Amphidinolides B, G, and H were isolated from the Cultured marine dinofragellate, Amphidinium sp. by Kobayashi and co-workers. These compounds share the 26 or 27-membered lactone with the S-cis diene and allyl eposice moieties, and exhibit potent cytotosic activity against L1210 murine leukemia cells and KB human epidermoid carcinoma cells. The unique structure and promising bioactivity of amphidinolides have attracted us to study the syntheses of amphidinolides. According to our retrosynthetic analysis, 1 was disconnected into the four fragments which were combined by esterification, aldol reaction, acetylide coupling, and ring closing metathesis, respectively (Scheme 1). In addition, the syntheses of 2 and 3 were performed by the same synthetic strategy. The fragment A was prepared from (2S,4S)-pentanediol featuring asymmetric dihydroxylation. The fragment B was synthesized from 3-methyl-3-butene-1-ol by using asymmetric dihydroxylation and Corey-Fuchs alkyne syntheiss. Synthesis of the fragment C was achieved by means of Evans alkylation between 15 and 16. The fragment D was synthesized from 4-pentene-1-ol in 3 steps. Acetylide coupling of the fragment B and C, followed by TPAP oxidation proceeded smoothly to afford the coupling product 21. After construction of the S-cis diene by means of Michael addition and Wittig reaction, TES deprotection and Dess-Martin oxidation provided 22. Then we explored the diastereoselectivility of aldol coupling (Table 1). The LHMDS-mediated reaction of the fragment A with the aldehyde 22 at -40℃ proceeded with poor diastereoselectivility favoring the 18S stereochemistry (d.r. 1.3:1). After introducing allyl epoxide moiety to 24, the 26-membered lactone was constructed by the Shiina esterification protocol and ring closing metathesis.
