortho-directed lithiation of the TBDMS-protected benzamide 15 using t-BuLi
combined with either Pd-catalyzed double-bond isomerization after quenching with
allyl bromide or formylation and subsequent Schlosser–Wittig olefination gave the
best results for versatile introduction of (E)-6-(1-alkenyl) substituents to b-resorcylic
acid derivatives. Because allylic halides and aldehydes are readily available as syn-
thetic building blocks, these approaches may be useful for the preparation of many
similar compounds as well as b-resorcylic acid lactones (RALs).
An optimized procedure for the chemical O-glucuronidation of these mimics and
the first reported chemical synthesis of ZEN-14-b,D-glucuronide was published very
recently.[21] Chemical sulfation of b-resorcylic acid esters and synthesis of zearalenone
sulfates are currently under investigation using the herein reported ZEN mimics.
EXPERIMENTAL
All reactions were performed under an argon atmosphere. The progress of the
reactions was monitored by thin-layer chromatography (TLC) over silica gel 60 F254

¨
H. MIKULA, C. HAMETNER, AND J. FROHLICH
1944
(Merck). The chromatograms were visualized by irradiation with ultraviolet light or
by heat staining with ceric ammonium molybdate in ethanol=sulfuric acid. Column
chromatography was performed on silica gel 60 (Merck, 40–63 mm) using a Buchi
¨
Sepacore Flash system. 1H and 13C NMR spectra were recorded on a Bruker
DPX 200-MHz or Avance DRX 400-MHz spectrometer. Data were recorded and
evaluated using Topspin 1.3 (Bruker Biospin). All chemical shifts are given in parts
per million (ppm) relative to tetramethylsilane (TMS). The calibration was done
using residual solvent signals. Multiplicities are abbreviated as s (singlet), d
(doublet), t (triplet), q (quartet), and b (broad signal).
General Procedure for Lithiation and Allylation of Benzamides 13–15
Benzamide 13, 14, or 15 (5 mmol) was dissolved in dry THF (20 ml), and
t-BuLi (7.5 ml, 12.75 mmol, 1.7 M in pentane) was added dropwise at ꢀ80 ꢁC and
the yellow-orange solution was stirred for 1 h. After addition of CuBr . Me2S
(2.26 g, 11 mmol), the reaction mixture was slowly warmed to ꢀ15 ꢁC and stirred
for 30 min. Allyl bromide (3.02 g, 25 mmol) was then added dropwise at ꢀ80 ꢁC,
and after warming to room temperature, the reaction mixture was filtered through
celite, diluted with EtOAc (50 ml), and washed with water (2 ꢂ 60 ml). The organic
layer was dried over Na2SO4 and evaporated. The residue was purified by column
chromatography (hexanes/EtOAc, 8:1 to 2:1) to afford the desired product.
General Procedure for Pd-Catalyzed Isomerization of 16–18
Benzamide 16, 17, or 18 (2.5 mmol) was dissolved in dry ethanol (10 ml) and
(CH3CN)2PdCl2 (65 mg, 0.25 mmol) was added. The reaction mixture was stirred
for 24 h at room temperature, filtered through celite, and concentrated. The residue
was purified by column chromatography (hexanes/EtOAc, 8:1 to 2:1) to afford the
desired product.
General Procedure for Schlosser–Wittig Olefination
Phenyllithium solution (1.9 ml, 3.6 mmol, 1.9 M in dibutyl ether) was slowly
added to a suspension of alkyl triphenylphosphonium bromide (3.6 mmol) and LiBr
(624 mg, 7.2 mmol) in dry THF (40 ml) at ꢀ75 ꢁC. After 30 min of vigorous stirring
at room temperature, the reaction mixture was cooled to ꢀ75 ꢁC to be treated with
compound 25 (1.40 g, 3 mmol) dissolved in dry THF (10 ml). A few minutes later,
complete decolorization occurred, again with phenyllithium solution (1.9 ml,
3.6 mmol, 1.9 M in dibutyl ether). After stirring each time 30 min at ꢀ75 ꢁC, room
temperature, and again ꢀ75 ꢁC, hydrogen chloride (3.6 ml, 3.6 mmol, 1 M in Et2O)
was added. After addition of potassium tert-butoxide (448 mg, 4 mmol), the reaction
mixture was stirred 1 h at room temperature before being poured into water (200 ml)
and extracted with CH2Cl2 (3 ꢂ 200 ml). The combined organic layer was dried over
Na2SO4 and evaporated. Purification by column chromatography (hexanes=EtOAc,
5:1 to 3:1) yielded the desired E-configured olefins.
The Supplemental Material, available online, contains experimental details and
characterization data for compounds 4, 10, 11, 14, 16–23 and 25–28. Furthermore,

SYNTHESIS OF ZEARALENONE MIMICS
1945
1H and 13C NMR chemical shifts of ZEN mimics 4, 11, and 28 were compared with
those of zearalenone (1).
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