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-...[ Read more ]

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 simplification of natural products and amphidinolide C congeners is presented. It includes the summary of the general process for the structural simplification of bioactive molecules and several reported examples of the structural simplification of natural products are illustrated. Then, the background information about amphidinolide C congeners, including isolations, structural elucidations and cytotoxicities, is briefly introduced. Three examples of the total synthesis of amphidinolide C1 and F are described. Finally, our simplification strategy of the amphidinolide C congeners is presented followed by the retrosynthetic analysis of the depleted analogues to be synthesized in this thesis research.

The preparation of the C9–C16 vinyl iodide fragment by three synthetic routes is presented in Chapter 2. For the conjugated enyne synthesis, HWE reaction, Cu-catalyzed methylboration and carboalumination were applied, respectively, to achieve high E/Z selectivity. For the synthesis of the C1–C8 tetrahydrofuran fragment, Noyori asymmetric hydrogenation and Sharpless asymmetric dihydroxylation (AD) were used to control the stereogenic centers. The α, β-unsaturated ester was achieved by Wittig reaction and was transformed into the tetrahydrofuran fragment via the AD–S_N2 sequence.

Chapter 3 compiles the initial results about the connection of the C9–C16 vinyl iodide and the C1–C8 tetrahydrofuran fragments by using vinyllithium addition and alkyl zincate addition reactions at C8–C9. In order to improve the results of the alkyl zincate addition, alternative methods were explored. The C1–C16 fragment was disconnected into a vinyl iodide fragment and a vinyl boronate fragment at C9–C10. The two fragments were then connected by Suzuki–Miyaura cross-coupling reaction under Johnson’s conditions. After obtaining the C1–C16 fragment, the C17–C26 fragment was attached to the C1–C16 fragment via Yamaguchi esterification and the macrolactone ring was closed by using RCM reaction successfully. After that, the short side arm similar to that of amphidinolide F was assembled by Suzuki–Miyaura cross-coupling reaction by using our Aphos-Y as the ligand.

The main experimental procedures, the characterization data of major compounds, and the cited references are found at the end of the thesis. The copies of original ¹H and ¹³C NMR spectra of key compounds are given in Appendix.