First total synthesis of vialinin A, a novel and extremely potent inhibitor of TNF-α production

Article abstract of DOI:10.1021/ol701590b

Vialinin A, a powerful inhibitor (IC₅₀ 90 pM) of TNF-α production, was synthesized from sesamol in 11 steps with 28% overall yield. The key reactions include a double Suzuki coupling of electron-rich aryl triflate with phenylboronic acid and an

Full text of DOI:10.1021/ol701590b

ORGANIC
LETTERS
2007
Vol. 9, No. 21
4131-4134
First Total Synthesis of Vialinin A, a
Novel and Extremely Potent Inhibitor of
TNF-
r Production
Yue Qi Ye,†,‡ Hiroyuki Koshino,† Jun-ichi Onose,‡ Kunie Yoshikawa,‡
Naoki Abe,‡ and Shunya Takahashi*,†
RIKEN (The Institute of Physical and Chemical Research), 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 July 6, 2007
ABSTRACT
Vialinin A, a powerful inhibitor (IC50 90 pM) of TNF-
r production, was synthesized from sesamol in 11 steps with 28% overall yield. The key
reactions include a double Suzuki coupling of electron-rich aryl triflate with phenylboronic acid and an oxidative deprotection of bis-MOM
ether. In addition, the related synthetic studies also suggest the necessity for structural revision of ganbajunin C, a positional isomer of
vialinin A.
The incidence of an immediate hypersensitive allergy (type
I) caused by immunoglobulin E, for example, food allergy,
pollinosis, asthma, drug-induced allergy, etc., is increasing
worldwide,1 and several therapeutic agents that inhibit the
release of chemical mediators such as histamine from mast
cells and basophils are currently used as therapeutic agents.2
Mast cells and basophils, which are high-affinity IgE
receptors (FcεRI), are activated by a specific antigen (IgE)
through cross-linking of the IgE-FcεRI complex. Cell
activation induces the degranulation and release of chemical
mediators such as histamine and leukotrienes and subse-
quently causes the release of cytokines including TNF (tumor
necrosis factor)-R, which have important roles in the late
phase inflammation of type I allergy. TNF-R is a potent
multifunctional cytokine that mediates a variety of biological
actions with a central role in the pathogenesis of many
inflammatory diseases.3 Thus, inhibitors of TNF-R produc-
tion in the activated mast cells and basophils are promising
candidates for a new type of anti-allergic agent.
In our search for bioactive compounds from edible Chinese
mushrooms, we isolated vialinin A (1) from the dry fruiting
bodies of Thelephora Vialis and reported that it had a
powerful 2,2-diphenyl-1-picrylhydrazyl (DPPH) free-radical-
scavenging activity with an EC50 value of 14 µM (cf. EC50
) 10 µM for BHT).4 Asakawa et al. also reported isolation
of the same compound from Thelephora terrestris and named
it terrestrin A.5 Recently, we found that this compound
strongly inhibited TNF-R production in rat basophilic
leukemia (RBL-2H3) cells: the IC50 was 90 pM when the
clinical immunosuppressant FK-506 was used in the same
† RIKEN.
(3) (a) Vassalli, P. Annu. ReV. Immunol. 1992, 10, 411-452. (b) Sieper,
J.; Braun, J. Expert Opin. Emerg. Drugs 2002, 2, 235-246. (c) Holgate, S.
T. Cytokine 2004, 28, 152-157.
(4) Xie, C.; Koshino, H.; Esumi, Y.; Takahashi, S.; Yoshikawa, K.; Abe,
N. Biosci. Biotechnol. Biochem. 2005, 69, 2326-2332.
(5) Radulovic, N.; Quang, D. N.; Hashimoto, T.; Nukada, M.; Aasakawa,
Y. Phytochemistry 2005, 66, 1052-1059.
‡ Tokyo University of Agriculture.
(1) (a) Kagan, R. S. EnViron. Health Perspect. 2003, 111, 223-225. (b)
Kheradmand, F.; Rishi, K.; Corry, D. B. EnViron. Health Perspect. 2002,
110, 553-556.
(2) Marone, G.; Spadaro, G.; De Marino, V.; Aliperta, M.; Triggiani,
M. Int. J. Clin. Lab. Res. 1998, 28, 12-22.
10.1021/ol701590b CCC: $37.00
© 2007 American Chemical Society
Published on Web 09/12/2007

run as a positive standard (IC50 ) 0.25 nM).6 The extremely
potent biological activity and the unique structure have
prompted us to develop an efficient method for preparing
this natural product. Herein, we describe the first total
synthesis of 1 and structural revision of its positional isomer,
ganbajunin C.
In the synthetic study of this unique molecule, selective
protection of hydroxyl groups in the central core and
construction of the terphenyl skeleton are the main problems
throughout the synthetic course. We envisioned densely
functionalized benzene 2 as a key intermediate and planned
a double Suzuki coupling7 of it with 4-(tert-butyldimethyl-
silyloxy)phenylboronic acid (3) (Scheme 1). The methylene
through bromination8 of an ortho-quinone9 obtained from 4
was not feasible, so the phenol 4 was transformed into
catechol 59 and then submitted to methoxymethylation
(MOMBr, sodium hydride (NaH)), giving bis-MOM ether
6. Introduction of two leaving groups into the para-position
of 6 was accomplished through a double lithiation. Thus, 6
was initially treated with 2.4 equiv of n-butyllithium at 0
°C, and then trapping with triisopropyl borate followed by
treatment with hydrogen peroxide/acetic acid gave rise to a
clean hydroxylation, affording hydroquinone derivative 7.
Upon treatment with triflic anhydride/pyridine, 7 gave triflate
8. The coupling reaction of 8 with 4.0 molar equiv of 3
proceeded nicely in the presence of tetrakis(triphenylphos-
phine)palladium (0.05 equiv), potassium bromide (2.1 equiv),
and potassium phosphate (4.0 equiv)10 in dioxane at 100 °C
to give terphenyl 9. At this stage, a selective deprotection
of methoxymethyl groups in 9 was needed. After several
experiments, we found this transformation could be achieved
by the use of 3.0 equiv of DDQ in the presence of p-TsOH
(1.5 equiv) in benzene at 50 °C,11 providing ortho-quinone
10. It is noteworthy that two TBS groups were retained under
these reaction conditions. This key reaction would enable
us to prepare many analogues of terphenyls.12 For example,
10 underwent hydrolysis under acidic conditions to give
4′,4′′-dihydroxyphlebiarubrone (11), which was isolated from
cultures of Punctularia atropurpurascens.13 The spectral and
physical properties of 11 were identical to those of the
reported 11. On the other hand, reduction of 10 with sodium
dithionite gave the corresponding catechol, which was
immediately submitted to phenylacetylation. We observed
that the reaction with phenylacetyl chloride in the presence
of organic bases such as pyridine/dimethylaminopyridine and
triethylamine was not satisfactory because it proceeded only
sluggishly, whereas the use of n-butyllithium at -78 °C
improved the reaction, and the desired product 12 was
Scheme 1
acetal moiety in 2 was expected to resist many reagents until
the later stage of total synthesis.
Therefore, we selected sesamol (4) as a starting material
for the central core (Scheme 2). Preparation of 2 (X ) Br)
Scheme 2
4132
Org. Lett., Vol. 9, No. 21, 2007

obtained. Hydrolysis of the methylene acetal moiety in 12
was a troublesome step. Conventional methods including the
use of boron trichloride or boron tribromide resulted in a
complex mixture because of the instability of phenylacetyl
groups toward the reaction conditions employed. However,
treatment of 12 with 2.5 equiv of lead tetraacetate14 in
benzene at 80 °C provided orthoester 13. Finally, exposure
of 13 to mild acidic conditions led to the removal of two
TBS groups concomitant with hydrolysis of the orthoester,
giving 1. The spectral and physical properties of 1 were
identical to those of natural 1.
Table 1. 13C NMR Data (δ) for Compounds 1, 14 (natural
ganbajunin C), 14 (synthetic), 15, and 16 in Acetone-d6
1
14 (natural)
14
position
1 (1′′)
vialinin A ganbajunin C (synthetic)
15
16
124.3
132.3
115.9
157.8
123.1
134.6
141.7
124.8
132.6
116.1
158.1
124.0
142.6
142.6
132.7
133.0
121.9
150.8
117.8
136.8
136.8
133.3 138.5
128.2 128.7
116.4 122.9
157.2 151.5
2 (2′′), 6 (6′′)
3 (3′′), 5 (5′′)
4 (4′′)
1′, 4′
2′, 3′
5′, 6′
In previous papers, one of us developed a new stereo-
chemical coding method, CAST (CAnonical representation
of STereochemistry)15 and successfully applied it to a
database-oriented 13C NMR chemical shift prediction system,
called CAST/CNMR.16 In the course of studies applying
CAST/CNMR to terphenyls, we found that 13C NMR data
of the terminal aromatic rings of 1 were similar to those of
ganbajunin C isolated from edible Chinese mushroom,
Thelephora ganbajun (Figure 1)17 and felt that the proposed
(Table 1). The characteristic difference is in the chemical
shift of the carbon atom attached to an oxygen atom: the
13C NMR spectrum of biphenol 15 in acetone-d6 showed one
aromatic carbon C-4 at 157.2 ppm, whereas C-4 of the
corresponding phenylacetate 16 was observed at δ 151.5.
The low chemical shift (158.1 ppm) of C-4 (4′′) in ganba-
junin C suggested the 4 (4′′)-OH was free. In order to confirm
these considerations, the proposed structure 14 was synthe-
sized in a similar strategy (Scheme 3). Bromanilic acid (17)
Scheme 3
Figure 1. Structures of ganbajunin C and biphenyls.
structure 14 was quite strange because two model compounds
(15 and 1618) exhibited clearly different 13C NMR spectra
(6) Onose, J.; Xie, C.; Ye, Y.-Q.; Takahashi, S.; Koshino, H.; Yasunaga,
K.; Abe, N.; Yoshikawa, K. To be submitted.
(7) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457-2483.
(8) Horner, L.; Sturm, K. Liebigs Ann. Chem. 1955, 597, 1-19.
(9) Hussain, H. H.; Babic, G.; Durst, T.; Wright, J. S.; Flueraru, M.;
Chichirau, A.; Chepelev, L. L. J. Org. Chem. 2003, 68, 7023-7032.
(10) Oh-e, T.; Miyaura, N.; Suzuki, A. Synlett 1990, 221-222.
(11) Barrero, A. F.; Alvarez-Manzaneda, E. J.; Herrador, M. M.; Valdivia,
M. V.; Chahboun, R. Tetrahedron Lett. 1998, 39, 2425-2428.
(12) Liu, J.-K. Chem. ReV. 2006, 106, 2209-2223.
was reduced and then subjected to etherification with
benzyloxymethyl chloride (BOMCl) and NaH to give tet-
rakis-BOM ether 18. Suzuki coupling of 18 with 3 (2.5
equiv) was effected by the use of palladium acetate19 (0.05
equiv) and triphenylphosphine (0.15 equiv) in the presence
of sodium carbonate in aqueous propanol at 100 °C to afford
terphenyl derivative 19. Coupling reaction using 17 or its
dimethoxy analogue instead of 18 failed because of the low
solubility of the substrate in the reaction solvent and
instability toward the reaction conditions employed. After
phenylacetylation of 19, the resulting diester 20 was hydro-
genated over palladium hydroxide under H2 to give 14.20,21
As expected, the spectral data of synthetic 14 were com-
pletely different from that of reported ganbajunin C. In
(13) Anke, H.; Casser, I.; Herrmann, R.; Steglich, W. Z. Naturforsch.
1984, 39c, 695-698.
(14) Ikeya, Y.; Taguchi, H.; Yoshioka, I. Chem. Pharm. Bull. 1981, 29,
2893-2898.
(15) (a) Satoh, H.; Koshino, H.; Funatsu, K.; Nakata, T. J. Chem. Inf.
Comput. Sci. 2000, 40, 622-630. (b) Satoh, H.; Koshino, H.; Funatsu, K.;
Nakata, T. J. Chem. Inf. Comput. Sci. 2001, 41, 1106-1112. (c) Satoh, H.;
Koshino, H.; Nakata, T. J. Comput.-Aided Chem. 2002, 3, 48-55.
(16) (a) Satoh, H.; Koshino, H.; Uzawa, J.; Nakata, T. Tetrahedron 2003,
59, 4539-4547. (b) Satoh, H.; Koshino, H.; Uno, T.; Koichi, S.; Iwata, S.;
Nakata, T. Tetrahedron 2005, 61, 7431-7437. (c) Koshino, H.; Satoh, H.;
Yamada, T.; Esumi, Y. Tetrahedron Lett. 2006, 47, 4623-4626. (d)
Takahashi, S.; Satoh, H.; Hongo, Y.; Koshino, H. J. Org. Chem. 2007, 72,
4578-4581.
(18) This was prepared by esterification (PhCH2COCl-NaH) of 15.
(19) Huff, B. E.; Koenig, T. M.; Mitchell, D.; Staszak, M. A. Organic
Syntheses; Wiley & Sons: New York, 2004; Collect. Vol. X, pp 102-107.
(17) (a) Hu, L.; Gao, J.-M.; Liu, J.-K. HelV. Chim. Acta 2001, 84, 3342-
3349. (b) Hu, L.; Liu, J.-K. Z. Naturforsch. 2003, 58c, 452-454.
Org. Lett., Vol. 9, No. 21, 2007
4133

analogy with the case of model compounds (15 and 16),
synthetic 14 contained one signal for C-4 (4′′) at δ 150.8,
which was observed at 158.1 ppm in the 13C NMR spectrum
of the natural product. These results show that the structure
of natural ganbajunin C is not 14 as proposed in ref 17.
Taking into account the origin and the spectral data, it is
likely that the correct structure of ganbajunin C closely
resembles that of vialinin A (terrestrin A) (1). The 13C NMR
data of the central core of reported ganbajunin C, however,
prevent us from stating that 1 and ganbajunin C are identical.
To clarify this, a direct comparison of our samples with the
authentic natural product would be necessary.
yield from a known catechol (5). This synthetic process
would be quite useful for preparing many analogues of 1
suitable for clinical usage. Furthermore, our synthetic studies
suggest the need to reinvestigate the structure of natural
ganbajunin C.
Acknowledgment. This work was supported by the
Chemical Biology Project (RIKEN) and in part by a Grant-
in-Aid for Scientific Research from the Ministry of Educa-
tion, Science, Sports, and Culture of Japan. We are grateful
to Dr. Y. Hongo for mass spectral measurements, and Ms.
K. Yamada in RIKEN for the elemental analyses.
In summary, we developed a short and efficient synthesis
of vialinin A (1), in only nine steps and with 44% overall
Supporting Information Available: Experimental pro-
cedures, NMR spectra of 1, 6-14, and 18-20. This material
is available free of charge via the Internet at http://pubs.acs.org.
(20) It was revealed that 14 was unstable and readily prone to change
into the corresponding p-quinone on standing at rt.
(21) Tetramethoxymethyl analogue of 20 was also synthesized, but
deprotection of the analogue under acidic conditions caused a partial
dephenylacetylation and oxidation, resulting in a low yield of 14.
OL701590B
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Org. Lett., Vol. 9, No. 21, 2007