Marine organisms present us a big number of secondary metabolites with complex and fascinating structures and useful properties. Among these marine metabolites, polyketide macrolides, isolated from sponges, algae, dinoflagellate, and other marine invertebrates, have attracted numerous attention from the synthetic and biological communities, due to their novel architectures and unexpected biological activities. From a chemical structure point of view, many of the polyketide macrolides are fancinating due to their highly oxygenated cores and stereochemical elaborations. As a continuation of our synthetic work, we are interested in the THF-containing amphidinolide C congeners, five of the polyketide macrolides largely possessing the same core. Amphidinolide C congeners are the 25-m...[ Read more ]

Marine organisms present us a big number of secondary metabolites with complex and fascinating structures and useful properties. Among these marine metabolites, polyketide macrolides, isolated from sponges, algae, dinoflagellate, and other marine invertebrates, have attracted numerous attention from the synthetic and biological communities, due to their novel architectures and unexpected biological activities. From a chemical structure point of view, many of the polyketide macrolides are fancinating due to their highly oxygenated cores and stereochemical elaborations. As a continuation of our synthetic work, we are interested in the THF-containing amphidinolide C congeners, five of the polyketide macrolides largely possessing the same core. Amphidinolide C congeners are the 25-membered macrolactones, which feature with largely conserved macrocyclic framework. Their macrolactone core is ornamented with some rare structural components, such as an s-cis-1,3-diene subunit, an exo-methlyene moiety, and two highly functionalized tetrahydrofuran entities. These compounds show significant cytotoxic activities and they have attracted numerous attentions from the synthetic community due to their remarkable bioactivities, low natural accessibility, and synthetic challenges for more than 20 years since their isolations. This thesis work mainly focuses on the synthesis of C9-C17 and C18-C26 fragments common to amphidinolide C1-C3 and F. Our strategies for Diverted Total Synthesis (DTS) are adopted, since these natural products contain the same core structure, but tethered with different side chains. The natural products could be built by connecting different side chains to a common core structure. The coupling reactions between the synthesized fragments are examined in order to assemble the macrolactone core.

In Chapter 1, the background information about amphidinolide C congeners, including isolations, structural elucidations and cytotoxicities, is briefed. It is followed by the priori synthetic studies, covering the review of the synthetic methodologies about both THFs, and two examples of the completed total synthesis as well as our planned studies in this thesis work.

The construction of the C18-C26 tetrahydrofuran fragment, including three generations of synthetic routes, is presented in Chapter 2. For the first generation synthetic route, all the stereogenic centers were secured by two asymmetric Sharpless dihydroxylation reactions. The two-carbon homologation was achieved by a Wittig reaction between the four-carbon aldehyde and the stablized ylide. The tetrahydrofuran ring was formed via an intramolecular S_N2 reaction. The Takai reaction was used to form the (E) alkenyl iodide. In the second generation route, the HWE reaction of the previous aldehyde should give the enyne product having the requisite carbon skeleton. A shorter route was established in the third generation synthesis. Noyori asymmetric hydrogenation and Sharpless asymmetric dihydroxylation were used to control the stereogenic centers. The same enyne compound was achieved by Sonagashira reaction and was transformed into the tetrahydrofuran fragment via the S_N2 reaction.

Two synthetic pathways toward the C9-C17 fragment are summarized in Chapter 3. For the first synthetic pathway, two Masamune anti-aldol reactions were considered to secure the stereogenic centers of this fragment. Starting from propane-1,3-diol, the requisite all carbon skeleton was obtained with the aldol reaction and the HWE reaction of the methyl ketone. The Noyori asymmetric hydrogenation and Fráter-Seebach methylation were used to create the anti-aldol subunit in the second generation synthetic route. The syn-Evans’ aldol reaction was used to secure the C16 chirality. It was found that reductive removal of the Evans’ chiral auxiliary was much easy than that of the Masamune counterpart in this substrate.

The results about the connection of the two fragments are compiled in Chapter 4. The main methodology used for the coupling of the C1-C8 and C9-C17 fragments is vinyl iodide-lithium exchange followed by its addition to the aldehyde. After standard transformations, the C1-C17 alkyl iodide fragment was obtained. Another iodide-lithium exchange followed by its addition to another aldehyde fragment should give the macrolactone core precursor.

The main experimental procedures, the characterization data of major compounds, and the cited references are found at the end of the thesis. A summary of other synthetic work not detailed in this thesis and the copies of original ¹H and ¹³C NMR spectra of key compounds are given in Appendix.