Total synthesis of 0231B, an inhibitor of 3α-hydroxysteroid dehydrogenase produced by Streptomyces sp. HKI0231

Article abstract of DOI:10.1271/bbb.67.659

The new inhibitors of 3α-hydroxysteroid dehydrogenase, 0231A 1 and 0231B 2, have a unique benz[c,d]indol-3(1H)-one structure in their molecules. In our advanced studies on indole chemistry, we have developed an efficient synthetic method for benz[c,d] ind

Full text of DOI:10.1271/bbb.67.659

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Total Synthesis of 0231B, an Inhibitor of 3α-
Hydroxysteroid Dehydrogenase Produced by
Streptomyces sp. HKI0231
Taichi KOMODAa, Yoshihiko SHINODAa & Shin-ichi NAKATSUKAa
a The United Graduate School of Agricultural Science, Gifu University1-1 Yanagido, Gifu
501-1193, Japan
Published online: 22 May 2014.
To cite this article: Taichi KOMODA, Yoshihiko SHINODA & Shin-ichi NAKATSUKA (2003) Total Synthesis of 0231B, an
Inhibitor of 3α-Hydroxysteroid Dehydrogenase Produced by Streptomyces sp. HKI0231, Bioscience, Biotechnology, and
Biochemistry, 67:3, 659-662, DOI: 10.1271/bbb.67.659
To link to this article: http://dx.doi.org/10.1271/bbb.67.659
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Biosci. Biotechnol. Biochem., 67 (3), 659–662, 2003
Preliminary Communication
Total Synthesis of 0231B, an Inhibitor of 3
a
-Hydroxysteroid Dehydrogenase
Produced by Streptomyces sp. HKI0231
†
Taichi KOMODA, Yoshihiko SHINODA, and Shin-ichi NAKATSUKA
The United Graduate School of Agricultural Science, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan
Received November 7, 2002; Accepted December 17, 2002
The new inhibitors of
hydrogenase, 0231A 1 and 0231B 2, have a unique
benz[ ]indol-3(1 )-one structure in their molecules.
In our advanced studies on indole chemistry, we have
developed an e‹cient synthetic method for benz[
indol-3(1 )-one derivatives. We report here its applica-
tion to the synthesis of 0231B in 10 steps (8.1 overall
yield) from 6-methylindole 8 by introducing an acyl
group into the 3-position of the indole nucleus, cycliza-
tion of the side chain at the 3-position to the 4-position
and subsequent elimination of the phenyl group, and
conjugate addition of the substituted phenyl group.
3
a
-hydroxysteroid de-
major constituent of natural inhibitors 0231A and
0231B, by e‹cient regioselective cyclization of 3-
cinnamoylindoles 4 toward the 4-position of the
indole nucleus (Fig. 2) (Komoda, T., and Nakatsuka,
S., submitted for publication).
c
,
d
H
c,d ]
H
Hegedus et al. have synthesized benz[
c,d ]indol-
3(1
H
)-one derivative 6 from 4-bromoindole by [Pd0]-
%
catalyzed cyclization and found 6 to be a highly
electrophilic and conjugate addition of 6 with H„ or
CH„3 giving benz[ ]indoline derivative 7 (Fig. 3).9)
c,d
We therefore conducted our synthesis of 1 or 2 via
benz[ ]indol-3-one 11 as key intermediate
(Scheme 1).
c
,
d
a
Key words: inhibitor;
3a
-hydroxysteroid
de-
We chose 6-methylindole 8 as the starting material.
hydrogenase; anti-in‰ammatory agent;
indole
After protecting the nitrogen with a pivaloyl group, a
*
trans
-p
-methylcinnamoyl group( ) was introduced at
The new inhibitors of
dehydrogenase, 0231A 1 and 0231B 2, were isolated
from a fermentation broth of Streptomyces sp
HKI0231 (Fig. 1).1) Since
-hydroxysteroid
3a-hydroxysteroid
.
3
a
dehydrogenase is an enzyme concerned with in‰am-
matory processes, these compounds are promising as
lead structures for anti-in‰ammatory agents. We
report in this paper a successful total synthesis of
0231B 2.
In our advanced studies on indole chemistry,2–8) we
have developed an e‹cient synthesis of benz[c,d ]
＝
H )-one derivatives 5 (R H, Me, Ph), a
indol-3(1
Fig. 1. Structures of 0231A and 0231B.
Fig. 2. Synthesis of Benz[c,d ]indol-3(1H )-one Derivatives with AlCl3.
†
To whom correspondence should be addressed. Fax: +81-58-293-2919; E-mail: nakatsu
＠
cc.gifu-u.ac.jp
*
In our recent study on cyclo-elimination, the trans-p-methylcinnamoyl derivative was found to be superior to cinnamoyl derivatives
(unpublished result).

660
T. KOMODA et al.
Fig. 3. Conjugate Addition of 1-Tosylbenz[c,d ]indol-3(1H
)-one (Hegedus et al.9)).
Scheme 1. a) Trimethylacetyl Chloride, DMAP, Et3N, CH2Cl2; b) trans
MeOH; d) AlCl3, CHCl2CHCl2, 80 C; e) TsCl, Py; f) sec-BuLi, TMEDA, THF; g) O2, KOH, CuCl, MeOH; h) PhMe, Re‰.; i) LiAlH4,
THF, „40 C; j) CSA, MeOH, Re‰.
-p-Methylcinnamoyl Chloride, AlCl3, CH2Cl2; c) 1N-NaOH,
9
9

Total Synthesis of 0231BTotal Synthesis of 0231B
661
the 3-position by Friedel-Crafts acylation,10,11) and
subsequent de-protection of the pivaloyl group
aŠorded trans -methylcinnamoyl derivative 10 in an
87
gave 0231B 2 (14
z
) as a yellow crystal, over-reduced
compound 15 (6
z
) and starting material 14 (45z)
-
p
[2: NMR
2.96 (3H, s, 8-OCH3), 4.00 (3H, s, 9-OCH3), 6.71
(1H, 9.6 Hz, 2-H), 6.77 (1H, s, 8-H), 7.04 (1H,
8.1 Hz, 10-H), 7.33 (1H, s, 4-H), 7.45 (1H, s,
d (500 MHz, CDCl3): 2.58 (3H, s, 5-CH3),
z
overall yield from 8. The trans conˆguration of
the side chain was determined from the coupling con-
d, J
＝
＝
J
1
＝
stant (
J
15.7 Hz) in the H-NMR spectrum of 10.
d,
＝
7.7, 8.1 Hz, 11-H), 7.65 (1H,
Cyclo-elimination of 10 was next achieved. To a
6-H), 7.57 (1H, dd,
J
＝
＝
7.7 Hz, 12-H);
stirred suspension of 5eq. AlCl3 in CHCl2CHCl2
d,
J
9.6 Hz, 3-H), 8.22 (1H, d,
J
heated to 80
9
C for 30 min, a solution of 10 in
EIMS m z: 331(M+), 300 (base peak), 285, 257, 228],
W
CHCl2CHCl2 was added drop-wise over 15 min, and
the mixture stirred for 30 min at 80 C. Puriˆcation
of the reaction mixture by silica gel column chro-
matography (100 ethyl acetate) aŠorded 7-methyl-
benz[ ]indol-3(1
(400 MHz, 10
[15: NMR
d
(500 MHz, CDCl3): 2.66 (3H, s, 5-CH3),
9
3.96 (3H, s, 9-OCH3), 5.69 (2H, s, 8-H), 7.12 (1H, d,
＝
＝
J
8.0 Hz, 10-H), 7.22 (1H, d,
J
8.5 Hz, 2-H), 7.49
＝
(1H, t, J
z
8.0 Hz, 11-H), 7.61 (1H, br.s), 7.88 (1H,
＝ ＝
8.5 Hz, 3-H), 8.09 (1H, d, J
c
,
d
H
)-one 11 (84
z
) [11: NMR
d
br.s), 7.93 (1H, d,
J
z
CD3OD in CDCl3): 2.55 (3H, s,
8.0 Hz, 12-H); EIMS m z: 301 (M+, base peak), 286,
W
7-CH3), 7.68 (1H, d,
J
9.4 Hz, 4-H), 7.40 (1H, s,
258, 228]. The H-NMR, 13C-NMR, MS, UV and IR
1
＝
＝
6-H), 7.46 (1H, s, 8-H), 7.73 (1H, d,
J
9.4 Hz,
data for synthetic 2 were identical with the reported
5-H), 8.24 (1H, s, 2-H); EIMS m z: 183 (M+, base
data.1) We thus achieved the ˆrst complete synthesis
W
*
peak), 154, 149, 139, 127].( ) The structure of 11 was
of 0231B in 10 steps (8.1z).
determined by H- and 13C-NMR, HMBC, HMQC
Unfortunately, 0231A 1 could not be obtained by
an acid treatment of 14 in MeOH. A synthetic study
of 0231A 1 is now in progress.
1
and MS data.
N
-Tosylate 12 was prepared from 11 [TsCl Py,
W
83
benz[
dimethyl-
THF at „78
13 (98 ) [13: NMR
z
]. Conjugate addition of 7-methyl-1-tosyl-
]indol-3-(1 )-one 12 with lithiated
-methylsalicylamide12) was achieved in
C to give benz[ ]indoline derivative
(500 MHz, CDCl3): 2.28 (3H,
c
,d
H
N, N-
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