Total synthesis of kehokorins A and B

Article abstract of DOI:10.1016/j.tetlet.2019.04.011

The total synthesis of a dibenzofuran rhamnoside, kehokorin A, and its aglycone, kehokorin B, was achieved via a route including Suzuki-Miyaura cross-coupling followed by Ullmann ether synthesis to form a dibenzofuran, stepwise bromination at C7 of the di

Full text of DOI:10.1016/j.tetlet.2019.04.011

Accepted Manuscript
Total synthesis of kehokorins A and B
Kenshu Fujiwara, Ryosuke Motousu, Daisuke Sato, Yoshihiko Kondo, Uichi
Akiba, Takanori Suzuki, Tetsuo Tokiwano
PII:
S0040-4039(19)30335-1
https://doi.org/10.1016/j.tetlet.2019.04.011
TETL 50726
DOI:
Reference:
Tetrahedron Letters
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Revised Date:
Accepted Date:
5 March 2019
30 March 2019
3 April 2019
Please cite this article as: Fujiwara, K., Motousu, R., Sato, D., Kondo, Y., Akiba, U., Suzuki, T., Tokiwano, T.,
Total synthesis of kehokorins A and B, Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.2019.04.011
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Total synthesis of kehokorins A and B
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Kenshu Fujiwara *, Ryosuke Motousu, Daisuke Sato,
Yoshihiko Kondo, Uichi Akiba, Takanori Suzuki, Tetsuo Tokiwano

1
Tetrahedron Letters
Total synthesis of kehokorins A and B
Kenshu Fujiwara a,  , Ryosuke Motousu a, Daisuke Sato a, Yoshihiko Kondo a, Uichi Akiba a, Takanori
Suzuki b, Tetsuo Tokiwano c
a Department of Life Science, Graduate School of Engineering Science, Akita University, Akita 010-8502, Japan
b Department of Chemistry, Faculty of Science, Hokkaido University, Sapporo 060-0810, Japan
c Department of Biotechnology, Faculty of Bioresource Sciences, Akita Prefectural University, Akita 010-0195, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The total synthesis of a dibenzofuran rhamnoside, kehokorin A, and its aglycone, kehokorin B,
was achieved via a route including Suzuki-Miyaura cross-coupling followed by Ullmann ether
synthesis to form a dibenzofuran, stepwise bromination at C7 of the dibenzofuran, a second
Suzuki-Miyaura cross-coupling to install a 4-methoxyphenyl group at C7, and rhamnosylation.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Natural product synthesis
Cytotoxin
Dibenzofuran rhamnoside
p-Terphenyl
———
 Corresponding author. e-mail: fjwkn@gipc.akita-u.ac.jp

2
Tetrahedron
A dibenzofuran rhamnoside, kehokorin A (1), and its
aglycone, kehokorin B (2), were isolated as cytotoxins from the
myxomycete Trichia favoginea var. persimilis by Ishibashi
(Figure 1).1 The kehokorins are structurally highlighted by a p-
terphenyl core skeleton, which is highly oxygenated and cyclized
with an oxygen atom to form a dibenzofuran. While many
dibenzofuran p-terphenyl natural products are known to date,2
kehokorin A (1) belongs to a rare class of glycoside derivatives.
From the IC50 values of 1 and its congeners against HeLa
epithelial carcinoma cell line (1.5 and 7.2 μg/mL for 1 and 2,
respectively), Ishibashi also suggested the importance of the
rhamnose unit of 1 in cytotoxicity. Prompted by the unique
structure and cytotoxicity against cancer cells, we started our
program toward the total synthesis of 1 and 2. During the course
of our study, the Takahashi group achieved the total synthesis of
1, 2 and other congeners3 in 2017 via a route including p-
terphenyl construction followed by dibenzofuran cyclization.4
Here, we describe our recent results on the total synthesis of 1
and 2 by a different strategy based on dibenzofuran formation
followed by p-terphenyl construction.5
Our plan for the synthesis of 1 and 2 is shown in Scheme 1.
First, p-terphenyl 4, having different protecting groups for the
oxygen atoms at C2 and C8, was designed as a common
intermediate for 1 and 2. In the final stage of the synthesis of 1, a
process including the removal of the benzyl group of 4 followed
by glycosylation with known rhamnosyl donor 36 and full
deprotection was scheduled. p-Terphenyl 4 would also produce 2
through
a
simple two-step deprotection process. The 4-
Scheme 1. Plan for the synthesis of kehokorins A and B
methoxyphenyl group at C7 of 4 would be installed by the
Suzuki-Miyaura cross-coupling7 of 7-bromodibenzofuran 5 with
boronic acid 6. Intermediate 5 was planned to be constructed
from dibenzofuran carbaldehyde 7 via Baeyer-Villiger oxidation
to form an oxygen functional group at C8 and regioselective
bromination at C7. Since the regio-controlled bromination of a
dibenzofuran having multiple oxygen functional groups was a
difficult challenge, an exhaustive study on the basis of an ample
supply of 7 was required to solve the challenge. Therefore, a
reliable synthesis of 7 was designed as follows. The furan of 7
would be formed via the Ullmann ether synthesis from 8, which
would be assembled by the Suzuki-Miyaura cross-coupling of
bromide 9 with boronic acid 10, prepared from known bromide
11.8
Scheme 2. Reagents and conditions: (a) (i-Pr)2NH, NBS, CH2Cl2,
0 °C, 45 min, 81%; (b) TMSCHN2, MeOH-toluene (1.45:1), 22 °C,
25 min, 95%; (c) BuLi, THF, –78 °C, 5 min, then B(Oi-Pr)3, –78
→ 0 °C, 1 h; (d) 10, Pd2(dba)3, SPhos, K3PO4, toluene, 105 °C, 24
h, 94%; (e) TsOH•H2O, MeOH, 21 °C,
1 h; (f) CuI,
MeNHCH2CH2NHMe, K2CO3, DMF, reflux, 4 h; (g) DDQ,
CH2Cl2-H2O (9:1), 21 °C, 1 h, 83% from 8.
As a first step of the synthesis of dibenzofuran 7, the
conversion of known phenol 129 to intermediate 9 was examined
Figure 1. Kehokorins A and B
(Scheme 2). While
a simple reaction of 12 with N-
bromosuccinimide (NBS) gave only an undesired mixture of 4-
bromophenol and 2,4-dibromophenol derivatives, the treatment
of 12 with NBS in the presence of diisopropylamine, according
to Fujisaki's selective ortho-bromination method,10 produced 13
predominantly (81%). The phenolic hydroxy group of 13 was
methylated with trimethylsilyldiazomethane (TMSCHN2) to
afford 9 (95%). The boronic acid 10 was prepared from bromide
118 by a process including lithiation, reaction with B(Oi-Pr)3 and
hydrolysis. The Suzuki-Miyaura coupling of
9 with 10
successfully furnished diphenyl 8 (94%) under the Buchwald
conditions using Pd2(dba)3, 2-dicyclohexylphosphino-2',6'-
dimethoxybiphenyl (SPhos) and K3PO4.11 The MOM group of 8
was removed with acidic methanol to give 14, which was then

3
treated with CuI, N,N'-dimethylethylenediamine and K2CO3 in
refluxing DMF for 4 h to afford dibenzofuran 15 successfully.12,13
The methoxymethyl group of 15 was oxidized with 2,3-dichloro-
5,6-dicyano-1,4-benzoquinone (DDQ) to furnish aldehyde 7
(83% over 3 steps).14 Thus, dibenzofuran 7 was synthesized in 6
steps and 60% overall yield from known phenol 12.
over-reduced product, the benzoate of 17. Therefore, in order to
consume 20, the resulting mixture was subjected to the same
reaction with reduced amounts of reagents to provide a
reasonable yield of 5 (34%) along with the benzoate of 17 (32%).
Bromide 5 showed decreased reactivity in the Suzuki-Miyaura
coupling with
6
even under the Buchwald conditions.11
Therefore, the coupling was repeated once again to give the
desired p-terphenyl dibenzofuran 4 in 55% yield. Thus, key
intermediate 4 was synthesized from dibenzofuran 7 via a process
including dibromination at C9 and C7, debromination at C9 and
the Suzuki-Miyaura coupling at C7.
Scheme 3. Reagents and conditions: (a) mCPBA, Sc(OTf)3 (cat.),
BHT, CH2Cl2, 20 °C, 1 h; (b) NaOMe, MeOH, 20 °C, 15 min, then
AcOH, 0 °C, 9 min; (c) NBS, MeOH, 0 °C, 15 min, 61% from 7;
(d) i-Pr2NH, Br2, CH2Cl2, 21 °C, 15 min, then 2-methylbut-2-ene,
0 °C, 5 min; (e) BzCl, DMAP, CH2Cl2, 0 °C, 80 min, 64% from
18; (f) Pd(PPh3)4 (cat.), BuOH, K2CO3, BuOAc, 90 °C, 6 h;
repeated once again: 13 h, 5: 34%, benzoate of 17: 32%; (g) 6,
Pd2(dba)3, SPhos, K3PO4, toluene, 105 °C, 5 h; repeated once
again: 14 h, 55%.
Scheme 4. Reagents and conditions: (a) H2, Pd/C, MeOH-EtOAc
(2:1), 21 °C, 15–17 h; (b) K2CO3, 1,4-dioxane-BuOH (25:1), 90
°C, 13 h, 70% from 4; (c) 3, TMSOTf, MS4A, CH2Cl2, –20 °C, 45
min; repeated once again: –20 °C → 0 °C, 45 min; (d) K2CO3, 1,4-
dioxane-BuOH (25:1), 90 °C, 15.5 h, 40% from 4; (e) H2, Pd/C,
MeOH-EtOAc (3:1), 25 °C, 63 h, 48%.
With the desired dibenzofuran 7 in hand, we next examined
the regioselective installation of a bromine group at C7 for the
preparation of intermediate 5 (Scheme 3). The formyl group of 7
was first rearranged to a formate ester via Baeyer-Villiger
oxidation under Kotsuki's conditions15 to give 16. Although the
basic methanolysis of 16 facilely produced phenol 17, the
difficulty in the isolation of 17 due to its instability urged us to
use 17 in situ for the next reaction. After intensive exploration of
the reaction conditions for the regioselective monobromination at
C7 of 17, it was found that the positional reactivity of 17 was
decreased in the order: C9 > C4 > C7. Since the high reactivity at
C9 could not be suppressed, we revised our plan, taking an
alternative route including dibromination at C9 and C7 followed
by debromination at C9. Thus, phenol 17, generated in situ, was
reacted with NBS to afford C9-bromide 18 as a stable product
(61% over 3 steps). Regioselective bromination at C7 of 18 was
achieved by Fujisaki's method10 with a modification using Br2
instead of NBS to produce 19 predominantly. Because
dibromophenol 19 was unstable under the isolation conditions,
the phenol was protected in situ as a benzoate to give stable 20
(64% over 2 steps). The conditions for the reductive removal of
the Br group at C9 of 20 were extensively screened. It was found
that C9-Br was more reactive than C7-Br under palladium-
catalyzed conditions, though the difference was small. At present,
the best production of the desired 5 was observed under Zhang's
conditions16 with a modification using a decreased amount of
reductant. Thus, dibromophenol 20 was treated with K2CO3 and a
catalytic amount of Pd(PPh3)4 in the presence of 2 equiv. of
BuOH as a reductant in butyl acetate at 90 °C. However, the
reaction tended to stop without completion to give an inseparable
mixture of 5 and unreacted 20 along with a small amount of an
At the final stage, the synthesis of kehokorins A and B from 4
was examined via a route including rhamnosylation and removal
of the protecting groups (Scheme 4). The benzyl group of 4 was
first removed by hydrogenolysis to give common intermediate
21. The removal of the benzoate ester of 21 by transesterification
with BuOH under basic conditions produced kehokorin B (2)
(70% over 2 steps). Because the rhamnosylation of 21 using
imidate 36 in the presence of TMSOTf was sluggish to afford a
mixture of desired 22 and unreacted 21, the mixture was again
reacted with 3 under the same conditions for the completion of
the rhamnosylation to provide 22 and byproducts from 3 as an
inseparable mixture. Treatment of the mixture with K2CO3 and
BuOH at 90 °C converted benzoate 22 to phenol 23,17 which was
separated from the byproducts (40% over 3 steps from 4). The
benzyl groups of 23 were removed by hydrogenolysis to furnish
kehokorin A (1) (48%). The spectral data of synthetic 1 and 2 as
well as the specific optical rotation of synthetic 1 were in
accordance with those reported in the literature,1,4 thereby
confirming the completion of the total synthesis of kehokorins A
and B.
In conclusion, the total synthesis of
a dibenzofuran
rhamnoside, kehokorin A, and its aglycone, kehokorin B, was
achieved via a route including Suzuki-Miyaura cross-coupling
followed by Ullmann ether synthesis to form a dibenzofuran,
stepwise bromination at C7 of the dibenzofuran, a second
Suzuki-Miyaura cross-coupling to install a 4-methoxyphenyl
group at C7, and rhamnosylation. Further optimization of the
synthesis of kehokorins A and B and biological studies on the
synthetic kehokorins and their derivatives are in progress.

4
Tetrahedron
Acknowledgments
We thank Dr. Eri Fukushi and Mr. Yusuke Takata (GC-MS
and NMR Laboratory, Faculty of Agriculture, Hokkaido
University) for the measurements of mass spectra. We are also
grateful to Prof. Mitsutoshi Jikei and Prof. Kazuya Matsumoto
(Department of Materials Science, Graduate School of
Engineering Science, Akita University) for the measurements of
NMR spectra. This work was supported by JSPS KAKENHI
Grant Numbers JP15K01794, JP18K05450.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/##.####/j.tetlet.####.##.###
References and notes
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17. No β-anomer of 23 was observed at this stage.

5
Successful total synthesis of kehokorins A and B
A strategy based on dibenzofuran formation
followed by p-terphenyl construction
Construction of the dibenzofuran unit by Suzuki
coupling and Ullmann ether synthesis
7-Bromodibenzofuran formation via dibromination
of the core followed by debromination