Novel Diels-Alder-type dimerization of 5-ethenyl-2-phenylsulfanyl-1H-imidazoles and its application to biomimetic synthesis of 12,12′-dimethylageliferin

Article abstract of DOI:10.1016/S0040-4039(02)00782-7

Diels-Alder-type dimerization of various 5-ethenyl-2-phenylsulfanyl-1H-imidazoles provided a novel highly regio- and stereoselective route to the preparation of multifunctionalized 4,5,6,7-tetrahydrobenzimidazoles, the basic skeleton of ageliferin, a biol

Full text of DOI:10.1016/S0040-4039(02)00782-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 4377–4380
Novel Diels–Alder-type dimerization of
5-ethenyl-2-phenylsulfanyl-1H-imidazoles and its application to
biomimetic synthesis of 12,12%-dimethylageliferin
Ikuo Kawasaki, Norihiro Sakaguchi, Norie Fukushima, Naoko Fujioka, Fumi Nikaido,
Masayuki Yamashita and Shunsaku Ohta*
Kyoto Pharmaceutical University, Misasagi Yamashinaku, Kyoto 607-8414, Japan
Received 22 March 2002; revised 15 April 2002; accepted 19 April 2002
Abstract—Diels–Alder-type dimerization of various 5-ethenyl-2-phenylsulfanyl-1H-imidazoles provided a novel highly regio- and
stereoselective route to the preparation of multifunctionalized 4,5,6,7-tetrahydrobenzimidazoles, the basic skeleton of ageliferin, a
biologically active pyrrole–imidazole marine alkaloid. The reaction was applied to the synthesis of 12,12%-dimethylageliferin.
© 2002 Elsevier Science Ltd. All rights reserved.
Recently, many types of biologically active pyrrole–imi-
dazole alkaloids have been isolated from marine lives
such as sponges, and they have become an important
focus of scientific attention.1 In 1990, ageliferins 1–3,
were isolated from Agelas sponges and found to have
various biological properties such as actomyosin
ATPase,2 antiviral, antibacterial3 and several other
interesting activities.4 The structural skeleton of 1–3 in
Fig. 1 has been considered to be biochemically synthe-
sized through [4p+2p] cycloaddition1e,2,3 of the simplest
pyrrole–imidazole alkaloids,1a oroidin 45 or/and
hymenidin 5.6 We have investigated total syntheses of
several biologically active imidazole alkaloids,7 and at
this time our attention was focused on the first total
synthesis of ageliferins via a biomimetic synthetic route.
In this paper, we would like to report the first synthesis
of 12,12%-dimethylageliferin 20.
Although there are several examples of Diels–Alder
(DA) reactions of 4- or 5-ethenylimidazole derivatives
as the diene component with active dienophiles such as
N-phenylmaleimide or 4-phenyl-1,2,4-triazoline-3,5-
dione,8 homonuclear DA-type dimerization of 5-
alkenylimidazole compounds 8 and 9 has remained
unknown.
NH2
N
O
O
NH
H
N
First, we examined the reactivity of various 5(4)-
ethenylimidazole under thermal reaction conditions.
The DA-type dimerization precursors 8 and 9 were
prepared from 1,2-substituted imidazoles 6 (Scheme 1).
The desired homonuclear DA-type dimerization of 8a,
8b, 8c, 9a and 9b successfully proceeded as shown in
Table 1.9 Fortunately, we found that the plane and
stereo structure of the major products (10c–e) were
consistent with those of ageliferins. The structure of 10a
was confirmed by HMBC experiment, and the regio-
and stereochemistry of 10c–d and 11a was determined
by HMBC and NOESY experiments. These correla-
tions of 10d and 11a were observed as shown in Fig.
2.10
X1
N
H
N
Br
Br
NH2
H
N
N
H
1 X1 = X2 = H
2 X1 = Br, X2 = H
3 X1 = X2 = Br
X2
N
H
N
H
N
Br
NH2
N
H
N
H
X
O
4 X = Br
5 X = H
Figure 1.
Next, we planned a synthesis of 12,12%-dimethyl-
ageliferin 20 from the DA product 10d (Scheme 2). The
* Corresponding author. Tel.: +81-75-595-4703; fax: +81-75-595-4795;
e-mail: sohta@mb.kyoto-phu.ac.jp
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00782-7

4378
I. Kawasaki et al. / Tetrahedron Letters 43 (2002) 4377–4380
3
N
N
N
4
5
2
b (for 8a, b) or c (for 8c)
a
SPh
SPh
SPh
H
1
N
N
R2
N
R1
R1
R1
O
d
6a: R1 = Me
6b: R1 = MOM
6c: R1 = SEM
7a: R1 = Me
7b: R1 = MOM
7c: R1 = SEM
8a: R1 = Me, R2 = H
8b: R1 = SEM, R2 = H
8c: R1 = R2 = Me (E/Z = 72:28)
N
SPh
EtO
N
R1
9a: R1 = Me (E/Z = 97:3)
O
9b: R1 = MOM (E/Z = 99:1)
9c: R1 = H, R2 = Me (E/Z = 98:2)
e
Scheme 1. Regents and conditions: (a) LTMP, DMF, THF, DME, −78°C, 98% (7a), 83% (7b), 95% (7c); (b) n-BuLi, Ph3P+MeBr−,
THF, 0°C to rt, 90% (8a), 77% (8b); (c) PhLi, Ph3P+EtBr−, AcOH, t-BuOK, THF, Et2O, −66°C to rt, 92% (8c); (d)
(EtO)2P(O)CH2CO2Et, LiCl, DBU, MeCN, rt, 99% (9a), 100% (9b); (e) 10% HCl aq., EtOH, 60°C, 71% (from 9b).
Table 1. DA dimerizations of the alkenyl imidazoles 8 and 9
SPh
R1
SPh
N
N
N
N
R1
N
+
4
R2
R2
R2
R2
3
8a-c,
9a-c
N
2
5
SPh
SPh
N
1
R1
N
6
7
R1
10a-e
11a-b
Entry
Starting compd. Reaction
conditiona
Reaction time
(h)
R1
R2
Yield (10+11) (%)b Ratio (10/11)c
Product(s)
1
2
3
4
5
6
8a
8b
8c
9a
9b
9c
A
A
A
B
C
D
30
30
75
30
60
60
Me
SEM
Me
Me
MOM
H
H
H
Me
CO2Et
CO2Et
CO2Et
93
36
42
55
14d
0e
–
–
1:0
50:1
4:1
–
10a
10b
10c
10d/11a
10e/11b
–
a Reaction condition: (A) neat in sealed tube at 150°C; (B) refluxed in xylene at 140°C; (C) neat in sealed tube at 100°C; (D) neat in sealed tube
at 120°C.
b Isolated yield.
c Determined by 1H NMR.
d Starting material was mainly recovered.
e Resinous product was formed.
ester 10d was reduced with LiAlH4 to give the diol 12 in
98% yield. Protection of the hydroxy groups of 12
followed by desulfurization with a combination of NiCl
steps. The diazide 18 was converted into the corre-
sponding diamine by selective reduction with PPh3 in
the presence of H2O,13 and then the diamine was
acylated with 4-bromo-2-(trichloroacetyl)pyrrole14 to
give the protected ageliferin analogue 19 (21% yield in
two steps). Finally, hydrolysis of the imino groups of 19
with diluted hydrochloric acid gave 12,12%-dimethyl-
ageliferin dihydrochloride 20 as a powdered material,
spectral data of which fully supported its structure.15
11
and NaBH4 gave the silyl ether 14 in 69% yield from
12. Introduction of azide groups into the 2- and 2%-posi-
tions of the imidazole nucleus of 14 was achieved by
lithiation with sec-BuLi followed by treatment with
trisyl azide1b to give the diazide 15a in 55% yield
accompanied with mono azides 15b and 15c (total 30%
yield). The diazide 15a was hydrogenated in the pres-
ence of 5% Pd–C, and the resulting primary amino
groups were protected with benzaldehyde to afford the
diimine 16 (50% in two steps). The TBDPS groups of
16 were removed by the action of CsF, and the resul-
tant diol 17 was subjected the Mitsunobu reaction
conditions12 to give the diazide 18 in 79% yield in two
In conclusion, we have successfully developed a conve-
nient and efficient preparation method for the highly
functionalized 4,5,6,7-tetrahydrobenzimidazole deriva-
tives by novel homonuclear DA-type dimerization reac-
tions of 5-alkenyl imidazoles with high regio- and
stereoselectivity. We are currently investigating the

I. Kawasaki et al. / Tetrahedron Letters 43 (2002) 4377–4380
4379
research in graduate schools in Subsidies for ordinary
expenses of private schools from the Promotion and
Mutual Aid Corporation for Private Schools.
R
H
H
H
H
H
R
H
H
N
R
H3C
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17: R = OH
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g
Scheme 2. Regents and conditions: (a) LiAlH4, THF, rt, 98%; (b) TBDPSCl, imidazole, DMF, rt, 99%; (c) NiCl·6H2O, NaBH4,
THF, MeOH, 0°C to rt, 70%; (d) sec-BuLi, trisyl azide, THF, DME, −40°C to rt, 55% (15a), 30% (15b+15c); (e) H2, Pd–C,
AcOEt, rt, then PhPHO, PhMe, reflux, 50% (from 15a); (f) CsF, DMF, 100°C, 83%; (g) DEAD, PPh3, (PhO)2P(O)N3, THF, rt,
95%; (h) PPh3, THF, H2O, rt, then K2CO3, 4-bromo-2-(trichloroacetyl)pyrrole, DMAc, rt, 21%; (i) 0.5 M HCl aq., EtOH, rt, 76%.

4380
I. Kawasaki et al. / Tetrahedron Letters 43 (2002) 4377–4380
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4.14 (m, 4H), 4.49 (br d, J=8.2 Hz, 1H), 6.86 (s, 1H),
7.09–7.24 (m, 10H); 13C NMR (l, ppm): 13.95, 14.01,
22.9, 31.2, 31.9, 35.9, 41.8, 47.8, 61.2, 61.4, 126.1, 126.6,
127.3, 127.6, 128.0, 129.1, 129.2, 129.7, 133.8, 134.6,
135.4, 135.5, 137.7, 137.8, 172.3, 172.6; IR: 3017, 1725,
1474, 1447, 1368, 1266, 1229, 1177, 1091, 1032; HRMS
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1H), 2.47 (m, 1H), 2.55 (br d, J=17.0, 1H), 2.75 (dd,
J=17.0, 5.0, 1H), 3.41 (s, 3H), 3.41 (s, 3H), 3.42–3.49 (m,
2H), 3.56 (dd, J=9.5, 5.1, 1H), 3.67 (dd, J=9.5, 4.2, 1H),
3.95 (br s, 1H), 6.73 (br s, 1H), 6.83 (d, J=1.5, 1H), 6.90
(d, J=1.5, 1H), 6.92 (d, J=1.5, 1H), 6.95 (d, J=1.5, 1H);
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647.0839.
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