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Amphidinolides C, F, and U, including C2-C4 analogs, are highly cytotoxic marine macrolides, mainly isolated from dinoflagellates of the genus Amphidinium. All these polyketides share a 75 % or more similar structure, highlighted by a macrolactone ring, at least one trans-2,5-substituted-THF motif and a characteristic polyenic side chain. From their isolation and absolute configurational assignment, the total synthesis of these marine macrolides represented an intense challenge to the organic synthesis community over the last 15 years, with around 14 research groups engaged in this inspiring task. In the first part of this review, we present the different approaches to the isolation and characterization of these natural products, including the most recent analogs, which may cast doubt on the biogenetic origin of these compounds. The various synthetic approaches to the total synthesis of C, F, and U amphidinolides are presented in a second part, focusing on key reactions and/or innovative strategies. The review concludes in a third section summarizing the successful approaches leading to the total synthesis of one of the members of this amphidinolide subfamily., (© 2024 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

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 C 1 -C 9 , C 10 -C 19 , and C 20 -C 29 or C 20 -C 34 disconnections. Whereas synthesis of all fragments was successful, the C-glycosylation reaction between C 19 and C 20 turned out to be an issue. Therefore, a second route was designed. The new disconnection between C 17 and C 18 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.