The first total synthesis of vinaxanthone, a fungus metabolite possessing multiple bioactivities

Article abstract of DOI:10.1246/cl.2007.10

Vinaxanthone (1) has been biomimetically synthesized from vanillin (2) through an intermolecular Diels-Alder cycloaddition between two molecules of the precursor 11. Copyright

Full text of DOI:10.1246/cl.2007.10

10
Chemistry Letters Vol.36, No.1 (2007)
The First Total Synthesis of Vinaxanthone,
a Fungus Metabolite Possessing Multiple Bioactivities
Kuniaki Tatsuta,Ã Soko Kasai, Yuki Amano, Takahiro Yamaguchi, Masashi Seki, and Seijiro Hosokawa
Department of Applied Chemistry, School of Science and Engineering, Waseda University,
3-4-1 Ohkubo, Shinjuku-ku, Tokyo 169-8555
(Received September 15, 2006; CL-061077; E-mail: tatsuta@waseda.jp)
Vinaxanthone (1) has been biomimetically synthesized from
vanillin (2) through an intermolecular Diels–Alder cycloaddition
between two molecules of the precursor 11.
ture 1 is biogenetically produced. It seems likely that an intermo-
lecular Diels–Alder (IMDA) cycloaddition between two mole-
cules of the precursor such as 11 is operative.
Herein, we report the implementation of a biomimetic strat-
egy for the first total synthesis of vinaxanthone (1).
From a retrosynthetic perspective for maximum convergen-
cy (Scheme 1), we initially envisioned the IMDA reaction of the
precursor 11 to be a means potentially well suited to the assem-
bly of the natural product 1. Access to this advanced intermedi-
ate was to be gained by a cross-coupling of 10 with methyl vinyl
ketone. The key compound 10 would be prepared through 7 from
5, which could be derived from vanillin (2) by Baeyer–Villiger
reaction.5
Vinaxanthone (1) was first isolated by the Yokose and Seto
group in 1991 from the culture broth of a fungus Penicillium
vinaceum to show selective inhibitory activity against phospho-
lipase C, and its structure was also determined by NMR studies.1
Subsequently, the two groups of Wrigley and Kumagai have
isolated vinaxanthone (1) in 1994 and 2003 as fungus metabo-
lites having potent CD4-binding activity and semaphorin inhib-
itory activity, respectively.2,3
The present synthesis began with the regioselective
bromination of vanillin (2),6 followed by O-methylation to
give the 3-bromobenzaldehyde 4 in almost quantitative yield
(Scheme 2). The aldehyde was submitted to the Baeyer–Villiger
reaction with mCPBA to give, after de-O-formylation, the
phenol 5. The Michael addition of 5 to acrylonitrile with DBU
afforded the adduct 6.7,8 The hydrolysis of the nitrile group to
the carboxylic acid was followed by the Friedel–Crafts type re-
action with AlCl3 to give the dihydrobenzopyranone 7 in 80%
yield. The structure 7 was supported by 1H NMR studies includ-
Especially, semaphorin 3A has been reported to cause col-
lapse of neurite growth cones, resulting in inhibition of neuronal
outgrowth in vitro and in vivo. Therefore, semaphorin inhibitors
are expected to be potential drugs for the treatment of traumatic
neuronal injury.4
Structurally, the unprecedented molecular architecture is
characterized by its polycyclic xanthone core with polyacidic
functions.
From the outset of our synthetic studies, we were motivated,
among other things, by the question of how the fascinating struc-
HO
O
MeO
O
O
Me
HO
O
O
OH
OH
MeO
MeO
O
O
MeO
MeO
O
O
MeO
MeO
OH
MeO
HO2C
O
MeO2C
O
Me
Me
I
O
OMe
OMe
11
O
O
CO2H
MeO2C
Br
Br
O
Vinaxanthone (1)
10
7
5
Me
O
CO2Me
11
Scheme 1.
NOE 9.0%
MeO
H
MeO
HO
CHO
MeO
HO
CHO
MeO
CHO
c, d
MeO
MeO
OH
MeO
MeO
O
MeO
MeO
O
O
a
e
g
b
f
MeO
CN
MeO
O
O
Br
Br
Br
Br
Br
Br
O
2
3
4
5
6
7
8
MeO
O
O
O
Me
MeO
MeO
O
MeO
O
O
MeO
MeO
O
m
h, i
j
k
l
MeO
1
O
OMe
OMe
Me
MeO2C
MeO
MeO2C
I
Me
MeO2C
O
MeO2C
O
O
O
O
CO2Me
9
10
11
12
Scheme 2. (a) Br2/AcOH, rt, 6 h, 95%, (b) Me2SO4, K2CO3/acetone, 50 ꢀC, 9.5 h, 94%, (c) mCPBA/CH2Cl2, reflux, 11 h, (d) 0.1 M Et3N–MeOH, rt, 2 h,
81% in 2 steps, (e) acrylonitrile, DBU, 75 ꢀC, 72 h, 74%, (f) AlCl3/aq. MeNO2, 60 ꢀC, 0.5 h, 80%, (g) ethylene glycol, TsOH, CH(OMe)3/PhMe, 80 ꢀC, 11 h,
84%, (h) n-BuLi, ClCO2Me/THF, À78 ꢀC, 1 h, (i) 5% HCl–MeOH, rt, 2 h, 44% in 2 steps, (j) I2/DMSO, 110 ꢀC, 5 h, 65%, (k) methyl vinyl ketone, Pd(OAc)2,
Et3N/MeCN, 50 ꢀC, 7.5 h, 88%, (l) DTBMP/PhMe, air, 200 ꢀC (sealed tube), 24 h, 40% (see Scheme 3), (m) AlCl3/PhMe, 110 ꢀC, 2 h, 74%.
Copyright Ó 2007 The Chemical Society of Japan

Chemistry Letters Vol.36, No.1 (2007)
11
O
O
Me
R
O
O
OMe
OMe
Me
Me
O
Me
O
CO2Me
R
Me
O
OMe
OMe
12 (40%)
Me
HO
O
O
13
CO2Me
R
OMe
OMe
O
O
O
15
CO2Me
O
OMe
OMe
DTBMP (4.0 equiv.)
Me
PhMe, air, 200 °C, 24 h
R
in a sealed tube
R
O
O
CO2Me
O
OMe
OMe
O
O
OMe
Me
Me
11
Me
O
O
R
OMe
CO2Me
O
OMe
OMe
O
O
O
16
CO2Me
O
Me
Me
17 (10%)
O
O
OMe
OMe
R
R =
O
CO2Me
HO
OMe
OMe
14
Me
CO2Me
O
CO2Me
18
Scheme 3.
ing NOE observation. As a direct conversion of 7 to 9 proved to
be problematic, the carbonyl group of 7 was protected by ethyl-
ene acetal to give 8.
The lithiated 8 reacted with methyl chloroformate to give
the carbomethoxy derivative, followed by deprotection to the
ketone 9. This was treated with iodine in DMSO to give the vinyl
iodide 10, which was subjected to a cross-coupling with methyl
vinyl ketone in the presence of Pd(OAc)2 to provide the key
intermediate 11.9
desired product.
Deprotection of 12 proceeded nicely with AlCl3 in PhMe at
110 ꢀC to give the hydroxy-carboxylic acid 1 (Scheme 2).12 This
was identical in all respects with natural vinaxanthone (1),13
completing the first total synthesis.
This work was financially supported by the 21COE ‘‘Center
for Practical Nano-Chemistry,’’ the Consolidated Research
Institute for Advanced Science and Medical Care, and Scientific
Research on Priority Area ‘‘Creation of Biologically Functional
Molecules’’ from the Ministry of Education, Culture, Sports,
Science and Technology.
In the IMDA cycloaddition studies, a large number of
variables including acid catalysts, solvents, reaction time, and
temperature were tested. The best results were realized by
heating a solution of 11 in PhMe with 4.0 equiv. of 2,6-di-t-bu-
tyl-4-methylphenol (DTBMP) in a sealed tube at 200 ꢀC for 24 h
with air.7 These conditions led to the aromatized product 12 as
crystals in 40% yield, after silica-gel column chromatography
with 1,2-dichloroethane–2-butanone and recrystallization from
acetone–CHCl3, with recovery (30%) of the starting 11. The
intact adduct 13 was not observed without aromatization
(Scheme 3). The formation of the regio-isomers 14 and 16 was
anticipated, but, in the event, only the deacetylated isomer 17
was obtained in 10% yield. Also, the ring-opened products 15
and 18 were isolated as minor products in less than 5% yields.
The structures of all these products were determined by NMR
studies, and the structure 12 was unambiguously confirmed by
X-ray crystallographic analysis.10
Without DTBMP, the IMDA reaction gave 15 and 18 as the
major products (22 and 30%) with the desired 12 (17%). These
ring-opened compounds result from a sequence including elim-
ination of the phenol portion in the intermediary adducts 13 and
14, and concomitant oxidative aromatization. For the formation
of 18, the deacetylation is further required. These findings
suggested that the additive DTBMP seemed to be first oxidized
to the corresponding quinone,11 which in turn oxidized the
intact adduct 13 to give the aromatized product 12. However,
the addition of oxidants (MnO2, PbO2, and TEMPO) gave no
This paper is dedicated to Professor Teruaki Mukaiyama on
the occasion of his 80th birthday.
References and Notes
1
2
3
4
M. Aoki, Y. Itezono, H. Shirai, N. Nakayama, A. Sakai, Y. Tanaka, A.
Yamaguchi, N. Shimma, K. Yokose, H. Seto, Tetrahedron Lett. 1991, 32, 4737.
S. K. Wrigley, M. A. Latif, T. M. Gibson, M. I. Chicarelli-Robinson, D. H.
Williams, Pure Appl. Chem. 1994, 66, 2383.
K. Kumagai, N. Hosotani, K. Kikuchi, T. Kimura, I. Saji, J. Antibiot. 2003, 56,
610.
K. Kikuchi, A. Kishino, O. Konishi, K. Kumagai, N. Hosotani, I. Saji,
C. Nakayama, T. Kimura, J. Biol. Chem. 2003, 278, 42985.
5
6
7
A. Furstner, F. Stelzer, A. Rumbo, H. Krause, Chem. Eur. J. 2002, 8, 1856.
¨
D. V. Rao, F. A. Stuber, Synthesis 1983, 308.
For experimental data of the IMDA reaction and characterization data
of all new products, see Supporting Information.
8
9
H. Saneyoshi, K. Seio, M. Sekine, J. Org. Chem. 2005, 70, 10453.
R. F. Heck, Org. React. 1982, 27, 345.
10 Crystallographic data reported in this manuscript have been deposited with
Cambridge Crystallographic Data Center as supplementary publication
No. CCDC-619253 for compound 12. Copies of the data can be obtained
free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html (or from the
Cambridge Crystallographic Data Center, 12, Union Road, Cambridge, CB2
1EZ, UK; fax: +44 1223 336033; or deposit@ccdc.cam.ac.uk).
11 C. D. Cook, J. Org. Chem. 1953, 18, 261.
12 K. Tatsuta, K. Akimoto, M. Annaka, Y. Ohno, M. Kinoshita, Bull. Chem. Soc.
Jpn. 1985, 58, 1699.
13 An authentic sample of natural vinaxanthone was kindly provided by Drs.
M. Nakatsuka, T. Kimura, and K. Kumagai, Dainippon Sumitomo Pharma
Co., Ltd.
Published on the web (Advance View) November 29, 2006; doi:10.1246/cl.2007.10