Amphidinolide F

The complete carbon framework of the macrocyclic marine natural product amphidinolide F has been prepared by a convergent synthetic route in which three fragments of similar size and complexity have been coupled. Key features of the syntheses of the fragments include the stereoselective construction of the tetrahydrofuran in the C1-C9 fragment by oxonium ylide (free or metal-bound) formation and rearrangement triggered by the direct generation of a rhodium carbenoid from 1-sulfonyl-1,2,3-triazole, the highly diastereoselective aldol reaction between a boron enolate and an aldehyde with 1,4-control to prepare the C10-C17 fragment, and the formation of the tetrahydrofuran in the C18-C29 fragment by intramolecular nucleophilic ring opening of an epoxide with a hydroxyl group under acidic conditions.

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.

Exploration of an ambitious new strategy for the total synthesis of the cytotoxic marine natural product amphidinolide F is described, which features fabrication of the core structure from four readily accessible fragments and macrocycle construction through C9-C10 bond formation by intramolecular Stille coupling between an alkenyl iodide and alkenyl stannane. Efficient stereoselective synthesis of each of the four building-blocks and subsequent coupling of them to produce the requisite cyclization precursor has been accomplished, but suitable conditions for high-yielding palladium-mediated closure of the macrocycle to produce the fully protected amphidinolide F ring system have yet to be identified.