Synthesis of depleted analogues of amphidinolide C congeners

Natural products are rich resources for drug discovery and development. However, the complex molecular structures of natural products always complicate the total synthesis, structure–activity relationship investigations and structural optimizations. Therefore, simplifying complex structures without decreasing the desired biological activity is an effective strategy for improving synthetic accessibility and accelerating the drug development process. Amphidinolide C congeners are the cytotoxic macrolides isolated from the genus Amphidinium. Except for amphidinolide C4, they possess the same functionalized 25-membered macrolactone core and differ only on the side chain appended at C28. The 25-membered macrolactone core is decorated with some unusual structural components, such as an s-cis-1,3-diene subunit, an exo-methlyene moiety, and two trans-substituted tetrahydrofuran units. These natural compounds exhibit significant cytotoxic activities and they have attracted much interest from the synthetic community due to their remarkable bioactivities, low natural accessibility, and synthetic challenges for more than 20 years since their isolations. Total synthesis of amphidinolide C1 and F has been achieved by the groups of Carter, Fürstner and Figadère. However, up to now, the action mode of the amphidinolide C congeners is still unknown. Based on the limited information on the bioactivity of amphidinolide C congeners, we envisioned synthesis of the structurally simplified amphidinolide C congeners by depleting four stereogenic centers at C4, C12, C13, and C16. Three fragments were prepared and assembled via the Suzuki-Miyaura cross-coupling reaction under the Johnson conditions at C9-C10, esterification of C24-OH, and ring-closing metathesis at C16-C17. Then, the side chain was assembled onto the macrolactone core via Suzuki–Miyaura cross-coupling reaction of the C-26 alkenyl iodide by using our Aphos-Y as the ligand. In Chapter 1, a brief introduction of the structural