Enantioselective Strategy to the Spirocyclic Core of Palau’amine and Related Bisguanidine Marine Alkaloids Anja S. Dilley and Daniel Romo* Department of Chemistry, Texas A&M UniVersity, P.O. Box 30012, College Station, Texas 77843-3012 romo@mail.chem.tamu.edu Received March 19, 2001 ABSTRACT An enantioselective strategy to the spirocyclic core found in the oroidin-derived family of bisguanidine marine alkaloids has been devised, premised on a biosynthetic proposal. Herein, we describe the successful implementation of this strategy, which entails a Diels-Alder reaction and a chlorination/ring contraction sequence that delivers the fully functionalized spirocyclic core. In this initial report, an intermolecular chlorination delivers a cyclopentane that is epimeric at C17 relative to the palau’amines and epimeric at C11 relative to the axinellamines. The remarkable structural diversity of guanidine-containing marine natural products makes them attractive synthetic targets. 1 In addition, many of these compounds possess potent biological activity that renders them potentially useful as biochemical probes. In this regard, the class of bioactive marine natural products that includes the palau’amines (1), 2 the styloguanidines (2), 3 and the axinellamines (3) 4 possess a common, highly complex cyclopentane that is stereogenic at every carbon including one quaternary spiro center (Figure 1). 5 These alkaloids also include two cyclic guanidines within their structure. Biosynthetically, these metabolites are thought to be derived from a common precursor, oroidin. Our interest in these natural products stems from their challenging structure coupled with the potent immunosuppressive activity of palau’amine. 6 Two approaches to these metabolites that have been described are a concise route to an abbreviated tetracyclic core structure by Overman 7a and a desymmetri- zation strategy to the axinellamine cyclopentane described by Carreira. 7b Herein, we describe our synthetic approach to this class of bisguanidine alkaloids that is premised on the biosynthetic proposal of Kinnel and Scheuer. 2a,8 This (1) (a) Berlinck, R. G. S. Nat. Prod. Rep. 1999, 16, 339-365. (b) Faulkner, D. J. Nat. Prod. Rep. 2000, 17,7-55. (2) (a) Kinnel, R. B.; Gehrken, H.-P.; Scheuer, P. J. J. Am. Chem. Soc. 1993, 115, 3376-3377. (b) Kinnel, R. B.; Gehrken, H.-P.; Swali, R.; Skoropowski, G.; Scheuer, P. J. J. Org. Chem. 1998, 63, 3281-3286. (3) Kato, T.; Shizuri, Y.; Izumida, H.; Yokoyama, A.; Endo, M. Tetrahedron Lett. 1995, 36, 2133-2136. (4) (a) Urban, S.; Leone, P. D. A.; Carroll, A. R.; Fechner, G. A.; Smith, J.; Hooper, J. N. A.; Quinn, R. J. J. Org. Chem. 1999, 64, 731-735. (b) It should be noted that the same name was previously given to related, simpler pyrrole alkaloids; see: Bascombe, K. C.; Peter, S. R.; Tinto, W. F.; Bissada, S. M.; McLean, S.; Reynolds, W. F. Heterocycles 1998, 48, 1461-1464. (5) The absolute configuration of these natural products has not been determined unambiguously; however, the absolute stereochemistry of palau’amine (as shown in Figure 1) has been tenatively assigned on the basis of similarities of its CD spectrum with monobromophakellin hydro- choride (see ref 2a). (6) Palau’amine has an IC 50 of 42.8 nM in the mixed lymphocyte reaction (ref 2a). (7) (a) Overman, L. E.; Rogers, B. N.; Tellew, J. E.; Trenkle, W. C. J. Am. Chem. Soc. 1997, 119, 7159-7160. (b) Starr, J. T.; Koch, G.; Carreira, E. M. J. Am. Chem. Soc. 2000, 122, 8793-8794. ORGANIC LETTERS 2001 Vol. 3, No. 10 1535-1538 10.1021/ol015864j CCC: $20.00 © 2001 American Chemical Society Published on Web 04/21/2001