Total Syntheses of Pusilatins A-C, Liverwort-Derived Macrocyclic Bisbibenzyl Dimers

Article abstract of DOI:10.1021/acs.orglett.8b01366

The total syntheses of pusilatins A (2), B (3), and C (5), macrocyclic bisbibenzyl dimers isolated from Japanese liverwort are reported. The common monomeric unit (6) was prepared via macrocyclization of an o-sulfinylfluorobenzene derivative by S_N

Full text of DOI:10.1021/acs.orglett.8b01366

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Total Syntheses of Pusilatins A−C, Liverwort-Derived Macrocyclic
Bisbibenzyl Dimers
Takahiro Yamada, Hiromu Takiguchi, Ken Ohmori,* and Keisuke Suzuki*
Department of Chemistry, Tokyo Institute of Technology, 2-12-1 O-okayama, Meguro-ku, Tokyo 152-8551, Japan
S
* Supporting Information
ABSTRACT: The total syntheses of pusilatins A (2), B (3), and C (5), macrocyclic bisbibenzyl dimers isolated from Japanese
liverwort are reported. The common monomeric unit (6) was prepared via macrocyclization of an o-sulfinylfluorobenzene
derivative by SNAr attack of an internal phenol, which was exploited for site-selective dimerizations en route to 2, 3, and 5.
These compounds are attractive synthetic targets in view of
the diverse and potent biological activities3,4 as well as the
unique structures differing in the connectivity of the
monomeric units. Herein, we report the total syntheses of
pusilatins A, B, and C via an efficient and divergent coupling
strategy.
Scheme 1 illustrates monomer 6 and the distinct
connectivities (C12−C12, C6′−C6′, C6′−C12 linkages)
toward 2, 3, and 5. The key challenge is the regiocontrolled
functionalization of the riccardin C (1) scaffold amenable for
the mutual connection of the two monomeric units at specific
positions. Importantly, symmetry consideration would allow
significant simplification of the synthesis by employing a
suitable common intermediate.
he pusilatins constitute a class of dimers of macrocyclic
Tbisbibenzyl, which were isolated from a Japanese thallic
liverwort, Blasia pusilla L., by Asakawa et al.1 Their structural
diversity stems from the modes of oxidative coupling of the
monomeric unit, i.e., riccardin C (1).2 Pusilatins A (2), B (3),
and E (4) are symmetrically coupled dimers, while pusilatin C
(5) is an unsymmetrically coupled dimer (Figure 1).
To this end, the design of phenol 6 should allow easy
differentiation between phenols on the B- and C-rings and also
allow a site-selective functionalization at the C12 (blue) or the
C6′ (red) position as a handle to perform the regioselective
dimerization.
We reasoned that preparation of the key intermediate 6
would be possible by exploiting the concise synthetic route of
riccardin C (1),2c,d which we previously reported, with an
exception that the B-ring unit is protected with a benzyl group
to enable the above-stated strategy (Scheme 2). Sonogashira
reaction of alkyne 75 with iodide 86 gave alkyne 9, and the
resulting phenol was treated with phenyl triflimide to give
triflate 10. Suzuki−Miyaura coupling of 10 with boronic acid
117 gave aldehyde 12, which was subjected to the Horner−
Received: April 30, 2018
Figure 1. Structures of pusilatins and riccardin C.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01366
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
genolysis gave phenol 6, ready for the key regiocontrolled
dimerizations.
Scheme 1. Divergent Approach to Pusilatins A−C
Our first target was pusilatin A (2), the symmetrical dimer
with the mutual connection at the C12 positions. We initially
focused on the oxidative dimerization, which is related to the
biosynthetic pathway (Scheme 3).10
Scheme 3. Unsuccessful Approaches toward Pusilatin A
a
Scheme 2. Preparation of Monomer 6
Despite various attempts, however, phenol 6 displayed poor
reactivity in the oxidative coupling. All oxidants screened,
including Mn(OAc)3,11 CuCl2,12 CuBr2, MnO2,13 FeCl3·
6H2O,14 DDQ, led to the recovery of the starting material.
At this juncture, we turned our attention to the Ullmann-
type dimerization of iodide 18,15 which was prepared by
regioselective iodination at the ortho position to the free phenol
in 6.2h Unfortunately, the trials failed to give the desired dimer
under various conditions. Iodide 18 was recovered unchanged
even under harsh conditions (NiCl2, PPh3, Zn, DMF, 150 °C).
On the basis of the previous report,15 electron-withdrawing
groups ortho to the halogen substituent increased the reactivity
of aryl halides, and thus, the free phenol in 18 was protected
with a tosyl or a mesyl group. However, the projected
dimerization attempts gave only deiodinated products.
At this stage, we became interested in the possibility of the
formal symmetrical dimerization by the sequential reactions of
the Miyaura borylation16 and the in situ Suzuki−Miyaura
coupling. After methylation of phenol 18 to give 19, the Pd-
catalyzed borylation was examined, which gave the correspond-
ing arylboronate, which turned to be highly unstable and, thus,
hardly tractable.
Our next idea came from the work of Miyaura (eq 1),16 who
observed direct, but unexpected, formation of biphenyl from
bromobenzene17 when a stronger base, such as K3PO4 or
K2CO3, was used instead of KOAc.
a
DME = 1,2-dimethoxyethane, TBS = tert-butyldimethylsilyl, DMF =
N,N-dimethylformamide, Tol = tolyl.
Emmons reaction with phosphonate 132c,d to give enyne 14 as
a mixture of geometrical isomers (E/Z = 2/1).
Enyne 14 was reduced with diimide giving the cyclization
precursor 15. The intramolecular SNAr reaction of 15 [CsF,
CaCO3, MS3 Å, DMF (1 × 10−3 M), 150 °C, 4 h]8 afforded the
product 16 in excellent yield. The sulfinyl group in 16 was
removed by the sulfoxide−lithium exchange9 followed by
protonolysis, and removal of the benzyl group by hydro-
Accordingly, we examined the Pd-catalyzed borylation by
using K3PO4 with 0.5 equiv of (Bpin)2 (Scheme 4). We were
pleased to find that direct dimerization of 19 proceeded to give
the desired symmetrical dimer 20 in 60% yield. Use of K2CO3
slightly improved the yield (66%). The best result was obtained
when Cs2CO3 was used as a base, giving 20 in 75% yield.
Finally, removal of the methyl protecting groups with BBr3
B
DOI: 10.1021/acs.orglett.8b01366
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With the substrate 22 in hand, we focused on oxidative
Scheme 4. Synthesis of Pusilatin A (2)
dimerization (Scheme 5). When Mn(OAc)3,11 FeCl3,14 or
18
TiCl4 was used as an oxidant, the desired dimer 23 was
obtained in low yield. However, after treatment of 22 with
CuCl2·2H2O12 in the presence of appropriate amines (i-
Pr2NEt, pyridine), the oxidative dimerization proceeded
smoothly (MeOH, 70 °C, 4 h) to give the desired dimer 23
in 91% yield. Finally, removal of all methyl protecting groups
with BBr3 (CH2Cl2, −78 °C → rt, 2 h) afforded pusilatin B (3),
which was purified by preparative thin-layer chromatography.
The synthetic material 3 showed the spectral data (1H and 13
C
NMR, IR, HRMS) in full agreement with those of the natural
product.1
The next challenge was the synthesis of pusilatin C (5), a
dimer connected unsymmetrically at the C6′ and the C12
positions. We envisioned that the dimerization could be
achieved by the Suzuki−Miyaura coupling of the two
fragments, iodide 19 and its regio-isomeric counterpart 25.
The initial attempt to convert iodide 19 to the corresponding
arylboronate met with limited success because of its extreme
instability. Therefore, we examined the conversion of iodide 25
to the corresponding arylboronate. Iodination at the ortho
position of phenol 22 followed by methylation gave iodide 25,
which was employed for the coupling.
Upon treatment of 25 with i-PrOBpin and n-BuLi (Et2O,
−78 °C → rt), the desired borylation proceeded smoothly.
Since the corresponding arylboronate was unstable, it was used
for the coupling without purification. Thus, the generated
arylboronate was employed for the next cross coupling with
iodide 19 [Cs2CO3, Pd(PPh3)4, dioxane, 80 °C], giving the
desired dimer 27 in 89% yield.
allowed clean production and isolation of pusilatin A (2). The
analytical data recorded were identical in all respects with the
reported data for the natural product (1H and 13C NMR, IR,
HRMS).1
We next turned our attention to pusilatin B (3), one of the
symmetrically coupled dimers with the connection at the C6′
positions. Previously, Asakawa reported the dimerization of the
natural sample of riccardin C (1) by oxidative coupling to
achieve the semisynthesis of pusilatin E (4).11 Based on this
precedent, we found that the oxidative dimerization was
effective for coupling of the monomeric units at the C6′
positions. Preparation of the precursor 22 started with the key
intermediate 6, where methylation gave the methylated
monomer 21. Selective removal of the methyl group at the
C1 position on the C-ring by using BBr3 furnished the
dimerization precursor 22.
Scheme 5. Total Syntheses of Pusilatins B (3) and C (5)
C
DOI: 10.1021/acs.orglett.8b01366
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Letter
M.; Huynh, A. M. Eur. J. Org. Chem. 2010, 2010, 6760−6778.
(k) Iwashita, M.; Fujii, S.; Ito, S.; Hirano, T.; Kagechika, H.
Tetrahedron 2011, 67, 6073−6082. (l) Kostiuk, S. L.; Woodcock, T.;
Dudin, L. F.; Howes, P. D.; Harrowven, D. C. Chem. - Eur. J. 2011, 17,
10906−10915. (m) Harada, K.; Makino, K.; Shima, N.; Okuyama, H.;
Esumi, T.; Kubo, M.; Hioki, H.; Asakawa, Y.; Fukuyama, Y.
Tetrahedron 2013, 69, 6959−6968. (n) Almalki, F. A.; Harrowven,
D. C. Eur. J. Org. Chem. 2016, 2016, 5738−5746.
Finally, removal of all methyl protecting groups followed by
the purification on preparative thin-layer chromatography
allowed clean isolation of pusilatin C (5). The spectral data
(1H and 13C NMR, IR, HRMS) for the final product were in
full agreement with those of the natural product.1
In conclusion, the total syntheses of pusilatins A (2), B (3),
and C (5) have been achieved from a common intermediate 6,
featuring (1) one-pot sequence of the Miyaura borylation
followed by the Suzuki−Miyaura coupling to synthesize 2, (2)
oxidative dimerization to synthesize 3, and (3) unsymmetrical
dimerization via Suzuki−Miyaura coupling to synthesize 5.
́ ́
(3) (a) Kerseru, G.; Nogradi, M. Bioorg. Med. Chem. 1995, 3, 1511−
̈
1517. (b) Tamehiro, N.; Sato, Y.; Suzuki, T.; Hashimoto, T.; Asakawa,
Y.; Yokoyama, S.; Kawanishi, T.; Ohno, Y.; Inoue, K.; Nagao, T.;
Nishimaki-Mogami, T. FEBS Lett. 2005, 579, 5299−5304.
(4) For reviews, see: (a) Asakawa, Y.; Ludwiczuk, A. Heterocycles
2012, 86, 891−917. (b) Harrowven, D. C.; Kostiuk, S. L. Nat. Prod.
Rep. 2012, 29, 223−242. (c) Asakawa, Y. In Progress in the Chemistry of
Organic Natural Products; Herz, W., Kirby, G. W., Moore, R. E.,
Steglich, W., Tamm, Ch., Eds.; Springer-Verlag: Wien, 1995; Vol. 65,
pp 1−5. (d) Li, A. C.; Glass, C. K. J. Lipid Res. 2004, 45, 2161−2173.
(e) Asakawa, Y. Nat. Prod. Commun. 2017, 12, 1335−1349.
(5) (a) Kaffy, J.; Pontikis, R.; Florent, J.-C.; Monneret, C. Org.
Biomol. Chem. 2005, 3, 2657−2660. (b) Gaukroger, K.; Hadfield, J. A.;
Hepworth, L. A.; Lawrence, N. J.; McGown, A. T. J. Org. Chem. 2001,
66, 8135−8138.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b01366.
Full experimental procedures, characterization data, and
NMR spectra for all new compounds (PDF)
(6) Fryatt, T.; Botting, N. P. J. Labelled Compd. Radiopharm. 2005,
48, 951−969.
AUTHOR INFORMATION
Corresponding Authors
■
(7) Kotian, P. L.; Krishnan, R.; Rowland, S.; El-Kattan, Y.; Saini, S.
K.; Upshaw, R.; Bantia, S.; Arnold, S.; Sudhakar Babu, Y.; Chand, P.
Bioorg. Med. Chem. 2009, 17, 3934−3958.
*E-mail: kohmori@chem.titech.ac.jp.
*E-mail: ksuzuki@chem.titech.ac.jp.
ORCID
(8) Crowley, B. M.; Boger, D. L. J. Am. Chem. Soc. 2006, 128, 2885−
2892.
Ken Ohmori: 0000-0002-8498-0821
Keisuke Suzuki: 0000-0001-7935-3762
Notes
(9) (a) Durst, T.; LeBelle, M. J.; Van den Elzen, R.; Tin, K.-C. Can. J.
Chem. 1974, 52, 761−766. (b) For a review see: Oae, S. Rev. Heteroat.
Chem. 1991, 4, 195−255.
(10) Friederich, S.; Maier, U. H.; Deus-Neumann, B.; Asakawa, Y.;
Zenk, M. H. Phytochemistry 1999, 50, 589−598.
The authors declare no competing financial interest.
(11) Yoshida, T.; Toyota, M.; Asakawa, Y. J. Nat. Prod. 1997, 60,
145−147.
ACKNOWLEDGMENTS
■
(12) (a) Hovorka, M.; Gunterova,
1990, 31, 413−416. (b) Hovorka, M.; Sci
M.; Zav
(13) Wang, K.; Hu, Y.; Li, Z.; Wu, M.; Liu, Z.; Su, B.; Yu, A.; Liu, Y.;
Wang, Q. Synthesis 2010, 2010, 1083−1090.
(14) Sue, D.; Kawabata, T.; Sasamori, T.; Tokitoh, N.; Tsubaki, K.
Org. Lett. 2010, 12, 256−258.
́
J.; Zav
́
ada, J. Tetrahedron Lett.
We thank Prof. Toshihiro Hashimoto and Prof. Yoshinori
Asakawa (Tokushima Bunri University) for providing an
authentic sample of pusilatin B and NMR data for pusilatins
A−C. This work was supported by JSPS KAKENHI Grant Nos.
JP23000006, JP16H06351, JP16H04107, and JP18H04391.
̌
̌
gel, R.; Gunterova, J.; Tichy,
́
́
́
ada, J. Tetrahedron 1992, 48, 9503−9516.
DEDICATION
(15) (a) Ullmann, F.; Bielecki, J. Ber. Dtsch. Chem. Ges. 1901, 34,
2174−2185. (b) Ullmann, F. Ber. Dtsch. Chem. Ges. 1903, 36, 2389−
2391. (c) Ullmann, F. Ber. Dtsch. Chem. Ges. 1904, 37, 853−857. For
reviews, see: (d) Fanta, P. E. Chem. Rev. 1946, 38, 139−196. (e) Ley,
S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400−5449.
(16) Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995, 60,
7508−7510.
■
Dedicated to Prof. Yoshinori Asakawa on occasion of his 77th
birthday.
REFERENCES
■
(1) (a) Yoshida, T.; Hashimoto, T.; Takaoka, S.; Kan, Y.; Tori, M.;
Asakawa, Y.; Pezzuto, J. M.; Pengsuparp, T.; Cordell, G. A.
Tetrahedron 1996, 52, 14487−14500. (b) Hashimoto, T.; Yoshida,
T.; Kan, Y.; Takaoka, S.; Tori, M.; Asakawa, Y. Tetrahedron Lett. 1994,
35, 909−910.
(17) For related works, see: (a) Zhu, L.; Duquette, J.; Zhang, M. J.
Org. Chem. 2003, 68, 3729−3732. (b) Neumeyer, M.; Bruckner, R.
̈
Angew. Chem., Int. Ed. 2017, 56, 3383−3388. (c) Dzhevakov, P. B.;
Topchiy, M. A.; Zharkova, D. A.; Morozov, O. S.; Asachenko, A. F.;
Nechaev, M. S. Adv. Synth. Catal. 2016, 358, 977−983 and references
cited therein.
(2) For isolation, see: (a) Asakawa, Y.; Matsuda, R. Phytochemistry
1982, 21, 2143−2144. (b) Anton, H.; Schoeneborn, R.; Mues, R.
Phytochemistry 1999, 52, 1639−1645. For synthesis, see: (c) Taki-
guchi, H.; Ohmori, K.; Suzuki, K. Chem. Lett. 2011, 40, 1069−1071.
(d) Takiguchi, H.; Ohmori, K.; Suzuki, K. Angew. Chem., Int. Ed. 2013,
(18) Doussot, J.; Guy, A.; Ferroud, C. Tetrahedron Lett. 2000, 41,
2545−2547.
́
́
rad
́ ́
52, 10472−10476. (e) Gottsegen, A.; Nog i, M.; Vermes, B.; Kajtar-
́
Peredy, M.; Bihat
́
si-Karsai, E. Tetrahedron Lett. 1988, 29, 5039−5040.
́
́ ́ ́ ́
(f) Gottsegen, A.; Nogradi, M.; Vermes, B.; Kajtar-Peredy, M.; Bihatsi-
́
Karsai, E. J. Chem. Soc., Perkin Trans. 1 1990, 315−320. (g) Eicher, T.;
́
Fey, S.; Puhl, W.; Buchel, E.; Speicher, A. Eur. J. Org. Chem. 1998,
̈
1998, 877−888. (h) Harrowven, D. C.; Woodcock, T.; Howes, P. D.
Angew. Chem., Int. Ed. 2005, 44, 3899−3901. (i) Hioki, H.; Shima, N.;
Kawaguchi, K.; Harada, K.; Kubo, M.; Esumi, T.; Nishimaki-Mogami,
T.; Sawada, J.; Hashimoto, T.; Asakawa, Y.; Fukuyama, Y. Bioorg. Med.
Chem. Lett. 2009, 19, 738−741. (j) Speicher, A.; Groh, M.; Hennrich,
D
DOI: 10.1021/acs.orglett.8b01366
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