Catalytic asymmetric total synthesis of (S)-(-)-zearalenone, a novel lipoxygenase inhibitor

Article abstract of DOI:10.1016/j.bmc.2013.06.024

A catalytic asymmetric synthesis of (S)-(-)-zearalenone is reported using asymmetric allylic alkylation for the introduction of the stereocenter. (S)-(-)-Zearalenone turned out to be a novel lipoxygenase inhibitor.

Full text of DOI:10.1016/j.bmc.2013.06.024

Bioorganic & Medicinal Chemistry 21 (2013) 5271–5274
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Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Catalytic asymmetric total synthesis of (S)-(À)-zearalenone, a novel
lipoxygenase inhibitor
b
a,
Marc P. Baggelaar a, Yange Huang a, Ben L. Feringa a, , Frank J. Dekker , Adriaan J. Minnaard
⇑
⇑
a Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 4, 9747 AG Groningen, The Netherlands
b Groningen Research Institute of Pharmacy, Anthonius Deusinglaan 1, 9713 AV Groningen, The Netherlands
a r t i c l e i n f o
a b s t r a c t
Article history:
A catalytic asymmetric synthesis of (S)-(À)-zearalenone is reported using asymmetric allylic alkylation
for the introduction of the stereocenter. (S)-(À)-Zearalenone turned out to be a novel lipoxygenase
inhibitor.
Received 18 April 2013
Revised 10 June 2013
Accepted 11 June 2013
Available online 20 June 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
(S)-(À)-Zearalenone
Resorcyclic acid lactone
Mycotoxin
Lipoxygenase
Allylic alkylation
Resorcylic acid lactones are mycotoxins produced by various
strains of fungi via polyketide biosynthesis. These medium-sized
macrocyclic lactones exhibit a wide variety of interesting biological
activities,1 among which selective kinase inhibition has been char-
acterized very well.2 Zearalenone, probably the best known mem-
ber of the resorcylic acid lactones, was first isolated from Gibberella
zeae in 19623 and four years later its structure was elucidated.4
Zearalenone shows estrogen agonistic properties most likely
because its macrocycle can adopt a confirmation that is similar
to steroids.1e Also of interest, is the fact that related 6-alkylsalicy-
lates inhibit histone acetyl transferase activity.5 In addition, Zearal-
enone has been shown to exhibit antibacterial, uterotropic and
anabolic activity.3,6 We envisioned that the salicylate core struc-
ture in Zearalenone could provide lipoxygenase inhibitory activity
for this compound,7 which has been indeed observed in this study.
Many of the synthetic routes to Zearalenone 1 either lead to the
racemate,8 are based on natural chiral starting materials,9 or on
chiral auxiliaries.10 Some groups used kinetic resolution or an
enzymatic approach to obtain the chiral building blocks.11 We felt
that a more concise synthesis of Zearalenone 1 that takes advan-
tage of a highly efficient and enantioselective catalytic allylic alkyl-
ation would make this compound more readily available for
biological studies. Herein, we report the asymmetric synthesis of
1 in an efficient and selective manner and describe its utilization
for the inhibition of lipoxygenase.
The target molecule 1 was retrosynthetically analyzed as shown
in Scheme 1. We opted for a late stage double demethylation of
dimethoxyzearalenone 2 to give 1, as the dihydroxybenzene unit
is too sensitive to carry through the synthesis. The 14-membered
macrocycle should be installed by intra-molecular ring closing
metathesis of diene 3, and retrosynthetic cleavage of the ester moi-
ety leads to the required acid fluoride 4 and chiral alcohol 5. The
latter one can in turn be prepared from ester 6, provided by enan-
tioselective copper-catalyzed asymmetric allylic alkylation devel-
oped in our group.12
The synthesis started from commercially available
7 as
described in Scheme 2. Vilsmeier–Haack formylation13 of 7 affor-
ded the aldehyde 8 in 82% yield, followed by Stille cross coupling
with tributylvinyltin14 to give compound 9 in 84% yield. Pinnick
oxidation of aldehyde 9 gave acid 10 in 85% yield.13 Carboxylic acid
10 was subsequently transformed into the corresponding acid fluo-
ride using cyanuric fluoride.15
The synthesis of chiral alcohol 5 started from readily available
11 using a copper/TaniaPhos catalyzed asymmetric allylic alkyl-
ation with methylmagnesium bromide which afforded ester 6 in
high yield and excellent enantioselectivity (82% and 98%, respec-
tively, Scheme 3).12 Hydrolysis of the ester 6 by aqueous KOH, fol-
lowed by protection of the resulting alcohol using
tert-butyldiphenylsilyl chloride (TBDPSCl), gave alkene 12 in an
overall yield of 80%. Initial hydroboration of the terminal alkene
using borane, after oxidation, afforded the alcohol as a mixture of
regioisomers. However, 9-borabicyclononane (9-BBN) provided,
after oxidation, primary alcohol 13 selectively. Alcohol 13 was sub-
⇑
Corresponding authors.
E-mail address: A.J.Minnaard@rug.nl (A.J. Minnaard).
0968-0896/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmc.2013.06.024

5272
M. P. Baggelaar et al. / Bioorg. Med. Chem. 21 (2013) 5271–5274
H
11'
O
O
O
6
O
1
double demethylation
10'
O
5
O
9'
8'
2
H
4
1'
O
O
7'
6'
3
4'
2'
5'
3'
O
O
RCM
1
2
O
O
O
ester bond
formation
F
O
O
O
Br
O
O
7
4
O
O
O
3
O
O
O
HO
6
5
Scheme 1. Retrosynthetic analysis of Zearalenone.
Bu3Sn
O
O
O
O
O
NaHClO2, NaH2PO4
2-methyl-2-butene
DMF, POCl3
Pd(PPh3)4, PhMe
100°C, 8 h, 84%
THF: t-BuOH: H2O
3:3:1, r.t. 5 h, 85%
100°C, 4 h, 82%
O
O
Br
O
Br
7
8
9
O
O
O
O
F
cyanuric fluoride,
pyridine
OH
85%
O
O
10
4
Scheme 2. Synthesis of the building block 4.
sequently transformed into iodide 14 using iodine and triphenyl-
phosphine in high yield.
Esterification of alcohol 5 and carboxylic acid 10 using carbodi-
imide-based coupling reagents or the Yamaguchi reagent did not
provide any desired product. This was anticipated as the acid func-
tion in 10 is sterically severely hindered. Fortunately, Fürstner et
al. solved this problem by using fluoride as the ‘smallest possible’
leaving group.19 Acid fluoride 4 can be easily prepared from the
corresponding acids with cyanuric fluoride. Coupling with alcohol
5 gave the desired product 20 in high yield (Scheme 5).
Ring closing metathesis of 20 using the Grubbs second genera-
tion catalyst gave the desired E-alkene 21 in high yield.10b Subse-
quent hydrolysis of the acetal under aqueous acidic conditions
went smoothly and gave (S)-(À)-zearalenone dimethyl ether in
83% yield.
Demethylation of 2 and related compounds is a recognized
problem as it requires harsh conditions. Initial attempt using AlI3
with tetrabutylammonium iodide reported by Yadav and Mur-
thy11e led to complex mixtures. Fortunately, the improved method
reported by Maier and co-workers20 using phloroglucine as an io-
dine scavenger works very well. The final product, (S)-(À)-zearale-
none 1, was obtained in 63% yield and spectroscopic data were in
agreement with the reported data.11d
The synthesis of coupling partner hydrazone 15 (Scheme 4)
started from a copper catalyzed addition of pentenylmagnesium
bromide to acetyl chloride 18 to provide ketone 19 in 75% yield.16
Hydrazone formation from 19 using dimethyl hydrazine in acetic
acid and ethanol resulted in 88% yield.17
Initial synthesis of ketone 16 by coupling of the corresponding
tosylate of 13 with 15 resulted in complicated products. However,
the a-alkylation of 15 with iodide 14, when carried out via the lith-
iated dimethylhydrazone, gave the desired product in high yield
and complete regioselectivity.18 Ketone 16 was subsequently ob-
tained by in situ hydrolysis. Before removal of the TBDPS group
the ketone had to be protected, as without this modification the
compound would suffer loss of enantiopurity by a reversible intra-
molecular hydride shift as already reported in 1968 by Wendler
and co-workers8a Acetal protection of the ketone using ethylene
glycol with a catalytic amount of p-TsOH in benzene gave 17 in
75% yield. Finally, removal of the silyl group by tetrabutylammo-
nium fluoride (TBAF) in THF gave the desired building block 5 in
88% yield.

M. P. Baggelaar et al. / Bioorg. Med. Chem. 21 (2013) 5271–5274
5273
MeMgBr (2 eq.)
O
O
CuBr-Me2S (1 mol%)
Taniaphos (1.2 mol%)
1. KOH, H2O
2. TBDPSCl
1. 9-BBN
O
Br
O
TBDPSO
imidazole, 80%
-80 oC, CH2Cl2
82%, 98% ee
, 18 h
2. NaOH, H2O2
87%
12
11
6
N
N
Imidazole,
1. n-BuLi, THF, 14, 0°C
PPh3, I2
TBDPSO
OH
TBDPSO
I
0 oC to rt, 88%
2. 2 M HCl, 81%
13
14
15
O
ethylene glycol, p-TsOH.H2O,
benzene, 80°C
O
O
TBAF, THF
88%
TBDPSO
TBDPSO
75%
16
17
O
O
HO
5
Scheme 3. Synthesis of chiral alcohol 5.
N
MgBr
N
O
O
Me2NNH2
AcOH, EtOH
reflux, 88%
5 mol% CuI
Cl
THF, -10°C to RT
75%
18
19
15
Scheme 4. Synthesis of hydrazone 15.
O
O
O
O
O
O
O
KHMDS
O
F
O
THF, 0°C
HO
O
O
82%
4
5
20
O
O
O
O
O
O
pTsOH.H2O
acetone/H2O, 40 oC
Grubs 2
O
O
toluene, 80 oC
O
O
21
83 %
88 %
2
O
OH
O
O
AlI3, TBAI
phloroglucine
HO
5 oC, benzene
63%
O
1
(S)-(−)-zearalenone
Scheme 5. Assembly of the building blocks to provide (S)-(À)-zearalenone.

5274
M. P. Baggelaar et al. / Bioorg. Med. Chem. 21 (2013) 5271–5274
Acknowledgments
We thank T.D. Tiemersma-Wegman for assistance with chro-
matography (Stratingh Institute for Chemistry). Financial support
from NRSC catalysis Grant 200910018B is gratefully
acknowledged.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmc.2013.06.024.
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