4
498
J . Org. Chem. 2002, 67, 4498-4500
Syn th esis of Axin oh yd a n toin s
Ana Carolina Barrios Sosa, Kenichi Yakushijin, and David A. Horne*
Department of Chemistry, Oregon State University, Corvallis, Oregon 97331
Received J anuary 28, 2002
A short synthesis of the hydantoin-containing marine sponge metabolites axinohydantoins is
described. A key feature of the synthesis is a putative biomimetic, intramolecular cyclization of
R-functionalized imidazolone 5, which affords the tricyclic pyrroloazepinone framework comprising
6
. In addition, the conversion of imidazolones to R,â-unsaturated hydantoins is outlined and
represents a new approach to these heterocyclic systems.
4
5
Over the last two decades, a series of tricyclic pyrrole
cocyamidine unit. In previous work from this lab, the
6
natural products have been isolated from various genera
of marine sponges.1 Each share in common a fused
bicyclic pyrrolo[2,3-c]azepine core to which either a
synthesis and stereoselective conversion of hymenin to
(Z)-hymenialdisines was reported (eq 1). Formation of the
thermodynamically less stable (E)-isomer was not ob-
served. In the present study, a similar approach for
installing the hydantoin unit of axinohydantoins 1 and
2 was envisioned from hymenin analogues 6. The prob-
lem of accessing the hydantoin nucleus from an imida-
zolone precursor as well as forming the less thermody-
namically stable (E)-axinohydantoins by this approach
remained an open question. Herein, we report the first
syntheses of (E)- and (Z)-debromoaxinohydantoins 1b and
2b and (E)-and (Z)-bromoaxinohydantoins 1c and 2c.
2
-aminoimidazole, glycocyamidine, or hydantoin unit is
2
appended. In 1990, Pettit and co-workers isolated (E)-
axinohydantoin (1a ) from the sponge Axinella, and its
structure was determined by X-ray crystallography.
Subsequently, the isolation of (Z)-axinohydantoin (2a )
and (Z)-debromoaxinohydantoin (2b) from Stylotella au-
rantium and Hymeniacidon sp., respectively, has been
reported by two groups.3 Axinohydantoins have been
shown to inhibit protein kinase C.3
a
The biosynthetic pathway to axinohydantoins is un-
known but plausible pathways may involve linear pre-
cursors such as R-functionalized imidazolones 5. An
(
4) (a) Sharma, G. M.; Buyer, J . S.; Pomerantz, M. W. J . Chem. Soc.,
The hydantoin-containing axinohydantoins are struc-
turally related to hymenialdisines which contain a gly-
Chem. Commun. 1980, 435-436. (b) Cimino, G.; DeRosa, S.; DeStefano,
S.; Mazzarella, L.; Puliti, R.; Sodano, G. Tetrahedron Lett. 1982, 23,
67-768. (c) Kitagawa, I.; Kobayashi, M.; Kitanaka, K.; Kido, M.;
7
Kyogoku, Y. Chem. Pharm. Bull. 1983, 31, 2321-2328. (d) Supriyono,
A.; Schwarz, B.; Wray, V.; Witte, L.; Muller, W. E. G., van Soest, R.;
Sumaryono, W.; Proksch, P. Z. Naturforsch. 1995, 50c, 669-674. (e)
Williams, D. H.; Faulkner, D. J . Nat. Prod. Lett. 1996, 9, 57-64. (f)
Eder, C.; Proksch, P.; Wray, V.; Steube, K.; Bringmann, G.; van Soest,
R. W. M.; Sudarsono; Ferdinandus, E.; Pattisina, L. A.; Wiryowidagdo,
S.; Moka, W. J . Nat. Prod. 1999, 62, 184-187.
(
1) Faulkner, D. J . Nat. Prod. Rep. 2001, 18, 1-49 and references
therein.
(2) Pettit, G. R.; Herald, C. L.; Leet, J . E.; Gupta, R.; Schaufelberger,
D. E.; Bates, R. B.; Clewlow, P. J .; Doubek, D. L.; Manfredi, K. P.;
R u¨ tzler, K.; Schmidt, J . M.; Tackett, L. P.; Ward, F. B.; Bruck, M.;
Camou, F. Can. J . Chem. 1990, 68, 1621-1624.
(3) (a) Patil, A. D.; Freyer, A. J .; Killmer, L.; Hofmann, G.; J ohnson,
(5) (a) Xu, Y.-z.; Yakushijin, K.; Horne, D. A. J . Org. Chem. 1997,
62, 456-464. (b) Barrios Sosa, A. C.; Yakushijin, K.; Horne, D. A. J .
Org. Chem. 2000, 65, 610-611.
R. K. Nat. Prod. Lett. 1997, 9, 201-207. (b) Inaba, K.; Sato, H.; Tsuda,
M.; Kobayashi, J . J . Nat. Prod. 1998, 61, 693-695. Although axino-
hydantoins were subsequently referred to as spongiacidins, we opted
to use the name originally given as axinohydantoins.
(6) Kobayashi, J .; Ohizumi Y.; Nakamura H.; Hirata, Y.; Waka-
matsu, K.; Miyazawa, T. Experientia 1986, 42, 1064-1065.
1
0.1021/jo020063v CCC: $22.00 © 2002 American Chemical Society
Published on Web 05/10/2002