Recently, an increasing number of structurally and bioactively unique 3-alkylpyridine alkaloids have been isolated from marine sponges of several genera. In 1999, Kobayashi and co-workers reported the isolation of a structurally novel cis-cyclopent[c]isoxazolidine alkaloid, pyrinodemin A, from the marine sponge Amphimedon sp. Pyrinodemin A shows potent cytotoxicity against murine leukemia L1210 (IC_<50>= 0.058μg/mL) and KB epidermoid carcinoma cells (IC_<50>=0.5μg/mL) in vitro. Although the plane structure and relative configuration of pyrinodemin A were primarily proposed as 1, the absolute configuration has not yet been determined. In this symposium, we report the racemic synthesis of possible structures 2-4 for pyrinodemin A and support the C14'-C15' double-bond positional isomer 3, which Baldwin's group proposed, as the correct structure (Scheme 1). Furthermore, we report the first enantioselective total synthesis of (-)-pyrinodemin A (3) through a highly diastereoselective intramolecular 1,3-dipolar cycloaddition reaction as the key step and the determination of its absolute configuration (Scheme 2). Two novel cytotoxic alkaloids haliclamines A (28) and B (29), isolated from a marine sponge of the genus Haliclona by Fusetani et al. in 1989, are most closely related to the key bisdihydropyridine intermediate 27 of the biogenetically unique manzamine family. We report the first total syntheses of 28 and 29 through a convergent and expeditious assembly of 3-substituted pyridine derivatives with different alkyl chains to the bispyridinium macrocycle as a general approach to the key bisdihydropyridine intermediate 27 (Schemes 3-5). In the course of our synthetic studies on macrocyclic marine alkaloids 28 and 29, it was determined that MsCl resulted in the deoxygenation of pyridine N-oxides 53 and 60 under mesylation conditions (MsCl, Et_3N). The problem is the reaction mechanism of these unusual deoxygenations. After many unsuccessful experiments, products, which are very significant for deducing the reaction mechanism, have been trapped. The treatment of N-oxide 64 with BnSO_2Cl and Et_3N in the presence of alkenes afforded a γ-sultone along with deoxygenated 2,4,6-trimethylpyridine (Scheme 6). Here we suggest the possibility of the generation and/or intermediacy of α-sultones as new reactive intermediates for the first time.
