Probing the influence of an allylic methyl group in zearalenone analogues on binding to Hsp90

Article abstract of DOI:10.1002/chem.201001752

By the replacement of an acetate with propionate by means of organic synthesis, a range of zearalenone analogues were prepared that feature an allylic methyl group. For the synthesis of the aliphatic region of the analogues, we used an asymmetric alkylati

Full text of DOI:10.1002/chem.201001752

FULL PAPER
DOI: 10.1002/chem.201001752
Probing the Influence of an Allylic Methyl Group in Zearalenone
Analogues on Binding to Hsp90
Christian Rink,[a] Florenz Sasse,[b] Asta Zubriene˙,[c] Daumantas Matulis,[c] and
Martin E. Maier*[a]
Dedicated to Professor Richard R. Schmidt on the occasion of his 75th birthday
Abstract: By the replacement of an
acetate with propionate by means of
organic synthesis, a range of zearale-
none analogues were prepared that
feature an allylic methyl group. For the
synthesis of the aliphatic region of the
analogues, we used an asymmetric al-
kylation to yield pentenol derivatives
16 and ent-16. By means of hydrobora-
tion the corresponding aldehydes were
secured. These were coupled with 2-
pentynol derivate 23 by means of a
Carreira acetylide addition. Further
routine steps led to the sulfones 29 and
45, respectively. After merging them
with 2-bromobenzaldehyde in
ketone stereoisomers were accessible.
In all, considering various protecting-
group decorations, 16 analogues were
obtained and tested for cytotoxicity
(L929 mouse fibroblast cell line).
Whereas most of the analogues were
less active than zearalenone (IC50 =
9.4 mm), the resorcinol derivatives were
comparable, with one stereoisomer
(40b) being slightly more active (IC50 =
6.6 mm). These results were also reflect-
ed in the binding assays to Hsp90 in
which 40b showed a dissociation con-
stant (Kd) value of 130 nm.
9
a
Julia–Kocienski reaction, metalation,
carboxylation, and protecting-group
manipulations gave the seco acids 35
and 49. By means of lactonization
under Mitsunobu (alcohol activation)
or Trost–Kita conditions (carboxyl acti-
vation), all four possible macrocyclic
Keywords: asymmetric synthesis ·
Hsp90 · macrolactonization · natu-
ral products · zearalenone
Introduction
the structural diversity among natural products is broader as
compared with synthetic small molecules. Moreover, only
about half of the natural-product-based drugs fully comply
with the Lipinski Rule of Five. The other half violate these
rules with the exception of the logP value.[2] On the other
hand, natural products share a common feature with syn-
thetic drugs, namely, clustering of similar compounds. In me-
dicinal chemistry, similar structures with comparable mode
of action are known as “me-too” drugs. With natural prod-
ucts, their diversity and similarity can be traced back to bio-
synthetic strategies. Thus, only a few building blocks are in
use, but repeated incorporation and branching leads to dif-
ferent scaffolds.[3] The tailoring of reactions—such as redox
reactions—on certain structures produce the compound
clusters. Despite their structural similarity, compounds from
a cluster (for example, steroids) may still have large differ-
ences in biological activity. Even though a large number of
natural products is known, many more seem theoretically
possible. Thus, about 10000 polyketide structures have been
isolated up to now.[4,5] However, according to a theoretical
analysis of polyketide biosynthesis, a billion structures seem
possible.[4c] In this regard, some key questions arise, such as
Various bioinformatic studies that employ chemical descrip-
tors highlight the difference in chemical space occupied by
natural products versus drugs.[1] In particular, it seems that
[a] Dipl.-Chem. C. Rink, Prof. Dr. M. E. Maier
Institut fꢀr Organische Chemie
Universitꢁt Tꢀbingen
Auf der Morgenstelle 18
72076 Tꢀbingen (Germany)
Fax : (+49)7071-2975247
E-mail: martin.e.maier@uni-tuebingen.de
[b] Dr. F. Sasse
Abteilung Chemische Biologie
Helmholtz-Zentrum fꢀr Infektionsforschung
Inhoffenstrasse 7, 38124 Braunschweig (Germany)
˙
[c] Dr. A. Zubriene, Prof. Dr. D. Matulis
Laboratory of Biothermodynamics and Drug Design
Institute of Biotechnology
Graiciu¯no 8, Vilnius LT-02241 (Lithuania)
ˇ
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201001752.
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why only such a small number is made biosynthetically and
why many conceivable structures are not known. Certainly,
nature might have missed some opportunities. For example,
polyketides are typically comprised of acetates and propio-
nate building blocks in various ratios. Surprisingly, some
polyketides are made up only of propionates, such as eryth-
ronolide B (1), whereas others such as zearalenone (2) rep-
resent pure polyacetates. The latter are typical for fungi,
analogue 6 does not bind to Hsp90 as determined by ther-
mal shift assay. Whereas the biosynthesis of polyketides is
akin to an assembly line, organic synthesis strives to be con-
vergent and treelike. As a consequence, the replacement of
an acetate by a propionate in zearalenone requires a differ-
ent synthesis strategy for each acetate replacement. In this
paper, we describe the synthesis and biological studies of
zearalenone analogues with a methyl group in the allylic po-
sition; that is, the fifth acetate was replaced by a propionate.
Results and Discussion
Chemistry: Although ring-closing metathesis (RCM) seems
like the best option for the formation of the macrolactone
ring,[18] we thought that the allylic methyl group might have
a detrimental influence on the outcome of the RCM. There-
fore, we opted for a classical macrolactonization approach.
Also, we wanted to prepare all possible diastereomers with
the methyl-bearing centers in a stereocontrolled manner.
Accordingly, the plan was to form the E double bond by
means of Julia–Kocienski olefination. In this setup, C-3’-Me
would be installed by asymmetric alkylation. As has been
described by Pan et al.[19] in the synthesis of aigialomycin D,
the carboxylic function of the orsellinic subunit would be in-
stalled at a late stage through an aryl lithium intermediate
(Scheme 1). Two aliphatic subunits 11 and 12, each contain-
ing a stereogenic center, would be combined by means of a
Carreira acetylide–aldehyde coupling.
since their biosynthetic machinery only can incorporate ace-
tates. Accordingly, incorporating the other lacking building
block into these structures, either in erythronolide B or
polyacetate-based macrolactones, should provide interesting
analogues. Considering this, we conceived the concept of
propionate scanning and applied it to the macrolide zearale-
none (2).[6,7] This benzolactone, which is of fungal origin,
consists of nine acetates.[8] Replacing the second acetate led
to propionate analogues of zearalenone that bind to the
heat shock protein 90 (Hsp90).[7] Compounds 3 and ent-3
showed dissociation constant (Kd) values of 0.33 and
0.25 mm, respectively. Hsp90 and related proteins are chaper-
ones that promote folding of denatured proteins. Since sev-
eral client proteins of Hsp90 are involved in cancer, Hsp90
is a promising target for cancer treatment.[9] Whereas a
range of heterocycles bind to the adenosine triphosphate
(ATP) pocket of Hsp90,[10] the natural products radicicol[11]
(4) and geldanamycin[12] (5) were also found to bind to
Hsp90. Both natural products stimulated the development
of synthetic analogues.[13–17]
Scheme 1. Retrosynthetic analysis for zearalenone analogues of type 7;
P=protecting group.
The synthesis of the aliphatic building block 29 is shown
in Scheme 2. Allylation of propionyloxazolidinone[20] 13,
which contained the Seebach auxiliary,[21] provided penteno-
yl derivative 14. Reductive removal of the auxiliary and
benzylation of alcohol 15 furnished ether 16. Hydroboration
of the double bond and Swern oxidation[22] of alcohol 17
À
Benzolactone 6, which features a propionate in place of
the fourth acetate, turned out to be an inhibitor for human
carbonyl reductase 1.[6] In contrast to zearalenone (2) itself,
gave rise to aldehyde 18, which corresponds to the C6’ C2’
region of the designed zearalenone analogues. The aldehyde
18 would be used as electrophile in an addition reaction
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Zearalenone Analogues
FULL PAPER
sulting in propargylic alcohol 24 (62%) as a single diastereo-
mer. After methoxymethyl ether (MOM) protection, cata-
lytic hydrogenation removed the triple bond and the benzyl
ether to provide primary alcohol 26. By means of Mitsunobu
substitution with 1-phenyl-1H-tetrazole-5-thiol (27) and sub-
sequent oxidation of thioether 28, sulfone 29 could be se-
cured on a gram scale.
Preparation of the aromatic aldehyde 9 commenced with
benzylalcohol[27] 30. Bromination with N-bromosuccinimide
(NBS)[28] provided aryl bromide 31, which was oxidized with
pyridinium chlorochromate to yield aldehyde[28,29]
(Scheme 3).
9
Scheme 3. Synthesis of 2-bromo-3,5-dimethoxybenzaldehyde (9). PCC=
pyridinium chlorochromate.
The two building blocks, benzaldehyde 9 and sulfone 29,
were combined by means of Julia–Kocienski coupling[30] by
using KN
N
This gave E alkene 32 in good yield. The subsequent metala-
tion and carboxylation proved challenging. Thus, metalation
with nBuLi (THF, À808C) followed by quenching the aryl-
lithium intermediate with CO2 (solid or gas) did not give
high yields of the corresponding benzoic acid. More consis-
tent results were obtained with methyl chlorocarbonate
(5 equiv), thereby providing ester 33 in good yield. Cleavage
of the silyl ether and saponification of the ester function led
to seco acid 35.
Scheme 2. Synthesis of aliphatic building block 29. NaHMDS=sodium
bis(trimethylsilyl)amide,
[3.3.1]nonane, TBS=tert-butyldimethylsilyl, DIPEA=N,N-diisopropyl-
ethylamine, DEAD=diethyl azodicarboxylate, mCPBA=meta-chloro-
Bn=benzyl,
9-BBN=9-borabicyclo-
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
perbenzoic acid.
with an alkyne. A suitable alkyne could be obtained from
(S)-propylenoxide 19 and trimethylsilyl acetylide. Alcohol
protection of homopropargylic alcohol[23] 21 to silyl ether[24]
22 and removal of the trimethylsilyl group provided frag-
ment 23. Aldehyde 18 and alkyne[25] 23 were now combined
by means of a Carreira reaction.[26] This secured uniform in-
termediates in subsequent transformations. Thus, N-methyl-
ephedrine (1.1 equiv), Et3N, and zinc triflate (1.1 equiv)
were combined followed by addition of alkyne 23
(1.1 equiv) and finally aldehyde 18 (1.0 equiv), thereby re-
Scheme 4. Synthesis of seco acid 35 by means of Julia coupling and car-
boxylation. TBAF=tetrabutylammonium fluoride.
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14471

M. E. Maier et al.
According to previous experience, macrolactonization is
generally possible with such sterically hindered hydroxy
acids under Mitsunobu conditions.[6,7,31] Indeed, lactoniza-
tion of hydroxy acid 35 (0.005m) in toluene using PPh3
(2.3 equiv) and diethyl azodicarboxylate delivered lactone
36a in 64% yield (Scheme 5). Since we also wanted to
functions proved to be more troublesome. Whereas alumi-
num triiodide (AlI3) in benzene did work to some degree on
dimethyl ether 38a, the reaction led to iodinated derivatives
as side products and gave variable yields of resorcinol 40a.
Reproducible yields of dihydroxy lactone 40a were possible
in presence of phloroglucine (5 equiv), which served as a
scavenger for iodine. In the same manner, diastereomeric
lactone 36b was converted to zearalenone analogues 37b–
40b with comparable yields for all steps.
Access to the enantiomeric series of zearalenone ana-
logues was started with propionyloxazolidinone ent-13 ((+)-
13). As described before, alkylation, reductive removal of
the auxiliary, protection of the primary alcohol as benzyl
ether, double-bond hydroboration, and oxidation led to ent-
18 (Scheme 6). By means of Carreira acetylide addition, al-
kynol 41 and then sulfone 45 could be reached. Coupling
with benzaldehyde 9, metalation, carboxylation, and protect-
Scheme 5. Lactonization of hydroxy acid 35 and refunctionalization of
lactones 36a and 36b. DMP=Dess–Martin periodinane, TBAI=tetrabu-
tylammonium iodide.
access the other diastereomer at C-10’, lactonization with
carboxyl activation was also tried. Whereas Yamaguchi con-
ditions were unsatisfactory (10% yield), the Kita–Trost var-
iant worked well.[32,33] Thus, hydroxy acid 35 was converted
to the mixed ketene acetal by ruthenium(II)-catalyzed addi-
tion to ethoxyacetylene. Thereafter, a solution of the inter-
mediate 1-ethoxyvinyl benzoate was slowly added to a hot
solution of camphorsulfonic acid (CSA) in toluene to pro-
duce lactone 36b in 84% yield. Cleavage of the MOM pro-
tecting group (HCl/MeOH) gave alcohol 37a, the oxidation
of which furnished ketone 38a. Selective cleavage of the 2-
OMe ether was possible in essentially quantitative yield to
give phenol 39a. Removal of both aromatic methyl ether
Scheme 6. Synthesis of the enantiomeric series of lactones ent-38–ent-40
from propionyloxazolidinone ent-13; for procedures and yields in this
series, see the Supporting Information.
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Zearalenone Analogues
FULL PAPER
ing-group manipulations secured seco acid 49. Macrolactoni-
zation under Kita–Trost conditions to give 50a proceeded in
84% yield, whereas Mitsunobu conditions furnished 59% of
diastereomer 50b. Through hydrolysis of the MOM acetal
to 51a and 51b, respectively, oxidation of the 6’-OH, and
cleavage of the methyl ether functions, analogues ent-38a–
ent-40a and ent-38b–ent-40b were obtained.
Biology
Growth inhibition: To assess the biological activity, ana-
logues 37a, 38a–40a, 37b, 38b–40b, 51a, ent-38a–ent-40a,
51b, and ent-38b–ent-40b (16 compounds) were tested for
growth inhibition on L929 mouse fibroblast cells. The ob-
tained IC50 values are included in Table 1. As can be seen,
Table 1. Cytoxicity of the tested macrolactones.
Compound
IC50 [mm]
37a
37b
51b
51a
38a
38b
ent-38b
ent-38a
39a
39
69
44
18
36
111
47
39
27
26
20
20
18
6.6
14
12
Figure 1. Hsp90N melting temperature (Tm) data as a function of added
ligand concentration Lt. Panels on the bottom compare denaturation
curves observed by fluorescence at 0 to 120 mm added ligand concentra-
tions. The top of the bottom panels shows data for 40b, the lower panel
for ent-40a.
39b
ent-39b
ent-39a
40a
40b
ent-40b
ent-40a
The melting curves allowed for a determination of the Kd
values, which are shown for resorcinols 40 in Table 2.
Although the strong binding of radicicol could not be
reached, zearalenone analogue 40b did display a Kd value of
130 nm.
the di-O-methyl ethers are much less active than zearale-
none (IC50 =9.4 mm). The least-active compounds are the
10’S,3’R diastereomers (10’up,3’up). There are four ana-
logues that show roughly half of the activity of zearalenone.
These are the monomethoxy analogues 39a, 39b, ent-39a,
and ent-39b. The fully deprotected analogues 40a, 40b, ent-
40a, and ent-40b turned out to be significantly more active.
Analogue 40b (IC50 =6.6 mm) is clearly more active than
zearalenone.
Table 2. Dissociation constants of selected compound binding to Hsp90N
as determined by the thermal shift assay.
Compound
Kd [mm]
40a
9.1
ent-40a
40b
ent-40b
radicicol (4)
26
0.13
182
0.001
Binding to Hsp90: The most promising analogues were then
further evaluated for binding Hsp90 by employing a thermal
shift assay.[34–36] To obtain the Kd values, the melting temper-
ature (Tm) measurements were performed at various con-
centrations for compounds ent-40a, ent-40b, 40a, and 40b,
for reasons of comparison with radicicol (4). The corre-
sponding Hsp90N melting temperature data as a function of
ligand concentration is plotted in Figure 1. Curves that show
the dependence of fluorescence on temperature for two li-
gands (ent-40a and 40b) are shown on the lower panels. The
stronger binder, 40b, shifted the Tm to a greater extent than
the weak binders. The Hsp90N protein was prepared as pre-
viously described.[37]
Conclusion
The purpose of this study was to elucidate the effect of an
additional methyl group in the binding of the fungal metab-
olite zearalenone to Hsp90. From a biosynthetic point of
view, a methyl group on a polyketide corresponds to a re-
placement of an acetate building block by a propionate.
Here we formally replaced acetate number five with a pro-
pionate, thereby resulting in zearalenone analogues with an
allylic methyl group. All four possible stereoisomers and
several differently methylated derivatives could be accessed.
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M. E. Maier et al.
tion was allowed to warm to room temperature overnight. In the case of
incomplete conversion, additional diisopropylethylamine (2.69 mL,
15.5 mmol, 5 equiv) and methoxy methylchloride (0.76 mL, 7.73 mmol,
2.5 equiv) were added at 08C under a nitrogen atmosphere and the mix-
ture was stirred again overnight at ambient temperature before saturated
NaHCO3 solution (100 mL) and CH2Cl2 (100 mL) were added. After sep-
aration of the layers, the aqueous phase was extracted with ethyl acetate
(3ꢃ150 mL). The combined organic layers were washed with saturated
NaCl solution (80 mL), dried over MgSO4, filtered, and concentrated in
vacuo. Purification by flash chromatography (petroleum ether/ethyl ace-
tate, 30:1) afforded protected MOM ether 25 (1.3 g, 92%) as a colorless
oil. Rf =0.50 (petroleum ether/EtOAc, 10:1); [a]2D0 =À90.8 (c=1.0 in
Key steps in the synthesis of the analogues include a Car-
reira acetylide addition to an aldehyde to reach the aliphatic
fragment. Its coupling with the aromatic building block was
realized by a Julia–Kocienski olefination. Halogen–metal ex-
change on the aryl bromide followed by carboxylation of
the anion led to the seco acids. Lactonization could be
ACHTUNGTRENNUNGachieved by Trost–Kita or Mitsunobu lactonization in a
stereodivergent manner. As determined by thermal shift
assay, one analogue, 40b, turned out to be a good binder
(Kd =130 nm) to Hsp90. Although this represents a focused
case study, it does underscore two important facts. Namely,
the resorcinol subunit (2,4-dihydroxy-6-alkenylbenzoic acid
part) seems to be important for binding to Hsp90. Further-
more, a methyl group represents a privileged aliphatic sub-
stituent. It seems that the secondary and tertiary structures
of proteins can provide hydrophobic pockets that can be
matched perfectly with a methyl group. The same should be
true for other privileged substituents, such as hydroxyl, keto,
or nitrogen-based groups. Accordingly, these natural sub-
stituents should be preferentially employed in drug-discov-
ery programs.
CH2Cl2); 1H NMR (400 MHz, CDCl3): d=0.05 (s, 6H; Si
9H; C
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
CH3), 1.20–1.37 (m, 1H; 7-H), 1.51–1.88 (m, 4H; 7-H, 8-H, 9-H), 2.25
(ddd, J=16.5, 7.3, 1.8 Hz, 1H; 3-H), 2.37 (ddd, J=16.4, 5.3, 1.5 Hz, 1H;
3-H), 3.25 (dd, J=9.1, 6.8 Hz, 1H; 10-H), 3.33 (dd, J=9.1, 6.8 Hz, 1H;
10-H), 3.35 (s, 3H; OCH3), 3.86–4.01 (m, 1H; 2-H), 4.24–4.31 (m, 1H; 6-
H), 4.49 (s, 2H; PhCH2), 4.56 (d, J=6.8 Hz, 1H; OCH2OCH3), 4.93 (d,
J=6.8 Hz, 1H; OCH2OCH3), 7.21–7.39 ppm (m, 5H; ar H); 13C NMR
(100 MHz, CDCl3): d=À4.7 (Si
ACHUTNTGERN(NUG CH3)2), 17.1 (9-CH3), 18.1 (CACHTUNGTRENNUNG(CH3)3),
23.4 (2-CH3), 25.8 (C(CH3)3), 29.3 (C-3 or C-8), 29.6 (C-3 or C-8), 33.3
AHCTUNGTRENNUNG
(C-9), 33.5 (C-7), 55.6 (OCH3), 66.1 (C-6), 67.6 C-2), 73.0 (C-10), 75.8
(PhCH2), 80.1 (C-5), 83.5 (C-4), 93.9 (OCH2OCH3), 127.5 (ar C), 128.3
(ar C), 138.8 ppm (ar C); HRMS (ESI): m/z: calcd for C26H44O4SiNa
[M+Na]+: 471.29011; found: 471.29003.
AHCTUNGTERG(NNUN 2R,5R,9S)-9-(tert-Butyldimethylsilyloxy)-5-(methoxymethoxy)-2-methyl-
decan-1-ol (26): A catalytic amount of palladium (10% Pd/C, 100 mg)
was added to a solution of alkyne 25 (5.5 g, 12.24 mmol) in dry THF
(100 mL). The black reaction mixture was stirred vigorously under a bal-
loon of hydrogen at room temperature. After 72 h, the reaction was fil-
tered through a pad of Celite, the filter cake was washed with THF
(100 mL), and the filtrate concentrated in vacuo. Purification by flash
chromatography (petroleum ether/ethyl acetate, 7:1) afforded alcohol 26
(4.3 g, 97%) as a colorless oil. Rf =0.20 (petroleum ether/EtOAc, 10:1);
Experimental Section
ACHTUNGTRENNUNG(2R,5S,9S)-1-(Benzyloxy)-9-(tert-butyldimethylsilyloxy)-2-methyldec-6-
yn-5-ol (24): Triethylamine (4.76 mL, 34.3 mmol, 1.5 equiv) was added to
a solution of N-methyl ephedrine (4.51 g, 25.2 mmol, 1.1 equiv) in dry tol-
uene (40 mL) under atmospheric pressure. In a separate flask, zinc tri-
flate (9.15 g, 25.2 mmol, 1.1 equiv) was dried under high vacuum at
1508C for 3 h. After cooling to room temperature, the triflate was treated
with the suspension of ephedrine/triethylamine in toluene in one portion
under a nitrogen atmosphere, and the light yellow suspension was stirred
vigorously for 2 h at ambient temperature before alkyne 23 (4.99 g,
25.2 mmol, 1.1 equiv) in dry toluene (5 mL) was added. The reaction mix-
ture was stirred for 1 h before aldehyde 18 (4.72 g, 22.9 mmol, 1.0 equiv)
in dry toluene (10 mL) was added dropwise over 4 h by syringe pump.
The light yellow mixture was allowed to warm to room temperature over-
night, before saturated NH4Cl solution (150 mL) and ethyl acetate
(150 mL) were added. After separation of the layers, the aqueous phase
was extracted with ethyl acetate (3ꢃ200 mL). The combined organic
layers were washed with saturated NaCl solution (100 mL), dried over
MgSO4, filtered, and concentrated in vacuo. Purification by flash chroma-
tography (petroleum ether/ethyl acetate, 15:1) afforded propargyl alcohol
24 (5.7 g, 62%) as a colorless oil. Rf =0.25 (petroleum ether/EtOAc,
10:1); [a]2D0 =+1.5 (c=1.0 in CH2Cl2); 1H NMR (400 MHz, CDCl3): d=
1
[a]2D0 =+16.2 (c=1.0 in CH2Cl2); H NMR (400 MHz, CDCl3): d=0.03 (s,
6H; SiACTHNUTRGENN(GU CH3)2), 0.87 (s, 9H; CCAHTUNTGREN(NUNG CH3)3), 0.92 (d, J=6.82 Hz, 3H; 2-CH3),
1.10 (d, J=6.1 Hz, 3H; 9-CH3), 1.20–1.70 (m, 11H; 2, 3, 4, 6, 7, 8-H),
3.37 (s, 3H; OCH3), 3.31–3.43 (dd, J=10.6, 6.3 Hz, 1H; 1-H) 3.46–3.55
(m, 1H; 9-H), 3.50 (dd, J=10.6, 6.3 Hz, 1H; 1-H), 3.71–3.84 (m, 1H; 5-
H), 4.64 ppm (s, 2H; OCH2OCH3); 13C NMR (100 MHz, CDCl3): d=
À4.72 (Si
N
G
ACHTUGNTRNEN(UNG CH3)3), 21.7
35.9 (C-2), 39.9 (C-8), 55.5 (OCH3), 68.2 (C-1), 68.6 (C-9), 77.8 (C-5),
95.5 ppm (OCH2OCH3); HRMS (ESI): m/z: calcd for C19H42O4SiNa
[M+Na]+: 385.27446; found: 385.17449.
5-[(2R,5R,9S)-9-(tert-Butyldimethylsilyloxy)-5-(methoxymethoxy)-2-
methyldecylthio]-1-phenyl-1H-tetrazole (28): A cooled (08C) solution of
alcohol 26 (3.22 g, 8.88 mmol, 1 equiv) in dry toluene (120 mL) was treat-
ed with 1-phenyl-1H-tetrazole-5-thiol (27) (1.90 g, 10.66 mmol, 1.2 equiv)
and triphenylphosphine (9.32 g, 35.5 mmol, 4 equiv) under a nitrogen at-
mosphere. Then diethyl azodicarboxylate (16.28 mL, 40% in toluene,
35.5 mmol, 4 equiv) was added dropwise. The brown suspension was al-
lowed to warm to room temperature over 2 h, before water (200 mL) and
ethyl acetate (200 mL) were added. After separation of the layers, the
aqueous phase was extracted with ethyl acetate (3ꢃ250 mL). The com-
bined organic layers were washed with saturated NaCl (100 mL), dried
over MgSO4, filtered, and concentrated in vacuo. Purification by flash
chromatography (petroleum ether/ethyl acetate, 9:1) afforded thioether
28 (4.0 g, 86%) as a colorless oil. Rf =0.74 (petroleum ether/EtOAc, 2:1);
[a]2D0 =+11.5 (c=1.0 in CH2Cl2); 1H NMR (400 MHz, CDCl3): d=0.03
0.06 (s, 3H; SiACHTUNGTRENNUNG(CH3)2), 0.07 (s, 3H; SiACHTUNRTEGNNG(UN CH3)2), 0.88 (s, 9H; CACHTUNGTRENN(UNG CH3)3), 0.94
(d, J=6.6 Hz, 3H; 2-CH3), 1.19–1.34 (m, 1H; 4-H), 1.51–1.89 (m, 4H; 2-
H, 3-H, 4-H), 2.25 (ddd, J=16.4, 7.2, 1.9 Hz, 1H; 8-H), 2.37 (ddd, J=
16.4, 5.6, 1.8 Hz, 1H; 8-H), 3.26 (dd, J=9.1, 6.6 Hz, 1H; 1-H), 3.32 (dd,
J=9.1, 6.1 Hz, 1H; 1-H), 3.86–3.93 (m, 1H; 9-H), 4.28–4.37 (m, 1H; 5-
H), 4.49 (s, 2H; PhCH2), 7.22–7.39 ppm (m, 5H; ar H); 13C NMR
(100 MHz, CDCl3): d=À4.64 (Si
ACHUTNTGERN(NUG CH3)2), 17.1 (2-CH3), 18.1 (CCAHUTNGTREN(NUGN CH3)3),
23.3 (C-10), 25.8 (C(CH3)3), 29.2 (C-8), 29.6 (C-3), 33.3 (C-2), 35.5 (C-4),
ACHTUNGTRENNUNG
63.0 (C-5), 67.6 (C-9), 73.0 (C-1), 75.7 (PhCH2), 82.6 (C-6 or C-7), 82.9
(C-6 or C-7), 127.5 (ar C), 128.3 (ar C), 138.7 ppm (ar C); HRMS (ESI):
m/z: calcd for C24H40O3SiNa [M+Na]+: 427.26389; found: 427.26420.
(d, J=2.5 Hz, 6H; SiACHTNUTRGENN(UG CH3)2), 0.86 (s, 9H; CAHCUTNGTREN(NUGN CH3)3), 1.04 (d, J=6.6 Hz,
3H; 2-CH3), 1.10 (d, J=6.1 Hz, 3H; 9-CH3), 1.15–1.75 (m, 10H; 3, 4, 6,
7, 8-H), 1.86–2.00 (m, 1H; 2-H), 3.27 (dd, J=12.6, 7.3 Hz, 1H; 1-H), 3.35
(s, 3H; OCH3), 3.45 (dd, J=12.6, 7.3 Hz, 1H; 1-H), 3.47–3.54 (m, 1H; 9-
H), 3.71–3.83 (m, 1H; 5-H), 4.62 (s, 2H; OCH2OCH3), 7.46–7.63 ppm
[ACHTUNGTRENNUNG(2R,6S,9R)-10-(Benzyloxy)-6-(methoxymethoxy)-9-methyldec-4-yn-2-
yloxy](tert-butyl)dimethylsilane (25): Diisopropylethylamine (5.38 mL,
30.9 mmol, 10 equiv), methoxy methylchloride (1.52 mL, 15.5 mmol,
5 equiv), and tetrabutylammonium iodine (114 mg, 0.31 mmol, 0.1 equiv)
were added to a cooled (08C) solution of propagyl alcohol 24 (1.25 g,
3.09 mmol, 1 equiv) in dry CH2Cl2 (30 mL). The stirred, light yellow solu-
(m, 5H; ar H); 13C NMR (100 MHz, CDCl3): d=À4.7 (Si
(CH3)2), À4.4
(Si
(C
AHCTUNGTRENNG(NU CH3)3), 31.3 (C-4), 31.5 (C-1), 33.1 (C-2), 34.4 (C-3), 39.8 (C-6), 40.4
14474
www.chemeurj.org
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 14469 – 14478

Zearalenone Analogues
FULL PAPER
(C-8), 55.6 (OCH3), 68.5 (C-9), 77.4 (C-5), 95.4 (OCH2OCH3), 123.9 (ar
C), 129.8 (ar C), 130.1 (ar C), 133.8 (ar C), 154.6 ppm (hetaryl C);
HRMS (ESI): m/z: calcd for C26H46N4O3SSiNa [M+Na]+: 545.29521;
found: 545.294970.
1 equiv) in dry THF (4 mL) under a nitrogen atmosphere, and the result-
ing yellow solution was stirred for 30 min. Then freshly distilled methyl
chlorocarbonate (0.036 mL, 0.436 mmol, 5 equiv) was added dropwise at
À808C and the reaction was stirred for 1 h at À808C. The colorless solu-
tion was allowed to warm to room temperature over 1 h, before saturated
NH4Cl solution (50 mL) and ethyl acetate (50 mL) were added. After
separation of the layers, the aqueous phase was extracted with ethyl ace-
tate (3ꢃ50 mL). The combined organic layers were washed with saturat-
ed NaCl solution (30 mL), dried over MgSO4, filtered, and concentrated
in vacuo. Purification by flash chromatography (petroleum ether/ethyl
acetate, 7:1) afforded benzoate 33 (35.8 mg, 75%) as a colorless oil. Rf =
0.25 (petroleum ether/EtOAc, 9:1); [a]2D0 =À13.0 (c=0.6 in CH2Cl2);
5-[(2R,5R,9S)-9-(tert-Butyldimethylsilyloxy)-5-(methoxymethoxy)-2-
methyldecylsulfonyl]-1-phenyl-1H-tetrazole (29): Predried m-chloroper-
benzoic acid (1.42 g, 5.74 mmol, 3 equiv) in dry CH2Cl2 (5 mL) was
added dropwise to
a cooled (08C) solution of thioether 28 (1.0 g,
1.91 mmol, 1 equiv) in dry CH2Cl2 (15 mL) under a nitrogen atmosphere,
and the white suspension was stirred 24 h at ambient temperature. In
case of incomplete conversion (TLC control), additional m-chloroperben-
zoic acid (0.95 g, 3.83 mmol, 2 equiv) in dry CH2Cl2 (5 mL) was added
dropwise and the mixture stirred again 24 h at ambient temperature
before aqueous sodium thiosulfate/1m sodium hydroxide (70 mL) and
CH2Cl2 (70 mL) were added. After separation of the layers, the aqueous
phase was extracted with CH2Cl2 (3ꢃ100 mL). The combined organic
layers were washed with saturated NaCl solution (50 mL), dried over
MgSO4, filtered, and concentrated in vacuo. Purification by flash chroma-
tography (petroleum ether/ethyl acetate, 9:1) afforded sulfone 29 (1.0 g,
1H NMR (400 MHz, CDCl3): d=0.02 (s, 6H; Si
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
3H; 3’-CH3 or 10’-CH3), 1.18–1.66 (m, 10H; 4’, 5’, 7’, 8’, 9’-H), 2.15–2.35
(m, 1H; 3’-H), 3.36 (s, 3H; OCH2OCH3), 3.47–3.55 (m, 1H; 6’-H), 3.72–
3.81 (m, 1H; 10’-H), 3.79 (s, 3H; OCH3), 3.82 (s, 3H; OCH3), 3.87 (s,
3H; OCH3), 4.63 (s, 2H; OCH2OCH3), 6.00 (dd, J=15.7, 7.8 Hz, 1H; 2’-
H), 6.29 (d, J=15.7 Hz, 1H; ar H), 6.33 (d, J=2.3 Hz, 1H; ar H),
6.56 ppm (d, J=2.0 Hz, 1H; 1’-H); 13C NMR (100 MHz, CDCl3): d=À4.7
96%) as a colorless oil. Rf =0.6 (petroleum ether/EtOAc, 2:1); [a]D20
+12.1 (c=1.0 in CH2Cl2); 1H NMR (400 MHz, CDCl3): d=0.02 (s, 3H;
Si(CH3)2), 0.03 (s, 3H; Si(CH3)2), 0.87 (s, 9H; C(CH3)3), 1.10 (d, J=
=
(Si
G
G
ACHTNUGRTEN(NUGN CH3)3), 20.5 (3’-CH3), 21.7 (C-8’),
23.8 (10’-CH3), 25.9 (CAHCTUNTGRENNUNG
A
R
ACHTUNGTRENNUNG
(C-3’), 39.9 (C-9’), 52.2 (CO2CH3), 55.5 (OCH3), 56.0 (OCH2OCH3), 68.6
(C-10’), 77.4 (C-6’), 95.45 (OCH2OCH3), 97.4 (ar C), 101.6 (ar C), 115.4
(C-1), 125.3 (C-1’), 138.0 (C-2’), 139.8 (C-2), 158.0 (C-1), 161.4 (ar
COCH3), 168.6 ppm (CO2CH3); HRMS (ESI): m/z: calcd for
C24H52O7SiNa [M+Na]+: 575.33745; found: 575.33750.
6.1 Hz, 3H; 9-CH3), 1.17 (d, J=6.6 Hz, 3H; 2-CH3), 1.20–1.72 (m, 10H;
3, 4, 6, 7, 8-H), 2.27–2.40 (m, 1H; 2-H), 3.35 (s, 3H; OCH3), 3.46–3.54
(m, 1H; 5-H), 3.59 (dd, J=14.5, 8.0 Hz, 1H; 1-H), 3.71–3.80 (m, 1H; 9-
H), 3.81 (dd, J=14.7, 4.8 Hz, 1H; 1-H), 4.59–4.67 (m, 2H; OCH2OCH3),
7.55–7.72 ppm (m, 5H; ar H); 13C NMR (100 MHz, CDCl3): d=À4.7 (Si-
Methyl 2-[(3R,6R,10S,E)-10-hydroxy-6-(methoxymethoxy)-3-methylun-
dec-1-enyl]-4,6-dimethoxybenzoate (34): Tetra-N-butylammonium fluo-
ride (275 mg, 0.872 mmol, 2 equiv) was added to a solution of ester 33
(235 mg, 0.436 mmol, 1 equiv) in dry THF (2 mL) under a nitrogen at-
mosphere. After stirring for 24 h at ambient temperature, saturated NaCl
solution (50 mL) and Et2O (50 mL) were added. After separation of the
layers, the aqueous phase was extracted with Et2O (3ꢃ50 mL). The com-
bined organic layers were washed with saturated NaCl (30 mL), dried
over MgSO4, filtered, and concentrated in vacuo. Purification by flash
chromatography (petroleum ether/ethyl acetate, 1:1) afforded hydroxy
ester 26 (176 mg, 92%) as a colorless oil. Rf =0.1 (petroleum ether/
EtOAc, 2:1); [a]2D0 =À15.7 (c=1.0 in CH2Cl2); 1H NMR (400 MHz,
CDCl3): d=1.06 (d, J=6.6 Hz, 3H; 3’-CH3), 1.16 (d, J=6.3 Hz, 3H; 10’-
CH3), 1.15–1.69 (m, 10H; 4’, 5’, 7’, 8’, 9’-H), 2.15–2.38 (m, 1H; 3’-H), 3.37
(s, 3H; OCH2OCH3), 3.48–3.57 (m, 1H; 6’-H), 3.68–3.89 (m, 1H; 10’-H),
3.78 (s, 3H; OCH3), 3.82 (s, 3H; OCH3), 3.87 (s, 3H; OCH3), 4.64 (s,
2H; OCH2OCH3), 5.99 (dd, J=15.7, 8.3 Hz, 1H; 2’-H), 6.29 (d, J=
15.7 Hz, 1H; 1’-H), 6.33 (d, J=2.0 Hz, 1H; ar H), 6.57 ppm (d, J=
2.0 Hz, 1H; ar H); 13C NMR (100 MHz, CDCl3): d=20.6 (3’-CH3), 21.5
(C-8’), 23.5 (10’-CH3), 31.9 (C-7’), 32.2 (C-5’), 34.3 (C-4’), 37.5 (C-3’), 39.4
(C-9’), 52.2 (CO2CH3), 55.4 (OCH3), 55.6 (OCH3), 56.0 (OCH3), 68.0 (C-
10’), 77.5 (C-6’), 95.4 (OCH2OCH3), 97.4 (ar C), 101.6 (ar C), 115.4 (C-
1), 125.3 (C-1’), 137.9 (C-2), 139.7 (C-2’), 158.0 (ar COCH3), 161.4 (ar
COCH3), 168.6 ppm (CO2CH3); HRMS (ESI): m/z: calcd for C29H38O7Na
[M+Na]+: 461.25097; found: 461.250741.
A
R
ACHTNUGTERN(NUGN CH3)3), 19.6 (2-CH3), 21.6 (C-7), 23.8
ACHTUNGTRENNUNG
39.8 (C-8), 55.6 (C-1), 61.7 (OCH3), 68.5 (C-9), 77.3 (C-5), 95.5
(OCH2OCH3), 125.1 (ar C), 129.7 (ar C), 131.5 (ar C), 133.1 (ar C),
154.0 ppm (hetaryl C); HRMS (ESI): m/z: calcd for C26H46N4O5SSiNa
[M+Na]+: 577.28504; found: 577.28505.
2-Bromo-1-[(3’R,6’R,10’S,E)-10-tert-butyldimethylsilyloxy-6-(methoxyme-
thoxy)-3-methylundec-1-enyl]-3,5-dimethoxybenzene (32): Potassium
hexamethyldisilazane (0.47 mL, 0.5m in toluene, 0.234 mmol, 1.3 equiv)
was added dropwise to a cooled (À808C) solution of sulfone 29 (100 mg,
0.18 mmol, 1 equiv) in dry THF (8 mL) under a nitrogen atmosphere.
After stirring the yellow solution for 45 min, aldehyde
9 (46 mg,
0.189 mmol, 1.05 equiv) in dry THF (2 mL) was added, and the colorless
reaction mixture was stirred for 30 min at À808C. The solution was al-
lowed to warm to room temperature for 1 h before saturated NaCl solu-
tion (70 mL) and ethyl acetate (70 mL) were added. After separation of
the layers, the aqueous phase was extracted with ethyl acetate (3ꢃ
100 mL). The combined organic layers were washed with saturated NaCl
solution (30 mL), dried over MgSO4, filtered, and concentrated in vacuo.
Purification by flash chromatography (petroleum ether/ethyl acetate,
15:1) afforded alkene 32 (88.0 mg, 83%) as a colorless oil. Rf =0.63 (pe-
troleum ether/EtOAc, 3:1); [a]2D0 =À5.85 (c=1.0 in CH2Cl2); 1H NMR
(400 MHz, CDCl3): d=0.02 (s, 3H; Si
0.86 (s, 9H; C(CH3)3), 1.09 (d, J=6.1 Hz, 3H; 3’-CH3 or 10’-CH3), 1.10
ACHTUNTGRENNGU(CH3)2), 0.02 (s, 3H; SiACHTUGNTREN(NUGN CH3)2),
ACHTUNGTRENNUNG
(d, J=6.6 Hz, 3H; 3’-CH3 or 10’-CH3), 1.18–1.65 (m, 10H; 4’, 5’, 7’, 8’, 9’-
H), 2.24–2.40 (m, 1H; 3’-H), 3.37 (s, 3H; OCH2OCH3), 3.48–3.59 (m,
1H; 6’-H), 3.68–3.84 (m, 1H; 10’-H), 3.81 (s, 3H; ar OCH3), 3.85 (s, 3H;
ar OCH3), 4.64 (s, 2H; OCH2OCH3), 5.98 (dd, J=15.8, 8.0 Hz, 1H; 2’-
H), 6.37 (d, J=2.5 Hz, 1H; ar H), 6.63 (d, J=2.5 Hz, 1H; ar H),
6.72 ppm (d, J=15.2 Hz, 1H; 1’-H); 13C NMR (100 MHz, CDCl3): d=
2-[(3R,6R,10S,E)-10-Hydroxy-6-(methoxymethoxy)-3-methylundec-1-
enyl]-4,6-dimethoxybenzoic acid (35): A solution of hydroxy ester 34
(50.0 mg, 0.114 mmol) in a 10% solution of potassium hydroxide in a
mixture of ethanol/water (1.5 mL, v/v=95:5) was heated at reflux for
36 h. After cooling, the mixture was diluted with water (20 mL) and Et2O
(20 mL). The layers were separated and the aqueous phase was extracted
with Et2O (2ꢃ30 mL), before it was carefully acidified (pH 3) with 1m
hydrochloric acid. The acidified aqueous layers were extracted with Et2O
(3ꢃ50 mL). The combined organic layers were dried over MgSO4, fil-
tered and concentrated in vacuo. Purification by flash chromatography
(CH2Cl2/methanol, 9:1) afforded hydroxy acid 35 (48.0 mg, 98%) as a
À4.7 (Si
(CH3)2), À4.4 (Si
G
ACHTUGNTRENUN(GN CH3)3), 20.6 (3’-CH3), 21.7 (C-
8’), 23.8 (10’-CH3), 25.9 (CAHCTNUGTRENNNUG
37.5 (C-9’), 39.9 (C-3’), 55.5 (ar OCH3), 56.3 (OCH3), 68.6 (C-10’), 77.2
(C-6’), 95.4 (OCH2OCH3), 98.4 (ar CBr), 102.9 (ar C), 104.2 (ar C), 127.8
(C-1’), 139.3 (C-1), 139.7 (C-2’), 156.7 (ar COCH3), 159.5 ppm (ar
COCH3); HRMS (ESI): m/z: calcd for C28H49BrO5SiK [M+K]+:
611.21642; found: 611.21601.
colorless oil. Rf =0.28 (petroleum ether/EtOAc/AcOH, 1:3:0.01); [a]D20
=
À9.3 (c=1.0 in CH2Cl2); 1H NMR (400 MHz, CDCl3): d=1.08 (d, J=
6.8 Hz, 3H; 3’-CH3), 1.19 (d, J=6.1 Hz, 3H; 10’-CH3), 1.21–1.68 (m,
10H; 4’, 5’, 7’, 8’, 9’-H), 2.17–2.38 (m, 1H; 3’-H), 3.38 (s, 3H; OCH3),
3.42–3.59 (m, 1H; 6’-H), 3.83 (s, 3H; OCH3), 3.84 (s, 3H; OCH3), 3.78–
3.95 (m, 1H; 10’-H), 4.51–4.55 (m, 2H; OCH2OCH3), 5.89 (dd, J=15.7,
Methyl 2-[(3R,6R,10S,E)-10-(tert-butyldimethylsilyloxy)-6-(methoxyme-
thoxy)-3-methylundec-1-enyl]-4,6-dimethoxybenzoate
(0.113 mL, 2.5m in hexane, 0.192 mmol, 2.2 equiv) was added dropwise to
a cooled (À808C) solution of aryl bromide 32 (50.0 mg, 0.087 mmol,
(33):
nBuLi
Chem. Eur. J. 2010, 16, 14469 – 14478
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
14475

M. E. Maier et al.
8.3 Hz, 1H; 2’-H), 6.36 (d, J=2.3 Hz, 1H; ar H), 6.55 (d, J=2.3 Hz, 1H;
ar H), 6.65 ppm (d, J=15.7 Hz, 1H; 1’-H); 13C NMR (100 MHz, CDCl3):
d=21.2 (3’-CH3), 21.5 (C-8’), 23.6 (10’-CH3), 31.4 (C-7’), 31.8 (C-5’), 34.0
(C-4’), 37.1 (C-3’), 39.1 (C-9’), 55.4 (ar OCH3), 56.2 (OCH2OCH3), 68.6
(C-10’), 77.6 (C-6’), 95.2 (OCH2OCH3), 97.4 (ar C), 103.3 (ar C), 114.0
(ar C), 127.0 (C-1’), 139.6 (C-2’), 140.1 (C-2), 158.3 (ar COCH3), 161.6 (ar
COCH3), 169.0 ppm (CO2H); HRMS (ESI): m/z: calcd for C23H36O7Na
[M+Na]+: 447.23532; found: 447.23534.
temperature. The reaction mixture was then treated carefully with satu-
rated sodium hydrogen carbonate at 08C until the mixture was neutral-
ized, then ethyl acetate (50 mL) was added. After separation of the
layers, the aqueous phase was extracted with ethyl acetate (3ꢃ50 mL).
The combined organic layers were washed with saturated NaCl (20 mL),
dried over MgSO4, filtered, and concentrated in vacuo. Purification by
flash chromatography (petroleum ether/ethyl acetate, 2:1) afforded hy-
droxy lactone 36a (36.1 mg, 81%) as a colorless oil. Rf =0.21 (petroleum
ether/EtOAc, 2:1); [a]D20 =À24.3 (c=1.0 in CH2Cl2); 1H NMR (400 MHz,
CDCl3): d=1.07 (d, J=6.8 Hz, 3H; 3’-CH3), 1.34 (d, J=6.3 Hz, 3H; 10’-
CH3), 1.14–1.88 (m, 10H; 9’, 8’, 7’, 5’, 4’-H), 2.17–2.33 (m, 1H; 3’-H),
3.67–3.85 (m, 1H; 6’-H), 3.78 (s, 3H; OCH3), 3.81 (s, 3H; OCH3), 5.12–
5.27 (m, 1H; 10’-H), 6.16 (dd, J=16.0, 7.0 Hz, 1H; 2’-H), 6.34 (d, J=
2.3 Hz, 1H; ar H), 6.42 (d, J=16.2 Hz, 1H; 1’-H), 6.55 ppm (d, J=
2.0 Hz, 1H; ar H); 13C NMR (100 MHz, CDCl3): d=20.6 (3’-CH3), 21.3
(10’-C), 22.5 (C-8’), 27.4 (C-9’), 31.4 (C-5’), 34.2 (C-7’), 35.4 (C-4’), 35.6
(C-3’), 55.4 (OCH3), 56.0 (OCH3), 70.3 (C-6’ or C-10’), 70.7 (C-6’ or C-
10’), 97.5 (ar CH), 101.6 (ar CH), 116.4 (C-1), 124.7 (C-1’), 137.0 (C-6),
138.9 (C-2’), 157.8 (C-2), 161.1 (C-4), 168.0 ppm (CO2); HRMS (ESI):
m/z: calcd for C21H30O5Na [M+Na]+: 385.19855; found: 385.19871.
ACHTUNGTRENNUNG(3’R,10’R)-Macrolactone 36a: Triphenylphosphine (114 mg, 0.433 mmol,
2.3 equiv) was added to a cooled (08C) solution of hydroxy acid 35
(80.0 mg, 0.188 mmol, 1 equiv) in dry toluene (40 mL) under a nitrogen
atmosphere followed by dropwise addition of N,N-diethyl azodicarboxy-
late (1.90 mL, 40% in toluene, 0.415 mmol, 2.2 equiv) over 5 h with a sy-
ringe pump. The reaction mixture was allowed to warm to room tempera-
ture overnight before it was concentrated in vacuo. Purification by flash
chromatography (petroleum ether/ethyl acetate, 4:1) afforded lactone
36a (49.0 mg, 64%) as a colorless oil. Rf =0.65 (petroleum ether/EtOAc,
2:1); [a]2D0 =À215 (c=1.0 in CH2Cl2); 1H NMR (400 MHz, CDCl3): d=
1.07 (d, J=6.8 Hz, 3H; 3’-CH3), 1.34 (d, J=6.3 Hz, 3H; 10’-CH3), 1.32–
1.80 (m, 10H; 9’-H, 8’-H, 7’-H, 5’-H, 4’-H), 2.15–2.33 (m, 1H; 3’-H), 3.37
(s, 3H; OCH2OCH3), 3.55–3.71 (m, 1H; 6’-H), 3.79 (s, 3H; OCH3), 3.81
(s, 3H; OCH3), 4.57–4.68 (m, 2H; OCH2OCH3), 5.13–5.26 (m, 1H; 10’-
H), 6.20 (dd, J=16.2, 7.1 Hz, 1H; 2’-H), 6.34 (d, J=2.0 Hz, 1H; ar H),
6.41 (d, J=16.2 Hz, 1H; 1’-H), 6.56 ppm (d, J=2.0 Hz, 1H; ar H);
13C NMR (100 MHz, CDCl3): d=14.1 (10’-CH3), 20.6 (C-8’), 21.2 (3’-
CH3), 22.6 (C-5’), 27.6 (C-7’C), 29.0 (C-9’), 30.9 (C-4’), 35.4 (C-3’), 35.7
(OCH2OCH3), 55.2 (OCH3), 55.9 (OCH3), 64.2 (OCH2OCH3), 70.7 (C-
10’), 75.2 (C-6’), 94.6 (OCH2OCH3), 97.5 (ar C), 101.5 (ar C), 116.5 (C-
1), 124.5 (C-1’), 136.8 (C-6), 138.8 (C-2’), 157.8 (C-2), 161.0 (C-4),
168.0 ppm (CO2); HRMS (ESI): m/z: calcd for C23H34O6Na [M+Na]+:
429.22476; found: 429.22476.
AHCTUNGERTG(NNUN 3’R,10’R)-Macrolactone 38a and ent-38a: A cooled (08C) solution of
hydroxy lactone 37a (32.0 mg, 0.088 mmol, 1 equiv) in dry CH2Cl2
(1.5 mL) was treated with Dess–Martin periodinane (74.9 mg,
0.177 mmol, 2 equiv) under a nitrogen atmosphere, and the mixture was
allowed to warm to room temperature overnight. The reaction mixture
was treated with a mixture of saturated Na2S2O3/saturated NaHCO3/
water (1:1:1, 30 mL) and with CH2Cl2 (30 mL). After separation of the
layers, the aqueous phase was extracted with ethyl acetate (3ꢃ50 mL).
The combined organic layers were washed with saturated NaCl (20 mL),
dried over MgSO4, filtered, and concentrated in vacuo. Purification by
flash chromatography (petroleum ether/ethyl acetate, 4:1) afforded keto-
lactone 38a (22.8 mg, 72%) as a white solid. Rf =0.39 (petroleum ether/
EtOAc, 2:1); [a]2D0 =+9.0 (c=1.0 in CH2Cl2 for 38a), À7.3 (c=1.0 in
CH2Cl2 for ent-38a); 1H NMR (400 MHz, CDCl3): d=1.06 (d, J=6.6 Hz,
3H; 3’-CH3), 1.33 (d, J=6.6 Hz, 3H; 10’-CH3), 1.41–1.54 (m, 1H; 4’-H),
1.57–1.71 (m, 2H; 9’-H), 1.66–1.85 (m, 2H; 8’-H), 1.83–1.95 (m, 1H; 4’-
H), 2.17 (dt, J=13.1, 7.5 Hz, 1H; 7’-H), 2.24–2.37 (m, 1H; 3’-H), 2.43
(dd, J=7.6, 5.8 Hz, 2H; 5’-H), 2.55 (dt, J=13.4, 6.7 Hz, 1H; 7’-H), 3.80
(s, 3H; OCH3), 3.82 (s, 3H; OCH3), 5.24–5.37 (m, 1H; 10’-H), 5.94 (dd,
J=15.9, 8.1 Hz, 1H; 2’-H), 6.37 (d, J=2.0 Hz, 1H; ar H), 6.51 (d, J=
2.0 Hz, 1H; ar H), 6.58 ppm (d, J=15.9 Hz, 1H; 1’-H); 13C NMR
(100 MHz, CDCl3): d=20.3 (10’-CH3), 21.5 (C-8’), 21.9 (3’-CH3), 29.5 (C-
4’), 35.4 (C-9’), 36.1 (C-3’), 38.0 (C-5’), 42.8 (C-7’), 55.4 (OCH3), 56.0
(OCH3), 70.7 (C-10’), 97.7 (ar CH), 102.5 (ar CH), 115.5 (C-1), 126.8 (C-
1’), 138.0 (C-6), 138.7 (C-2’), 158.4 (CO2 or C-4 or C-2), 161.4 (CO2 or C-
4 or C-2), 167.4 (CO2 or C-4 or C-2), 212.0 ppm (C-6’); HRMS (ESI):
m/z: calcd for C21H28O5Na [M+Na]+: 383.18290; found: 383.18313 (38a),
383.182893 (ent-38a).
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
0.007 mmol, 0.02 equiv) and ethoxy acetylene (0.113 mL, 40% in hexane,
0.53 mmol, 1.5 equiv) under a nitrogen atmosphere, and the resulting
dark brown solution was stirred at ambient temperature for 3 h. The mix-
ture was then concentrated in vacuo and the residue was dissolved in tol-
uene (15 mL) again. This resulting brown solution was added dropwise to
a stirred solution of (Æ)-camphorsulfonic acid (16.4 mg, 0.071 mmol,
0.2 equiv) in toluene (100 mL) by syringe pump over 3 h at 808C under a
nitrogen atmosphere. After further stirring at 808C for 30 min, the reac-
tion mixture was allowed to cool to room temperature overnight before
saturated NaHCO3 solution (100 mL) and ethyl acetate (100 mL) were
added. After separation of the layers, the aqueous phase was extracted
with ethyl acetate (3ꢃ100 mL). The combined organic layers were
washed with saturated NaCl solution (50 mL), dried over MgSO4, fil-
tered, and concentrated in vacuo. Purification by flash chromatography
(petroleum ether/ethyl acetate, 4:1) afforded lactone 36b (64.0 mg, 84%)
as a colorless oil. Rf =0.65 (petroleum ether/EtOAc, 2:1); [a]2D0 =+5.5
(c=1.0 in CH2Cl2); 1H NMR (400 MHz, CDCl3): d=1.01 (d, J=6.6 Hz,
3H; 3’-CH3), 1.23 (d, J=6.3 Hz, 3H; 10’-CH3), 1.16–1.86 (m, 10H; 9’, 8’,
7’, 5’, 4’-H), 2.28–2.44 (m, 1H; 3’-H), 3.31 (s, 3H; OCH2OCH3), 3.42–3.57
(m, 1H; 6’-H), 3.72 (s, 3H; OCH3), 3.76 (s, 3H; OCH3), 4.50 (d, J=
7.1 Hz, 1H; OCH2OCH3), 4.64 (d, J=6.8 Hz, 1H; OCH2OCH3), 5.30–
5.41 (m, 1H; 10’-H), 5.75 (dd, J=15.7, 9.4 Hz, 1H; 2’-H), 6.28 (d, J=
1.8 Hz, 1H; ar H), 6.32 (d, J=15.7 Hz, 1H; 1’-H), 6.54 ppm (d, J=
2.0 Hz, 1H; ar H); 13C NMR (100 MHz, CDCl3): d=19.4 (10’-CH3), 20.2
(C-8’), 21.9 (3’-CH3), 30.9 (C-5’), 32.2 (C-7’), 33.6 (C-9’), 35.0 (C-4’), 36.3
(C-3’), 55.4 (OCH3), 55.9 (OCH3), 60.3 (OCH2OCH3), 70.7 (C-10’), 75.0
(C-6’), 94.9 (OCH2OCH3), 97.6 (ar CH), 101.1 (ar CH), 116.7 (C-1),
126.7 (C-1’), 136.8 (C-6), 139.2 (C-2’), 157.4 (C-2), 161.2 (C-4), 167.8 ppm
(CO2); HRMS (ESI): m/z: calcd for C23H34O6Na [M+Na]+: 429.22476;
found: 429.225013.
AHCTUNGERTG(NNUN 3’R,10’R)-Macrolactone 39a and ent-39a: Boron trichloride (0.386 mL,
1m in CH2Cl2, 0.386 mmol, 20 equiv) was added dropwise to a cooled
(À608C) solution of keto lactone 38a (7.0 mg, 0.019 mmol, 1 equiv) in
dry CH2Cl2 (0.5 mL) under a nitrogen atmosphere. The dark brown solu-
tion was allowed to warm to room temperature over 1 h. After complete
conversion, the reaction mixture was again cooled to À608C before
methanol (1 mL) was added dropwise. The brown mixture was allowed
to warm to room temperature and concentrated in vacuo. Purification of
the residue by flash chromatography (petroleum ether/Et2O, 3:1) afford-
ed mono-deprotected lactone 39a (6.5 mg, 99%) as a white solid. Rf =
0.65 (petroleum ether/EtOAc, 2:1); [a]2D0 =147.8 (c=1.0 in CH2Cl2 for
39a), À130.1 (c=1.0 in CH2Cl2 for ent-39a); 1H NMR (400 MHz,
CDCl3): d=1.01 (d, J=6.8 Hz, 3H; 3’-CH3), 1.01–1.28 (m, 2H; 5’-H),
1.31 (d, J=6.3 Hz, 3H; 10’-CH3), 1.38–1.79 (m, 4H; 9’-H, 8’-H, 5’-H),
1.96–2.15 (m, 2H; 7’-H, 4’-H), 2.18–2.36 (m, 1H; 3’-H), 2.48–2.61 (dt, J=
12.4, 8.8, 3.8 Hz, 1H; 7’-H), 2.70–2.85 (dt, J=18.7, 12.6, 2.3 Hz, 1H; 4’-
H), 3.76 (s, 3H; OCH3), 4.93–5.05 (m, 1H; 10’-H), 5.45 (dd, J=15.3,
10.0 Hz, 1H; 2’-H), 6.33 (s, 1H; ar H), 6.38 (s, 1H; ar H), 6.96 (d, J=
15.4 Hz, 1H; 1’-H), 12.11 ppm (s, 1H; 2-OH); 13C NMR (100 MHz,
CDCl3): d=21.1 (10’-CH3), 22.4 (C-8’), 22.7 (3’-CH3), 29.6 (C-4’), 34.7 (9’-
C), 36.7 (C-3’), 37.3 (C-7’), 42.9 (C-5’), 55.4 (OCH3), 73.4 (C-10’), 99.8 (ar
ACHTUNGTRENNUNG
a
0.123 mmol) in methanol (2.5 mL), and the mixture was allowed to warm
to room temperature over 1 h before it was stirred for 36 h at ambient
14476
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Chem. Eur. J. 2010, 16, 14469 – 14478

Zearalenone Analogues
FULL PAPER
CH), 103.5 (C-1), 108.5 (ar CH), 131.9 (C-1’), 138.2 (C-2’), 143.4 (C-6),
164.0 (C-2), 165.8 (C-4), 171.4 (CO2), 211.1 ppm (C-6’); HRMS (ESI):
m/z: calcd for C20H26O5Na [M+Na]+: 369.16725; found: 369.16735 (39a),
369.167249 (ent-39a).
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M. E. Maier, ChemBioChem 2009, 10, 2203–2212.
ACHTUNGTRENNUNG(3’R,10’R)-Macrolactone 40a and ent-40a: A suspension of aluminum
powder (29.0 mg, 1.074 mmol, 43 equiv) in dry benzene (2 mL) was treat-
ed with iodine (101 mg, 0.400 mmol, 16 equiv) under a nitrogen atmos-
phere and the violet mixture was stirred under reflux for 30 min until the
color had changed to a colorless mixture. After cooling to 58C, a few
crystals of tetra-N-butylammonium iodide and phloroglucine (15.8 mg,
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0.125 mmol, 5 equiv) were added before
a solution of lactone 38a
(9.0 mg, 0.025 mmol, 1 equiv) in dry benzene (0.3 mL) was added in one
portion. The resulting green brown suspension was stirred for 30 min at
58C before saturated Na2S2O3 solution (30 mL) and ethyl acetate
(30 mL) were added. After separation of the layers, the aqueous phase
was extracted with ethyl acetate (3ꢃ50 mL). The combined organic
layers were washed with saturated NaCl solution (20 mL), dried over
MgSO4, filtered, and concentrated in vacuo. Purification by flash chroma-
tography (petroleum ether/ethyl acetate, 3:1) afforded zearalenone deriv-
ative 40a (28.5 mg, 80%) as a white solid. Rf =0.54 (petroleum ether/
EtOAc, 2:1); [a]2D0 =+107.1 (c=0.5 in CH2Cl2 for 40a), À109.1 (c=0.5 in
CH2Cl2 for ent-40a); 1H NMR (400 MHz, CDCl3): d=1.01 (d, J=6.6 Hz,
3H; 3’-CH3) 1.04–1.27 (m, 1H; 5’-H), 1.31 (d, J=6.1 Hz, 3H; 10’-CH3),
1.43–1.77 (m, 5H; 9’, 8’, 5’-H), 1.98–2.15 (m, 2H; 7’-H, 4’-H), 2.21–2.35
(m, 1H; 3’-H), 2.56 (dd, J=9.2, 4.3 Hz, 1H; 7’-H), 2.79 (ddd, J=18.7,
12.5, 2.2 Hz, 1H; 4’-H), 4.88–4.98 (m, 1H; 10’-H), 5.46 (dd, J=15.3,
10.0 Hz, 1H; 2’-H), 6.31 (d, J=2.5 Hz, 1H; ar H), 6.96 (d, J=2.5 Hz,
1H; ar H), 7.01 (d, J=15.2 Hz, 1H; 1’-H), 12.07 ppm (s, 1H; 2-OH);
13C NMR (100 MHz, CDCl3): d=21.1 (10’-CH3), 22.4 (C-8’), 22.7 (3’-
CH3), 29.6 (C-9’), 34.7 (C-4’), 36.8 (C-3’), 37.3 (C-5’), 42.9 (C-7’), 73.5 (C-
10’), 102.4 (ar CH), 103.9 (C-1), 108.5 (ar CH), 131.8 (C-1’), 138.4 (C-2’),
144.2 (C-6), 160.4 (CO2, C-4, C-2), 165.6 (CO2, C-4, C-2), 171.3 (CO2, C-
4, C-2), 211.3 ppm (C-6’); HRMS (ESI): m/z: calcd for C19H24O5Na
[M+Na]+: 355.15159; found: 355.151720 (40a), 355.151846 (ent-40a).
Cytotoxicity assay: The toxicity of the compounds with L929 cells was
tested with an 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bro-
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Financial support by the Deutsche Forschungsgemeinschaft (grant no.
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Received: June 21, 2010
Published online: October 27, 2010
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Chem. Eur. J. 2010, 16, 14469 – 14478