90(P-16) Asymmetric Total Synthesis of (-)-Nakadomarin A
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A manzamine alkaloid nakadomarin A (1) was isolated from Okinawan Marine sponge Amphimedon sp. by Kobayashi and co-workers in 1997. Although some interesting biological activities of 1 have been reported, its limited availability has prevented a complete survey of its biological activity. Recently, we accomplished the first total synthesis of rac- and ent-1. However, an optical resolution of the key carboxylic acid gave only undesired isomer efficiently. Therefore, we have developed a new synthetic route to natural form of 1. Since the stereocenters of nakadomarin A are as same as those of ircinal A, we planed a new synthetic route using the same intermediate 7 which was developed for our previous synthetic study of ircinal A. The key intermediate 7, which was obtained by Diels-Alder reaction of 8 and 9, gave the tricyclic intermediate 10 via allylic cation intermediate (S_N' reaction) under the acidic conditions. Ozonolysis of 11, followed by aldol condensation with TAMA gave ring contracted intermediate 12, ABD rings. The furan ring (C ring) was constructed from endoperoxide 20 which was prepared by oxidation of 1,3-diene 19 with singlet oxygen. A presence of alkynyl side chain is essential to prevent isomerization of a terminal unsaturated bond under strong acidic conditions. We have observed that a dicobalt hexacarbonyl complex was useful as the protection of alkyne under RCM conditions. E ring was constructed using second-generation Grubbs catalyst. F ring was constructed by reduction of a dicobalt hexacarbonyl complex into an olefin, followed by the second RCM. Finally reduction of bislactum has accomplished the first asymmetric total synthesis of natural (-)-1.
