Abstract
Amphidinolide B (1), G (2), and H (3), isolated from the cultured marine dinofragellate, Amphidinium sp. by Kobayashi and co-workers, contain ally' epoxide, s-cis-diene units, five hydroxyl groups, and nine stereocenters in respective 26 and 27-membered macrocydic lactone moieties. In addition, these compounds exhibit potent cytotoxic activity against L1210 murine leukemia cells and KB human epidermoid carcinoma cells, and amphidinolide H (3) has the potential to activate actin polymerization by covalently linking to the actin cytoskeleton. The unique structure and promising bioactivity of amphidinolides have attracted us to study the syntheses of amphidinolides (1-3). Herein we report the total synthesis of amphidinolide B (1) using aldol reaction and ring dosing metathesis as key steps. Acetylide coupling of the fragments B (6) and C (7), followed by TPAP oxidation proceeded smoothly to afford the coupling product 9. Treatment of 9 with Gilman reagent led to the desired E enone as a major product (E:Z=9:1), which was then converted into the diene product by Wittig olefination. Removal of the TES group and Dess-Martin oxidation provided aldehyde 10. With the requisite intermediate 4 in hand, we explored the optimal conditions in aldol reaction between 4 and 5. As a result, the desired aldol 11-(S) was obtained in good yield by performing the reaction at -20℃ (72%, S:R = 2.5:1). After introduction of the ally' epoxide moiety in 5 steps, the 26-membered lactone was constructed by the Yamaguchi esterification protocol and ring dosing metathesis. Finally, the total synthesis of amphidinolide B (1) was achieved by deprotection of all TBS groups. In addition, total syntheses of amphidinolide G (2) and H (3) were also accomplished in the same synthetic strategy. Our strategy will be applied to the structure-activity relationship studies of amphidinolides (1-3).
