Total synthesis of a marine imidazole alkaloid, clathridine A

Article abstract of DOI:10.1016/S0040-4039(00)00678-X

The first total synthesis of clathridine A (8), a marine imidazole alkaloid, was achieved by using a novel regioselective condensation as a key step, in which preclathridine A (2) was treated with 1-methylparabanic acid (11) in the presence of a silylating agent. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00678-X

Tetrahedron Letters 41 (2000) 4623±4627
Total synthesis of a marine imidazole alkaloid,
clathridine A
Shunsaku Ohta,* Naoki Tsuno, Kazushi Maeda, Seikou Nakamura, Norio Taguchi,
Masayuki Yamashita and Ikuo Kawasaki
Kyoto Pharmaceutical University, Misasagi Yamashinaku, Kyoto 607-8414, Japan
Received 27 March 2000; revised 17 April 2000; accepted 21 April 2000
Abstract
The ®rst total synthesis of clathridine A (8), a marine imidazole alkaloid, was achieved by using a novel
regioselective condensation as a key step, in which preclathridine A (2) was treated with 1-methylparabanic
acid (11) in the presence of a silylating agent. # 2000 Elsevier Science Ltd. All rights reserved.
Keywords: clathridine A; preclathridine A; marine alkaloid; total synthesis; parabanic acid; regioselective condensation;
imidazole.
Recently, many marine imidazole alkaloids such as 1±10 in Table 1 have been isolated from
sponges, and their antitumor and antibacterial activities have also been found.1,2 Structural
characteristics of these alkaloids are that one or two alkoxy benzyl group(s) locates at the 1-, 4-
and/or 5-positions of the 1H-imidazole ring and the 2-position is substituted with a primary
amino group or a (1-methyl-2,5-dioxo-3-imidazolin-4-yl)amino moiety2 (Table 1).
Hitherto, we have reported total synthesis of several marine imidazole alkaloids such as
nortopsentin A±D,3 topsentin,4 kealiiquinone (10),5 and preclathridine A (2).6 In this paper, we
would like to report the ®rst total synthesis of clathridine A (8) starting from 1-methyl-1H-
imidazole.
It is necessary for the conversion of preclathridine A (2) into clathridine A (8) to condense 2
with 1-methylparabanic acid (11) regioselectively at the 4-position of 11 (Scheme 2). We ®rst
examined the condensation of 11 with primary amines in the presence of water-soluble carbodiimide
(WSC); however, the amines were incorporated into the heterocyclic ring to produce 3-substituted
1-methylparabanic acids (12a±c) (Scheme 1, Table 2).
In order to change the reactivity of 11, it was treated with trimethylsilyl chloride in the presence
of triethylamine in chloroform, and then aniline was added to the reaction mixture to give, inter-
estingly, the desired 4-phenylamino-1-methyl-2,5-dioxo-3-imidazoline (15a, mp 224±227ꢀC). The
structure of 15a was ®nally determined by X-ray crystallographical analysis, by which intermolecular
* Corresponding author. Fax:+81-75-595-4795; e-mail: sohta@mb.kyoto-phu.ac.jp
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00678-X

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Table 1
Several marine imidazole alkaloids
Scheme 1.
Table 2
Reaction of 1-methylparabanic acid (11) with primary amines

4625
0
0
...
...
hydrogen bonds were observed between O2 H±N3 and N3±H O2 as shown in Fig. 1. It was
also clari®ed that the 4-amino form 15B predominates rather than the 4-imino form 15A in the
crystalline state (Scheme 2).
Figure 1.
Scheme 2.
Table 3 shows the results obtained by examining in¯uences of the silylating agents and various
primary amines on the condensation. In entry 13, the used primary amine is preclathridine A (2),
and the product, clathridine A (8), was isolated as dark-red crystals, physical and spectral data of
which were almost in agreement with those of the natural product (Scheme 3).y The present total
synthesis of 8 is the ®rst one in the series of imidazole alkaloids bearing a (1-methyl-2,5-dioxo-3-
imidazolin-4-yl)amino moiety (Table 3).
Data for the synthetic clathridine A (8): Dark-red granules (recryst. from CH3OH), mp 233±235.6ꢀC. IR (CHCl3):
y
3315, 1784, 1732, 1716, 1672, 1611, 1439, 1392, 1300, 1093 cm^1. H NMR (400 MHz in CDCl3) ꢀ ppm: 3.19 (s, 3H,
>N-CH3), 3.71 (s, 3H, >N-CH3), 3.81 (s, 2H, Ar-CH2-Ar), 5.94 (s, 2H, O-CH2-O), 6.53 (s, 1H, C5-H), 6.71 (dd, 1H,
J=1.7 and 7.7 Hz, Ar-H), 6.73 (dd, 1H, J=0.6 and 1.7 Hz, Ar-H), 6.76 (dd, 1H, J=0.6 and 7.7 Hz, Ar-H). 13C NMR
(100 MHz in CDCl3): 24.7, 32.2, 34.4, 100.9, 108.3, 109.2, 117.6, 121.6, 129.0, 132.6, 139.6, 144.2, 146.2, 147.8, 154.9,
162.0. HRMS m/z: calcd for C16H15N5O4: 341.1121. Found: 341.1119 (M+). Anal. calcd for C16H15N5O4: C, 56.30; H,
4.43; N, 20.52. Found: C, 56.42; H, 4.52; N, 20.13.
1

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Table 3
Condensation of 11 with primary amines in the presence of silylating agentd
Scheme 3.
Synthesis 15a as a typical procedure: A solution of 1-methylparabanic acid (11; 256 mg, 2.0
mmol), DMAP (2 mg), triethylamine (0.59 ml, 4.2 mmol), imidazole (150 mg, 2.2 mmol) and
TMSCl (0.54 ml, 4.2 mmol) in CHCl3 (2.0 ml) was stirred for 2 h at room temperature under an
N2 atmosphere. Aniline (0.83 ml, 2.0 mmol) was added to the mixture, and the whole was
re¯uxed at 78ꢀC for 24 h. After cooling, water (2.0 ml) and CHCl3 (20 ml) were added to the
reaction mixture. The organic layer was dried over anhydrous sodium sulfate and evaporated to
give a colorless solid mass. The crude product was puri®ed by column chromatography
(CHCl3:MeOH=10:1 in volume) and the crystalline main fraction was recrystallized from MeOH
to give colorless needles, mp 224±227ꢀC. Yield, 259 mg (63.8%); IR (KBr): 3252, 1729, 1639,
1
1587, 1495, 1446, 1128 cm^1. H NMR (300 MHz in DMSO-d6) ꢀ 2.95 (s, 3H, N-CH3), 7.20 (t,
1H, J=7.4 Hz, Ar-H), 7.41 (t, 2H, J=7.6 Hz, Ar-H), 7.83±7.92 (m, 2H, Ar-H). 13C NMR (75
MHz in DMSO-d6): 24.9, 121.6, 125.7, 129.3, 138.4, 162.8, 163.0. HRMS m/z: calcd for
C10H9N3O2: 203.0695. Found: 203.0691 (M+). Anal. calcd for C10H9N3O2: C, 59.11; H, 4.46; N,
20.68. Found: C, 58.90; H, 4.55; N, 20.43.

4627
Acknowledgements
The authors are grateful to Dr. Motoo Shiro (Rigaku Corporation) for the X-ray crystallo-
graphic analysis of 15a. This research was ®nancially supported in part by the Frontier Research
Program of the Ministry of Education, Science, Sports and Culture of Japan.
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