Syntheses of 5′-O-desmethylterphenyllin and related p-terphenyls and their inhibitory activity of TNF-α release from RBL-2H3 cells

Article abstract of DOI:10.1016/j.tetlet.2013.07.062

The first total syntheses of 5′-O-desmethylterphenyllin and three related p-terphenyls have been achieved. The methodology features a Suzuki-Miyaura coupling reaction with a hindered aryl chloride as the key step. Two of the four synthesized 5′-O-desmethylterphenyllins exhibit moderate TNF-α release-inhibitory activity toward RBL-2H3 cells.

Full text of DOI:10.1016/j.tetlet.2013.07.062

Tetrahedron Letters 54 (2013) 4986–4989
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Syntheses of 50-O-desmethylterphenyllin and related p-terphenyls
and their inhibitory activity of TNF-
a
release from RBL-2H3 cells
a
b
b
a
a
Arata Yajima a, , Shota Urao , Yasukiyo Yoshioka , Naoki Abe , Ryo Katsuta , Tomoo Nukada
⇑
a Department of Fermentation Science, Faculty of Applied Bioscience, Tokyo University of Agriculture (NODAI), Sakuragaoka 1-1-1, Setagaya-ku, Tokyo 156-8502, Japan
b Department of Nutritional Science, Faculty of Applied Bioscience, Tokyo University of Agriculture (NODAI), Sakuragaoka 1-1-1, Setagaya-ku, Tokyo 156-8502, Japan
a r t i c l e i n f o
a b s t r a c t
The first total syntheses of 50-O-desmethylterphenyllin and three related p-terphenyls have been
Article history:
Received 24 June 2013
Revised 9 July 2013
Accepted 11 July 2013
Available online 17 July 2013
achieved. The methodology features a Suzuki–Miyaura coupling reaction with a hindered aryl chloride
as the key step. Two of the four synthesized 50-O-desmethylterphenyllins exhibit moderate TNF-
a
release-inhibitory activity toward RBL-2H3 cells.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
p-Terphenyls
Suzuki–Miyaura coupling
TNF-a
Ubiquitin-specific peptidase
A number of bioactive polyhydroxy-p-terphenyls have been
isolated from various microorganisms.1 There are several groups
of bioactive, naturally occurring p-terphenyls with common struc-
ture features. One group of polyhydroxy-p-terphenyls is featured
by an acylated catechol structure in the center ring such as terrest-
rins,2 vialinin A,3 and thelephantins (Fig. 1). Although vialinin A (1)
was originally isolated from the edible mushroom Thelephora vialis
as a DPPH radical inhibitor,3 it was also shown to be a potent inhib-
co-workers also reported the isolation of 50-O-desmethylterphe-
nyllin (6) from endophytic Aspergillus sp. YXf3.13 Compound 7
was also isolated from the sclerotia of P. raistrickii and was re-
ported to reduce the growth rate of the larvae of the corn earworm
Helicoverpa zea.14 In addition, Takahashi and Abe et al. reported
that DMT (10), a simplified synthetic analogue of vialinin A,
exhibited potent inhibitory activity—as high as that of vialinin
A—against TNF-
a
release from RBL-2H3 cells.15 Although no
itor of tumor necrosis factor (TNF)-a release from rat basophilic
leukemia (RBL)-2H3 cells.4 Thelephantin O (2) is an acylated
p-terphenyl isolated from Thelephora aurantiotincta, and that is
cytotoxic against HepG2 and Caco2.5 The second group of polyhy-
droxy-p-terphenyls consists of prenylated p-terphenyls (Fig. 1) and
includes terprenins6 (3) and prenylterphenyllins7 (4) isolated from
Aspergillus candidus RF-5672 and A. candidus IF10, respectively.
Terprenin was reported to be a strong immunosuppressive agent,6
and the phenylterphenyllins were reported to be cytotoxic.7
In addition, other p-terphenyls without acyl or prenyl groups
have been isolated from some fungi. In 1975, Marchelli and Vining
isolated terphenyllin (5) from A. candidus,8 and 5 was subsequently
shown to have anticancer,9 DPPH radical scavenging,10 and
HIV-1-integrase inhibitory11 activities. Recently, Lin and She
co-worker isolated 50-O-desmethylterphenyllin (6), together with
its hydroxylated derivatives 7 and 8, from the mangrove endo-
phytic fungus Penicillium chermesinum (ZH4-E2) and found these
compounds to be
a
-glucosidase inhibitors.12 Meanwhile, Ge and
⇑
Corresponding author. Tel./fax: +81 3 5477 2264.
E-mail address: ayaji@nodai.ac.jp (A. Yajima).
Figure 1. Structures of p-terphenyls.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.07.062

A. Yajima et al. / Tetrahedron Letters 54 (2013) 4986–4989
4987
The retrosynthetic analysis for 6 is based on double or sequen-
tial Suzuki–Miyaura cross-couplings, as shown in Scheme 1. Con-
sidering the vast number of available methods for the
introduction of various aryl groups, the incorporation of different
functional groups required for the Suzuki–Miyaura coupling reac-
tions in the center ring is favorable. For example, in the total syn-
thesis of terprenin by Kawada and Ohtani, bromo and iodo groups
were installed in the central aryl core, and sequential Suzuki–
Miyaura cross couplings followed.18
The synthesis began with commercially available 11 (Scheme
2). However, a preliminary study showed that it was difficult to
introduce the bromo or iodo group at the C-3 position of 11 under
standard conditions, such as with bromine or iodine and NBS or
NIS. Although there have been some reports on the synthesis of
3-bromo derivatives of 11 employing sodium hypobromite as the
bromine source,19 we obtained only the 5-bromo derivative as a
major product. Fortunately, using Liebert’s method,19 the regiose-
lective chlorination of 11 using sodium hypochlorite produced 12
in high yield. Although the Suzuki–Miyaura coupling with a
sterically hindered aryl chloride was anticipated to be relatively
difficult, we decided to employ the aryl chloride as the key inter-
mediate in the total synthesis and take on the challenge of devel-
oping efficient conditions for the coupling reaction that would be
appropriate for natural product synthesis. Therefore, the hydroxy
groups of 12 were protected as MOM ethers, and subsequent Bae-
yer–Villiger oxidation and methanolysis produced 13, as shown in
Scheme 2. The halogenation of the ortho position of the phenol was
again troublesome. However, we found that pyridinium hydrobro-
mide perbromide was effective, producing the corresponding bro-
mide in 64% yield. The methylation of the hydroxy group of 14
afforded the key intermediate 15 (X1 = Cl, X2 = Br in C). With the
key intermediate 15 in hand, the regioselective Suzuki–Miyaura
coupling at the bromo moiety with boronic acid 16a was investi-
gated. As expected, no reaction was observed at the chloro substi-
tuent under all standard conditions, and the corresponding
biphenyl 17a was chemoselectively obtained in good yield by
employing a catalyst generated from Pd(OAc)2 and DavePhos.20
Next, the second Suzuki–Miyaura coupling of the sterically hin-
dered chloro moiety of 17a was investigated. Although there have
been various reports on the Suzuki–Miyaura reaction of aryl
chlorides employing palladium catalysts with a wide variety of
Scheme 1. Retrosynthetic analysis of 50-O-desmethylterphenyllins.
immunosuppressive activity for 50-O-desmethylterphenyllin and
its related p-terphenyls has yet been reported, we proposed that
these compounds should have immunosuppressive or inhibitory
activity against TNF-a release because of their structural similarity
to DMT, terphenyllins, and terprenins.
Recent advances in techniques used in chemical biology
prompted synthetic organic chemists to elucidate the mode of ac-
tion and target molecules of bioactive natural products.16 Very re-
cently, Yajima and co-workers identified the binding protein for
vialinin A and DMT, ubiquitin-specific peptidase 5 (USP5), using
a biotinylated derivative of DMT.17 Using chemical probes derived
from DMT, it should be possible to fully elucidate the unique path-
way of this immunosuppressive effect, which is different from that
of FK-506. However, because DMT contains a catechol moiety in its
central aromatic ring, it is relatively sensitive to oxidation under
aerobic conditions, which is disadvantageous in the preparation
of chemical probes. However, because 6 is not a catechol deriva-
tive, it would be expected to be more stable than DMT against oxi-
dation. Thus, we propose that 6 is a promising alternative for DMT
both as a template for chemical probes for the identification of the
target protein and as a candidate for the development of immuno-
suppressive agents. Therefore, to confirm the immunosuppressive
activity of 50-O-desmethylterphenyllins, we synthesized 6, 7, 8,
and the unnatural derivative 9 by employing Suzuki–Miyaura
coupling reactions as the key steps.
Scheme 2. Synthesis of 50-O-desmethylterphenyllins. Reagents, conditions, and yields: (a) NaClO aq, NaOH (Ref. 19), 95%; (b) MOMCl, DIPEA, DMF, 99%; (c) m-CPBA, CH2Cl2,
reflux; (d) Et3N, MeOH, 97% in two steps; (e) PyHBr-Br2, py, 0 °C to rt 63%; (f) MeI, K2CO3, acetone, 45 °C, 99%; (g) Pd(OAc)2, DavePhos, K3PO4, toluene, 90 °C, 16a for 17a, 83%
or 16b for 17b, 71%; (h) Pd(OAc)2, SPhos, NaOH, toluene, 95 °C, 16a for 18a, 95%, or 16b for 18b, 83%, 16a for 18c, 93%, or 16b for 18d, 84%; (i) HCl aq, MeOH, 83% for 6 or HCl,
MeOH, 71% for 7, 86% for 8, or 98% for 9; (j) Pd(OAc)2, SPhos, NaOH, toluene, 95 °C, 16a for 18a, 92%, or 16b for 18b, 89%.

4988
A. Yajima et al. / Tetrahedron Letters 54 (2013) 4986–4989
Table 1
Suzuki–Miyaura couplings generating p-terphenyl 18aa
Entry
Catalyst/ligand
Base
Yield (%)
b
1
2
3
4
5
6
7
Pd(OAc)2/P(t-Bu)3
Pd(OAc)2/XPhos
Pd(OAc)2/DavePhos
Pd(OAc)2/SPhos
NaOH
NaOH
NaOH
NaOH
K2CO3
tBuOK
K2CO3
—
14
24
95
13
Pd(OAc)2/SPhos
b
Pd-PEPPSI-IPentc
PdCl2[P(tBu)2C6H4NMe2]2
—
—
d
b
a
b
c
Conditions: 10 mol % palladium catalyst and 10 equiv base in toluene at 95 °C.
Not observed.
Reaction was performed at 65 °C.
d
Reaction was performed at 100 °C in dioxane–water.
phosphine ligands,21 the reaction with 17a did not proceed well
under the reported conditions (Table 1). Fortunately, we found
the combination of Pd(OAc)2 and the SPhos ligand22 to be highly
effective in this reaction during our screen of phosphine ligands.
The desired terphenyl 18a was obtained in 95% isolated yield
under the optimized conditions (entry 4). Finally, the deprotection
of the four MOM groups of 18a with aqueous HCl afforded
50-O-desmethylterphenyllin (6) (Scheme 2). The 1H and 13C NMR
spectra were in good agreement with the reported data.12,13 In
the same manner, sequential Suzuki–Miyaura coupling reactions
with boronic acids 16a and 16b produced the other three terphe-
nyls, 18b, 18c, and 18d. The deprotection of the MOM groups of
these intermediates with methanolic HCl produced the two natural
terphenyls 3,300-dihydroxy-50-O-desmethylterphenyllin14 (7) and
300-hydroxy-50-O-desmethylterphenyllin13 (8), as well as the
unnatural terphenyl 3-hydroxy-50-O-desmethylterphenyllin (9).
The terphenyls 18a and 18b were also obtained via the double
Suzuki–Miyaura coupling of 15 with 16a and 16b, respectively,
using the palladium catalyst with SPhos. These results suggest that
the established reaction condition would be one of the most pow-
erful and useful conditions for Suzuki–Miyaura coupling.
Then, the TNF-a and b-hexosaminidase release-inhibitory activ-
ities of the four synthesized 50-O-desmethylterphenyllins were
evaluated for RBL-2H3 cells according to the previously reported
procedure.4 Figure 2 shows the results of the assays. As expected,
Figure 2. Effects of 50-O-desmethylterphenyllins on TNF-
b-hexosaminidase release (B) from RBL-2H3 cells. Each value represents the
mean standard deviation of triplicate determinations.
a release (A) and
compounds 6 and 7 were active against TNF-
a release from
RBL-2H3 cells, and the release of the granular enzyme b-hexosa-
minidase from RBL-2H3 cells23 was weakly inhibited by 6–9
(IC50: 1–10
l
M). Although the IC50 values of 6 and 7 for anti-
Miyaura coupling reactions, and we confirmed that a palladium
catalyst with SPhos ligand is highly effective in the Suzuki–Miya-
ura coupling of a hindered aryl chloride. In addition, we discovered
new biological activity of 50-O-desmethylterphenyllins, and the
TNF- release were comparable to vialinin A and DMT (0.09 and
a
0.02 nM respectively), the levels of activity reached saturation at
approximately 1 nM. This phenomenon was also observed with
the 20,30-bis-MOM ether derivative of DMT.15 In contrast, vialinin
different behavior in their TNF-
a release-inhibitory activity com-
A and DMT dose-dependently inhibited TNF-
a
release.4,15 As
pared to that of the vialinins suggests that the target molecules
for 50-O-desmethylterphenyllins and vialinins might be different.
Because our synthetic methodology is versatile and it is easy to in-
stall various aryl moieties into the central aryl group, this route
should enable the development of more advanced immunosup-
pressive agents based on the 50-O-desmethylterphenyllin core
structure.
described above, Yajima and co-workers identified USP5 as the tar-
get protein for vialinins, and vialinins strongly inhibited USP5
activity.17 However, the above results suggest the possibility that
the vialinins might inhibit additional proteins related to TNF-
a
release from RBL2H3 cells, while 50-O-desmethylterphenyllins
might inhibit only a single protein, such as USP5, thereby causing
the saturation of the inhibitory activity. This hypothesis may be
confirmed using 50-O-desmethylterphenyllins as the backbones of
molecular probes for the identification of their target molecules.
In summary, we achieved the first total syntheses of 50-O-desm-
ethylterphenyllin and three related p-terphenyls via Suzuki–
Acknowledgments
We would like to thank Dr. Takuya Tashiro (RIKEN) for the col-
lection of the MS spectra. This work was supported by a grant from

A. Yajima et al. / Tetrahedron Letters 54 (2013) 4986–4989
4989
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Supplementary data
Supplementary data (experimental procedures and 1H and 13C
NMR spectra of the synthetic compounds) associated with this arti-
cle can be found, in the online version, at http://dx.doi.org/
10.1016/j.tetlet.2013.07.062.
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