An aryne route to cytosporone B and phomopsin C

Article abstract of DOI:10.1246/cl.2010.508

The octaketide cytosporone B has been synthesized in six steps using 1,3,5-trihydroxybenzene as a starting material via aryne insertion reaction into a carbon-carbon σ-bond.

Full text of DOI:10.1246/cl.2010.508

doi:10.1246/cl.2010.508
508
Published on the web April 10, 2010
An Aryne Route to Cytosporone B and Phomopsin C
Hiroto Yoshida,* Takami Morishita, and Joji Ohshita
Department of Applied Chemistry, Graduate School of Engineering, Hiroshima University,
Higashi-Hiroshima 739-8527
(Received March 2, 2010; CL-100192; E-mail: yhiroto@hiroshima-u.ac.jp)
The octaketide cytosporone B has been synthesized in six
steps using 1,3,5-trihydroxybenzene as a starting material via
aryne insertion reaction into a carbon-carbon ·-bond.
OMe
OMe
OMe
Ac2O
NBS
Br
CH2Cl2
MeO
OH
MeO
OMe
OAc
MeO
OAc
88% yield over 2 steps
OMe
Br
Cytosporones are octaketide metabolites isolated by
Clardy’s group from the broth of two endophytic fungi,
Cytospora sp. CR200 and Diaporthe sp. CR146 (Figure 1).1,2
Among these, cytosporone B (1) has been recently demonstrated
to bind to the ligand-biding domain of nuclear orphan receptor
Nur77 and stimulate the transactivational activity of Nur77.3
Moreover, cytosporone B enhances gluconeogenesis in mouse
liver, increases Nur77-mediated induction of apoptosis, and
retards xenograft tumor growth. These biological effects clearly
reveal that cytosporone B would be useful in developing new
therapeutic drugs for cancers and hypoglycemia; however, its
total synthesis has hitherto appeared only in a Chinese patent,4
to the best of our knowledge. We report herein the shortcut
to cytosporone B starting from commercially available 1,3,5-
trihydroxybenzene through aryne insertion into a carbon-carbon
·-bond (eq 1).5,6
(TMS)2NH
KOH
Br
MeOH
MeO
65% yield
OH
MeO
OTMS
OMe
OMe
TMS
1. n-BuLi
2. Tf2O
Na/TMSCl
toluene
TMS
ether
MeO
OTMS
MeO
OTf
2: 35% yield over 3 steps
O
O
OMe O
EtO
KF/18-Crown-6
(CH2)6Me
THF
MeO
3: 43% yield
O
OEt
OH
O
BBr3 (3 equiv)
CH2Cl2
OH
O
MeO
OP
OH
Phomopsin C (4): 71% yield
O
OEt
ð1Þ
HO
PO
HO
OH
Scheme 1. Synthesis of phomopsin C.
O
OEt
Cytosporone B (1)
Initially we examined the synthesis of 3,5-di-O-methylcy-
methylene moiety and the ketone carbonyl) and introduction of
the octanoyl moiety into the aromatic ring (ortho to the 3-MeO
group) took place regioselectively.11 Although an attempt to
convert 3 into 1 by use of BBr3 (3 equiv) was unsuccessful, a
71% yield of phomopsin C (4), which has been recently isolated
from mangrove endophytic fungus, Phomopsis sp. ZSU-H76,12
was found to be formed as the sole product through the
regioselective monodemethylation instead.13 Unfortunately,
treatment of 3 with other demethylation reagents including
Me3SiCl/NaI14 and HBr/NaI15 also failed to provide 1.
tosporone B (3)7 via the insertion of 3,5-dimethoxybenzyne into
a carbon-carbon ·-bond of ethyl 3-oxodecanoate.8 As described
in Scheme 1, the required aryne precursor 2 was prepared from
3,5-dimethoxyphenol in six steps in 20% overall yield.9,10a
Subsequent reaction of 2 with ethyl 3-oxodecanoate in the
presence of a fluoride ion (KF/18-Crown-6) led to the selective
formation of 3 in 43% yield among four possible insertion
products, where cleavage of the C-C ·-bond (between the active
OH
O
We thus turned our attention to 3,5-bis(methoxymethoxy)-
benzyne, envisaging that deprotection of MOM moieties would
occur more smoothly. At first we attempted to transform 1,3,5-
trihydroxybenzene into 3,5-bis(methoxymethoxy)phenol, which
should be convertible into the required aryne precursor accord-
ing to Scheme 1, however selective introduction of two MOM
moieties into 1,3,5-trihydroxybenzene proved to be difficult.16
Hence we designed another route to the aryne precursor by use
of TBDMS-protected trihydroxybenzene 5, which was readily
accessible by the reaction with t-BuMe2SiOTf as outlined in
Scheme 2. Monobromination of 5 followed by the reaction of
the resulting product 6 with n-BuLi/Tf2O gave 3,5-disiloxy-
benzyne precursor 7 (74% yield over three steps),10b which was
then treated with chloromethyl methyl ether in the presence of
HO
O
OR
R = H, Cytosporone A
R = Et, Cytosporone B (1)
OH
HO
OH
R
O
O
HO
HO
O
O
R = H, Cytosporone C
R = OH, Cytosporone D
Cytosporone E
Figure 1. Cytosporones isolated from endophytic fungi.
Chem. Lett. 2010, 39, 508-509
© 2010 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

509
OH
t-BuMe2SiOTf
Et3N
OTBDMS
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NBS
CH2Cl2
CH2Cl2
HO
OH
TBDMSO
OTBDMS
3
5
OTBDMS
Br
OTBDMS
1. n-BuLi
2. Tf2O
TBDMS
ether
4
5
TBDMSO
KF
OTBDMS
TBDMSO
7: 74% yield over 3 steps
OTf
6
O
O
OMOM
EtO
KF/18-Crown-6
(CH2)6Me
18-Crown-6
MeOCH2Cl
TBDMS
DME
THF
6
MOMO
OTf
8: 82% yield
MOMO
O
TMSBr
CH2Cl2
MOMO
9
7
8
9
P. A. Paranagama, E. M. K. Wijeratne, A. A. L. Gunatilaka,
J. Nat. Prod. 2007, 70, 1939.
V. T. H. Nguyen, E. Bellur, B. Appel, P. Langer, Synthesis 2006,
2865.
Synthesis of 2-bromo-3,5-dimethoxyphenol, see: M. Runge, G.
Haufe, J. Org. Chem. 2000, 65, 8737.
O
OEt
OH
O
Cytosporone B (1): 26% yield over 2 steps
HO
10 Synthesis of aryne precursors, see: a) Y. Himeshima, T. Sonoda,
H. Kobayashi, Chem. Lett. 1983, 1211. b) D. Peña, A. Cobas, D.
Pérez, E. Guitián, Synthesis 2002, 1454.
11 Similar regioselectivities have been already observed in the
reaction of 3-methoxybenzyne, see Refs. 5a and 6a.
12 Z. Huang, X. Cai, C. Shao, Z. She, X. Xia, Y. Chen, J. Yang, S.
Zhou, Y. Lin, Phytochemistry 2008, 69, 1604.
13 This selectivity can be ascribed to the formation of a boron-
containing six-membered ring as shown below: F. M. Dean, J.
Goodchild, L. E. Houghton, J. A. Martin, R. B. Morton, B.
Parton, A. W. Price, N. Somvichien, Tetrahedron Lett. 1966, 7,
4153.
(16% overall yield based on 1,3,5-trihydroxybenzene)
O
OEt
Scheme 2. Synthesis of cytosporone B.
fluoride ion to furnish the target aryne precursor 8 without loss
of the C(aryl)-Si bond (82% yield). As was the case of 3,5-
dimethoxybenzyne, 3,5-bis(methoxymethoxy)benzyne (from 8)
was found to be also inserted into the active methylene-ketone
carbonyl ·-bond of ethyl 3-oxodecanoate, providing 3,5-di-O-
(methoxymethyl)cytosporone B (9) in a regioselective manner,17
which could be finally transformed into the desired cytosporone
B (1) by deprotection using TMSBr (16% overall yield based on
1,3,5-trihydroxybenzene).18 It should be noted that only three
isolations sufficient to obtain the final product throughout the
process, showing the efficacy of the present method.
Br2
Br-
+
Me
B
O
O
MeO
O
OEt
In conclusion, the aryne insertion reaction into a carbon-
carbon ·-bond has been demonstrated to be potent for the total
synthesis of octaketides, allowing cytosporone B to be fabricated
in 6 steps from commercially available 1,3,5-trihydroxybenzene.
Moreover, the first synthesis of phomopsin C has also been
accomplished relying on the present method.19 Further studies
on the total synthesis of other natural products by use of arynes
as key intermediates are in progress.
14 G. A. Olah, S. C. Narang, B. G. B. Gupta, R. Malhotra, J. Org.
Chem. 1979, 44, 1247.
15 G. Li, D. Patel, V. J. Hruby, Tetrahedron Lett. 1993, 34, 5393.
16 For example, the reaction of 1,3,5-trihydroxybenzene, which
was pretreated with NaH (2.2 equiv), with chloromethyl methyl
ether (2.1 equiv) in DMF at 0 °C afforded the desired product
only in 21% yield, accompanied by the formation of mono- and
trimethoxymethylated products. Furthermore, attempted mono-
bromination of the resulting 3,5-bis(methoxymethoxy)phenol
using NBS gave a mixture of a desired monobrominated and a
dibrominated products. Therefore, we abandoned the synthesis
of 3,5-bis(methoxymethoxy)benzyne precursor from 3,5-bis-
(methoxymethoxy)phenol.
This work was financially supported by The Kurata
Memorial Hitachi Science and Technology Foundation and
The 2007 Hiroshima University Fujii Research Promotion Fund.
We thank Central Glass Co., Ltd. for a generous gift of
trifluoromethanesulfonic anhydride. T.M. also acknowledges the
support of JSPS Research Fellowships for Young Scientists.
17 In addition to 9, we also observed the formation of small
amounts of unidentified by-products.
18 We also examined the reaction of 7 with ethyl 3-oxodecanoate
in the presence of a fluoride ion, expecting the direct formation
of 1 via the insertion reaction accompanied by the deprotection
of the silyl ether moieties, however, this reaction only gave a
complex mixture.
19 Supporting Information is available electronically on the CSJ-
Journal Web site, http://www.csj.jp/journals/chem-lett/index.
html.
References and Notes
1
S. F. Brady, M. M. Wagenaar, M. P. Singh, J. E. Janso, J. Clardy,
Org. Lett. 2000, 2, 4043.
2
Total synthesis of cytosporone E, see: a) T. Ohzeki, K. Mori,
Biosci. Biotechnol. Biochem. 2003, 67, 2584. b) J. D. Hall,
Chem. Lett. 2010, 39, 508-509
© 2010 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/