Amphidinolides F and C2: An Odyssey in Total Synthesis

Amphidinolides F, C, C2, and C3 are marine natural products isolated from dinoflagellates Amphidinium species. They share the same macrolactone core, with the difference between them residing at the side chain level. A predominant feature of these amphidinolides is the presence of two trans-THF rings inside the macrolactone core, which is thought to be built by C-glycosylation with titanium enolate of N-acetyl oxazolinethiones. Thus, the original strategy for their total synthesis was based on the assembly of three main fragments corresponding to C₁-C₉, C₁₀-C₁₉, and C₂₀-C₂₉ or C₂₀-C₃₄ disconnections. Whereas synthesis of all fragments was successful, the C-glycosylation reaction between C₁₉ and C₂₀ turned out to be an issue. Therefore, a second route was designed. The new disconnection between C₁₇ and C₁₈ was based on a sulfone addition and a desulfonylation sequence. Our convergent strategy allowed the total synthesis of amphidinolide F and enabled a new unifying route toward the synthesis of amphidinolides C, C2, and C3 using a late-stage divergent approach. Although there were unsatisfying yields at some critical steps, our work culminated into the first total synthesis of amphidinolide C2.