Nakadomarin A (1) was first isolated from the Okinawan marine sponge Amphimedon sp. by Kobayashi in 1997, and was found to be biogenetically closely related to manzamine alkaloids, such as manzamine A and ircinal A. Its structure was elucidated spectroscopically and consists of an unprecedented hexacyclic ring system (8/5/5/5/15/6) that includes a furan ring. An interesting biogenetic transformation of ircinal A to nakadomarin A has been proposed. Although some biological activities of nakadomarin A, such as cytotoxicity against murine lymphoma L1210 cells, inhibitory activity against Cdk4, and anti-microbial activity, have been reported, its limited availability (1.8×10^<-3>%, wet weight) has prevented a complete survey of its biological activity. In connection with our ongoing project on the total synthesis of manzamine alkaloids, we were interested in nakadomarin A because of its unique structure and began a synthetic study. We report here the first total synthesis of (±)-nakadomarin A (1) and also a different synthetic approach toward chiral nakadomarin A. 1) Total synthesis of (±)-nakadomarin A: 4-Oxopiperidine carboxylate was converted to the spiro-lactam 26 (AD ring intermediate). To this intermediate a furan ring was introduced by Suzuki-Miyaura coupling to give ACD ring intermediate 29. Intramolecular cyclization of the furan ring to acyliminium cation afforded the central core of nakadomarin A, ABCD ring intermediate 35. Both 8-membered ring (E ring) and 15-membered ring (F ring) was constructed using ring closing metathesis to give 20,29-dioxonakadomarin A 40 and its (24E)-isomer 41. Finally, both dioxonakadomarins were reduced to nakadomarin A 1 and its (24E)-isomer 42, respectively. 2) Optically active ABCD ring intermediate 56, which already have suitable substituents for further elaboration of both E and F rings, was synthesized from chiral hydroisoquinolinone 46 derived from Diels-Alder reaction of chiral piperidinone derivative 43 and siloxydiene 44.
