Synthetic Studies toward the C₁-C₁₂ Fragment of Amphidinolide U

Amphidinolide U is a cytotoxic marine macrolide isolated from Amphidinium sp., sharing 75% of the amphidinolide C backbone. We report here a synthetic study of the C₁-C₁₂ fragment of amphidinolide U. The C₆-C₁₂ pattern was built using consecutive regioselective ring opening of epoxides, a directed reaction to control newly formed stereogenic centers. In parallel, the C₁-C₅ moiety was constructed by taking advantage of a symmetrical diol. Attempts to cross-couple the C₁-C₅ and C₆-C₁₂ fragments by using a Suzuki cross-coupling reaction led to poor conversion rates. The same transformation on a close substrate model used during past studies on the total synthesis of amphidinolides F and C2 was successful. These contrasting results could be explained by a presumed steric hindrance of the protecting group adjacent to the vinyl function involved in the cross-coupling reaction. Our investigations will stimulate the optimization of C(sp²)-C(sp³) cross-coupling reactions with bulky substrates, with the aim of achieving a total synthesis of amphidinolide U.