Ptilomycalin A (1) and crambescidines, the unique guanidine alkaloid family, consist of novel pentacyclic guanidine units (so-called vessel part) and a spermidine unit linked by a linear long chain fatty acid (so-called anchor part), and they show significant biological activities including the inhibition of Na^+, K^+, Ca^<2+>-ATPases. In 2000, Braekman group reported the novel guanidine alkaloid crambescidin 359 (3). This newly isolated guanidine alkaloid is the first derivative which lacks the anchor part of crambescidins, so its biological properties as the vessel part alone are intriguing. Firstly, we have developed a facile and stereoselective method for the synthesis of the novel pentacyclic guanidine system. Our procedure features (1) the stereoselective synthesis of 2,5-disubstituted pyrrolidine based on sequential 1,3-dipolar cycloaddition followed by hydrogenation or oxidation-hydrogenation of the resulting isoxazolidines, and (2) efficient synthesis of pentacyclic guanidine based on guanylation followed by double N,O-acetalization. This synthetic method could be successfully applied to the stereoselective total synthesis of (-)-crambescidine 359 (3). This synthesis has established the absolute stereochemsitry of 3 and would suggest the counterion of 3 as chloride. We next have studied the Ca^<2+>-ATPase inhibition activities of 3 and its synthetic analogs 26-29. Although crambescidine 359 (3), 26 and 27 did not show the significant activities, 28 and 29, which have the spermidine contained alkyl long chain, exhibited the inhibition of Ca^<2+>-ATPase with an IC_<50> value of 3μM and 1μM, respectively. We finally designed and synthesized the novel C_2-symmetric chiral pentacyclic guanidine compound 30 as an organocatalyst. The structure of 30 was based on the mother skeleton of 3 and was rationally designed to have a C_2-symmetrical chiral reaction cavity around the substrate recognition/activation site. The catalyst 30 effectively induced the asymmetric induction of alkylation reaction with the glycynate-benzophenone Schiff base 31, and the epoxidation reaction with chalcone and its derivatives 33.
