3
Scheme 2. Reagents and conditions: (a) NaBH4, 2 h, 54%; (b) Br2, Et3N, N-Boc-guanidine, 45 min, 31% (11), 18% (12); (c) Pd/C, H2,
CH3COOH, EtOH, 2 h, 31% (13), 32% (14); (d) 6 M HCl/MeOH, 2 h, 33%; (e) EtOH, HCl(g), 30 min, 94%.
5. Al-Mourabit, A.; Zancanella, M. A.; Tilvi, S.; Romo, D. Nat.
Prod. Rep. 2011, 28, 1229.
6. Lindel, T.; Breckle, G.; Hochgürtel, M.; Volk, C.; Grubeb, A.;
Köck, M. Tetrahedron Lett. 2004, 45, 8149.
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With amine intermediates I and II now available, clathrodin was
prepared by acylation of II with 4,5-dibromo-2-(trichloroacetyl)-1H-
pyrrole or 5-bromo-2-(trichloroacetyl)-1H-pyrrole in the presence of
triethylamine. Oroidin and hymenidin were prepared from II and
pyrrole-2-carboxylic acid, using a standard coupling procedure with
O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
tetrafluoro-
borate (TBTU)24 in N,N-dimethylformamide, since coupling of II
with 2-(trichloroacetyl)-1H-pyrrole proceeded in very low yield. A
library of analogs of alkaloids 1a-c possessing saturated or
unsaturated linker moieties could be prepared from I or II and the
respective aryl/heteroaryl carboxylic acids, using various coupling
procedures.25
10. (a) Rentas, A. L.; Rosa, R.; Rodriguez, A. D.; De Motta, G. E.;
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Nanteuil, G.; Ahond, A.; Poupat, C.; Thoison, O.; Potier, P. Bull.
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13. Ando, N.; Terashima, S. Tetrahedron 2010, 66, 6224.
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In conclusion, we have described two improved approaches to the
synthesis of 4-(3-aminopropyl)-1H-imidazol-2-amine (I) and
(E)-4-(3-aminoprop-1-en-1-yl)-1H-imidazol-2-amine (II), which are
key intermediates for the synthesis of the marine alkaloids
clathrodin, oroidin and hymenidin and libraries of their synthetic
analogs. Starting from L-ornithine, a combination of Weinreb amide
strategy and di-Boc protection provides a viable, environmentally
more acceptable and scalable alternative to Horne’s method17 for the
synthesis of I and II. As an important extension of Al-Mourabit’s
synthesis of marine pyrrole-2-aminoimidazoles via acyl-1,2-
dihydropyridine intermediates,19 N-benzyloxycarbonyl protection of
15. Lindel, T.; Hochgürtel, M. J. Org. Chem. 2000, 65, 2806.
16. Wang, Y. G.; Morinaka, B. I.; Reyes, J. C. P.; Wolff, J. J.; Romo,
D.; Molinski, T. F. J. Nat. Prod. 2010, 73, 428.
17. Olofson, A.; Yakushijin, K.; Horne, D. A. J. Org. Chem. 1998, 63,
1248.
a
1,2-dihydropyridine intermediate, in combination with
18. Little, T. L.; Weber, S. E. J. Org. Chem. 1994, 59, 7299.
19. Schroif-Gregoire, C.; Travert, N.; Zaparucha, A.; Al-Mourabit, A.
Org. Lett. 2006, 8, 2961.
20. Rasapalli, S.; Kumbam, V.; Dhawane, A. N.; Golen, J. A.; Lovely,
C. J.; Rheingold, A. L. Org. Biomol. Chem. 2013, 11, 4133.
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22. Valeur, E.; Bradley, M. Chem. Soc. Rev. 2009, 38, 606.
23. Compound 5 was not isolated and its structure was determined by
1H NMR spectroscopy of the crude product.
24. Ivanov, A. S.; Zhalnina, A. A.; Shishkov, S. V. Tetrahedron 2009,
65, 7105.
25. Zidar, N.; Montalvão, S.; Hodnik, Ž.; Nawrot, D. A.; Žula, A.;
Ilaš, J.; Kikelj, D.; Tammela, P.; Mašič, L. P. Mar. Drugs 2014,
12, 940.
ring-opening/deprotection under hydrogenolytic or acidic conditions,
provides direct access to both amine key intermediates I and II from
the same precursor.
Acknowledgments
This work was supported by the Slovenian Research Agency
(Grant P1-0208) and by the EU FP7 Integrated Project MAREX
(Project No. FP7-KBBE-2009-3-245137). The authors thank
Professor Roger Pain for critical reading of the manuscript.
References and notes
Supplementary Material
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Supplementary data associated with this article can be found, in
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