Expeditious synthesis of vialinin B, an extremely potent inhibitor of TNF-aα production

Article abstract of DOI:10.1021/ol9020833

A first total synthesis of vialinin B, a powerful inhibitor (IC ₅₀ 20 pM) of TNF-a production, Is described. The key reactions include a double Suzukl-Mlyaura coupling of electron-rich aryl bromide with a couple of phenylboronic acids, a Cu-med

Full text of DOI:10.1021/ol9020833

ORGANIC
LETTERS
2009
Vol. 11, No. 21
5074-5077
Expeditious Synthesis of Vialinin B, an
Extremely Potent Inhibitor of TNF-r
Production
Yue Qi Ye,†,‡ Hiroyuki Koshino,† Jun-ichi Onose,‡ Kunie Yoshikawa,‡ Naoki Abe,‡
and Shunya Takahashi*,†
RIKEN, Wako, Saitama 351-0198, Japan, and Department of Nutritional Science,
Faculty of Applied Bio-Science, Tokyo UniVersity of Agriculture, 1-1-1 Sakuragaoka,
Setagaya-ku, Tokyo 156-8502, Japan
shunyat@riken.jp
Received September 9, 2009
ABSTRACT
A first total synthesis of vialinin B, a powerful inhibitor (IC50 20 pM) of TNF-r production, is described. The key reactions include a double
Suzuki-Miyaura coupling of electron-rich aryl bromide with a couple of phenylboronic acids, a Cu-mediated Ullmann reaction, and a LHMDS-
promoted phenylacetylation. This synthesis proceeded in 11 steps with 18% overall yield from a known sesamol derivative.
Vialinin B (1) is a highly oxygenated dibenzofuran bearing
p-hydroxyphenyl and phenylacetoxy groups that was isolated
by us from the dry fruiting bodies of an edible Chinese
mushroom, Thelephora Vialis, and shows an extremly potent
inhibitory activity against tumor necrosis factor (TNF)-R
production in rat basophilic leukemia (RBL-2H3) cells (IC50
) 20 pM vs. 0.25 nM for FK-506).1 TNF-R is a potent
multifunctional cytokine that mediates a variety of biological
actions with a central role in the pathogenesis of inflamma-
tory diseases such as rheumatoid arthritis (RA).2 Thus,
inhibitors of TNF-R production in activated mast cells and
basophils are promising candidates for a new type of
antiallergic agent. The mode of action of 1 and its inhibition
mechanism, however, still remain unresolved. Its occurrence
in nature was also limited. To clarify the target molecule of
1 and synthesize new antiallergic drugs, development of an
efficient method for the synthesis of 1 is required. Although
many oligoarenes including p-terphenyls have been synthe-
sized so far,3 no paper has appeared dealing with the
synthesis of highly oxygenated dibenzofurans.4 Described
herein is the first total synthesis of vialinin B (1), thus
providing a general method for the synthesis of this family.
In the synthetic study of this unique molecule, construction
of the dibenzofuran skeleton and selective protection of
(3) For recent review, see: (a) Stanforth, S. P. Tetrahedron 1998, 54,
263–303. (b) Bellina, F.; Carpita, A.; Rossi, R. Synthesis 2004, 2419–2440.
(c) Doucet, H. Eur. J. Org. Chem. 2008, 201, 2013–2030. (d) Manabe, K.;
Ishikawa, S. Chem. Commun. 2008, 382, 3829–3838, and references cited
therein.
† RIKEN.
(4) For recent syntheses of simple benzofuran derivatives without
polyoxy functions, see: (a) Wang, C.; Piel, I.; Glorius, F. J. Am. Chem.
Soc. 2009, 131, 4194–4195. (b) Hussain, M.; Hung, N. T.; Langer, P.
Tetrahedron Lett. 2009, 50, 3929–3932. (c) Yamashita, M.; Hirano, K.;
Satoh, T.; Miura, M. Org. Lett. 2009, 11, 2337–2340. (d) Komine, Y.;
Kamisawa, A.; Tanaka, K. Org. Lett. 2009, 11, 2361–2364. (e) Kawaguchi,
K.; Nakano, K.; Nozaki, K. Org. Lett. 2008, 10, 1199–1202.
‡ Tokyo University of Agriculture.
(1) Xie, C.; Koshino, H.; Esumi, Y.; Onose, J.; Yoshikawa, K.; Abe,
N. Bioorg. Med. Chem. Lett. 2006, 16, 5424–5426.
(2) (a) Vassalli, P. Annu. ReV. Immunol. 1992, 10, 411–452. (b) Sieper,
J.; Braun, J. Expert Opin. Emerging Drugs 2002, 2, 235–246. (c) Holgate,
S. T. Cytokine 2004, 28, 152–157.
10.1021/ol9020833 CCC: $40.75
Published on Web 10/05/2009
 2009 American Chemical Society

hydroxyl groups in the central core are the main problems
throughout the synthetic course. To resolve such problems,
we designed a synthetic strategy as shown in Scheme 1.
Scheme 2
Scheme 1
first successful example was demonstrated by the coupling
of 4 with 5 and 6 as follows. We initially examined a
coupling with a simple boronic acid 5, and found that reaction
with Pd(PPh3)4 in the presence of cesium carbonate afforded
a coupling product 9 in 84% yield.8 The position of the newly
1
introduced phenyl group was determined by the H NMR
analyses including HMBC and NOE experiments (Scheme
2).9 Second coupling was achieved by the action of Pd(OAc)2
in the presence of the lignad 13,10 giving desymmetrical
p-terphenyl 11 in 84% yield. Encouraged by the above
results, we next changed the order of the coupling partner.
Reaction of 4 and 6 under the same conditions (Pd(PPh3)4-
cesium carbonate) gave 10 in moderate yield (∼54%)
whereas a combination of Pd(OAc)2 and 13 or 2-di-tert-
butylphosphino-2′,4′,6′-triisopropylbiphenyl resulted in no
reaction or a complex mixture. The best results were obtained
by the use of Pd(OAc)2 and triphenylphosphine instead of
the sterically hindered ligands to give 10 in 78% yield.8 The
ring connectivity was also confirmed by the 1H NMR
analysis. As anticipated, the second coupling did not proceed
by using a system of Pd(OAc)2-triphenylphosphine-
potassium phosphate. But an exchange of the phophine from
triphenyl phosphine to 13 dramatically improved the reaction,
providing 12 in 91% yield. This compound was also obtained
through a one-pot Suzuki-Miyaura coupling. Thus, after
completion of the first coupling between 4 and 6 (TLC
analyses), 5, 13, and Pd(OAc)2 (0.05 equiv) were added in
Removal of two phenylacetyl groups in the target molecule
leads to the O-protected dibenzofuran catechol 2. Cleavage
of the internal ether linkage can revert 2 back to the
desymmetrical p-terphenyl 3. This would be synthesized by
Suzuki-Miyaura coupling5 of bromide 4 with a couple of
boronic acids 5 and 6.6 The methylene acetal moiety in 4
was expected to resist many reagents until the later stage of
total synthesis, and the formyl group was introduced for a
regioselective coupling as well as for an equivalent of a
masked hydroxyl group. These retrosynthetic analyses al-
lowed us to select sesamol (7) as the starting material.
Synthesis began with preparation of the central core 4
(Scheme 2). According to De Kimpe’s procedure,7 sesamol
(7) was transformed into 8 in 2 steps. The hydroxyl group
in 8 was protected as methoxymethyl (MOM) ether to give
4. This compound seems to be a potential precursor and a
versatile starting material for the synthesis of p-terphenyls
bearing a variety of substituents on the central ring as well
as 1 provided that a regioselective Suzuki-Miyaura coupling
of 4 with different types of boronic acids is possible. The
(5) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457–2483.
(6) Boronic acid 6 was prepared from 4-chlorocatechol via 1,2-
bis(benzyloxy)-4-bromo-5-chlorobenzene (22) in 3 steps: (1) Br2, acetic acid,
rt; (2) BnBr, K2CO3, n-Bu4NI, acetone, 60 °C (86% in 2 steps); (3) n-BuLi,
(i-PrO)3B, THF, -78 to 0 °C (97%); see the Supporting Information.
(7) Maes, D.; Vervisch, S.; Debenedetti, S.; Davio, C.; Mangelinckx,
S.; Giubellina, N.; De Kimpe, N. Tetrahedron 2005, 61, 2505–2511.
(8) Although several spots were observed on TLC, a double coupling
product could not be isolated.
(9) In the 1H NMR spectra of 9 and 10, the up-field shift of the formyl
proton due to the shielding effect of the neighboring aromatic ring was
observed.
(10) Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L.
J. Am. Chem. Soc. 2005, 127, 4685–4696.
Org. Lett., Vol. 11, No. 21, 2009
5075

Scheme 3
the same flask, and the reaction was continued for a further
3 h. Standard workup followed by chromatography on silica
gel gave a 67% yield of 12.
tion, the major product was de-MOM product not a desired
orthoester when 17 was treated with LTA in benzene.18 We
found that the oxidation was sensitive to the O-protecting
group at the C-6 position of 17. For example, the use of
ether-type protecting groups such as MOM, Bn, and TBDMS
resulted in a complex mixture or no reaction while introduc-
tion of electron-withdrawing groups like acetate into 6-OH
of 18 gave good results. Consequently, the MOM group in
17 was exchanged to a benzyloxycarbonyl group. LTA
oxidation of 19 thus obtained proceeded nicely, giving the
corresponding monoacetate 20 in good yield. Exposure of
this to mild acidic conditions led to removal of the acetal
group, providing an unstable catechol 2 (R ) OZ), which
was immediately submitted to phenylacetylation. Deproto-
nation from two hydroxyl groups in 2 was accomplished by
the action of lithium bis(trimethylsilylamide) (LHMDS) in
THF at -78 °C,19 and the resulting lithium salt reacted with
phenylacetyl chloride to provide 21 in good yield. Finally,
all benzyl groups in 21 were removed by hydrogenolysis
with Pd(OH)2 to give vialinin B (1). The spectral data of 1
were identical with those of the natural product.20
In constructing the p-terphenyl skeleton, we next turned
our attention to the benzofuran formation. Prior to the
reaction, the MOM group in 11 was hydrolyzed, giving 14
as an unstable solid (Scheme 3). The intramolecular O-
arylation of 14 was investigated under several conditions
including Pd(OAc)2 or Pd2(dba)3 in the presence of 13 or
2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl or 2-(di-
tert-butylphosphino)biphenyl,10,11 or Cu catalyst such as
Nano-CuO12 and Cu2O.13 All attempts, however, were
unsuccessful, and a desired benzofuran could not be isolated.
On the other hand, Bayer-Villiger oxidation14,15 of 12
provided the corresponding formate 15, which, upon treat-
ment with base, afforded an unstable phenol 16. The
cyclization from 16 to 17 was a troublesome step again. Pd-
catalyzed etherification of 16 did not proceed while the Cu-
mediated cyclization reaction gave 17 (∼54%) along with
an o-quinone without the MOM group (∼25%). These results
reflected the instability of 16 toward the reaction conditions
employed. After extensive experimentation, it was found that
treatment of the formate 15 with a Cu catalyst directly
produced 17. The use of Cu2O-pyridine was quite effective;
an 88% yield of 17 was attained. Removal of the methyl-
eneacetal moiety was performed by lead tetraacetate (LTA)
oxidation,16 which was previously employed in the total
synthesis of natural p-terphenyls.17 Contrary to our expecta-
We have developed a short and efficient method for the
synthesis of vialinin B (1) in 13 steps from a commercially
available sesamol (7). The key features of this synthesis are
as follows: (1) synthesis of a highly functionalized p-
terphenyl skeleton based on a Suzuki-Miyaura coupling;
(2) construction of a benzofuran skeleton by a Cu-mediated
(16) Ikeya, Y.; Taguchi, H.; Yoshioka, I. Chem. Pharm. Bull. 1981, 29,
2893–2898.
(11) Burgos, C. H.; Barder, T. E.; Huang, X.; Buchwald, S. L. Angew.
Chem., Int. Ed. 2006, 45, 4321–4326
.
(17) (a) Ye, Y.-Q.; Koshino, H.; Onose, J.; Yoshikawa, K.; Abe, N.;
Takahashi, S. Org. Lett. 2007, 9, 4131–4134. (b) Ye, Y.-Q.; Koshino, H.;
Onose, J.; Negishi, C.; Yoshikawa, K.; Abe, N.; Takahashi, S. J. Org. Chem.
2009, 74, 4642–4645.
(12) (a) Kidwai, M.; Mishra, N. K.; Bansal, V.; Kumar, A.; Mozumdar,
S. Tetrahedron Lett. 2007, 48, 8883–8887. (b) Zhang, J.; Zhang, Z.; Wang,
Y.; Zheng, X.; Wang, Z. Eur. J. Org. Chem. 2008, 511, 5112–5116. (c)
Schareina, T.; Zapf, A.; Cotte´, A.; Mu¨ller, N.; Beller, M. Tetrahedron Lett.
2008, 49, 1851–1855, and references cited therein.
(18) LTA oxidation of 5,6-bis(methoxymethoxy)benzo[d][1,3]dioxole
as a model compound gave the corresponding orthoester in high yield.
(19) Esterification of 2 in the presence of DMAP in pyridine or
triethylamine gave a mixture of 21 and its mono-phenylacetate.
(20) The original 13C NMR data (δ 119.83 for C-9b) of 1 denoted in
ref 1 was a typographical errror and should be revised to 119.38 ppm.
(13) Wipf, P.; Jung, J.-K. J. Org. Chem. 2000, 65, 6319–6337.
(14) Camps, F.; Coll, J.; Messeguer, A.; Perica´s, M. A. Tetrahedron
Lett. 1981, 22, 3895–3896
.
(15) No presence of potassium fluoride decreased the yield of 15.
5076
Org. Lett., Vol. 11, No. 21, 2009

intramolecular Ullmann reaction; and (3) LHMDS-promoted
phenylacetylation. This method would be quite useful for
the preparation of new antiallergic drugs21 as well as for
bioprobes to clarify the target molecule.
Grant-in-Aid for Scientific Research from the Ministry of
Education, Science, Sports, and Culture of Japan. We are
grateful to Dr. Y. Hongo (RIKEN) for mass spectral
measurements, and Ms. K. Yamada in RIKEN for the
elemental analyses.
Acknowledgment. This work was supported by the
Supporting Information Available: Experimental pro-
cedures and NMR spectra of 1, 4, 9-12, and 14-21. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Chemical Genomics Project (RIKEN) and in part by a
(21) For recent anti-RA drugs, see: (a) Brennan, F. M.; Chantry, D.;
Jackson, A.; Maini, R.; Feldmann, M. Lancet 1989, 334, 244–247. (b) Maini,
R.; St. Clair, E. W.; Breedveld, F.; Furst, D.; Kalden, J.; Weisman, M.;
Solen, J.; Emery, P.; Harriman, G.; Feldmann, M.; Lipsky, P. Lancet 1999,
354, 1932–1939.
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