Marine dinoflagellates have attracted many chemists as the promising producers of structurally fascinating and biologically active natural products. Among these natural products, amphidinolides have drawn much attention since their first isolation by Kobayashi and coworkers in 1986. The amphidinolide B family was proved as one of the most cytotoxic group of macrolides among amphidinolides. In connection with our total synthesis of amphidinolactone B, we were interested in the total synthesis of the structurally related amphidinolide B4 using a multimodule assembly strategy. This thesis mainly documents the efforts and results related to the total synthesis of amphidinolide B4 by using the B-alkyl Suzuki−Miyaura cross-coupling, Yamaguchi esterification, and ring-closing metathesi...[ Read more ]

Marine dinoflagellates have attracted many chemists as the promising producers of structurally fascinating and biologically active natural products. Among these natural products, amphidinolides have drawn much attention since their first isolation by Kobayashi and coworkers in 1986. The amphidinolide B family was proved as one of the most cytotoxic group of macrolides among amphidinolides. In connection with our total synthesis of amphidinolactone B, we were interested in the total synthesis of the structurally related amphidinolide B4 using a multimodule assembly strategy. This thesis mainly documents the efforts and results related to the total synthesis of amphidinolide B4 by using the B-alkyl Suzuki−Miyaura cross-coupling, Yamaguchi esterification, and ring-closing metathesis (RCM) as the key steps to assemble the macrolactone ring. The results on an attempted formation of the C20−C22 α,β-unsaturated ketone moiety via the gold-catalyzed Meyer−Schuster rearrangement of a propargyl alcohol and the optimization on the synthesis of the C13−C19 THF fragment of amphidinolactone B are also complied for future reference.

Described in Chapter 1 are the general background information of amphidinolide B4 and the related amphidinolactone B, including isolation, structures, bioactivities and total synthesis of amphidinolide B congeners and amphidinolactone B stereoisomers. It is followed by the planned study in this thesis research targeting at a novel total synthesis of amphidinolide B4.

The synthesis of the C13−C26 fragment using two different synthetic routes is presented in Chapter 2. Our first approach attempted at using the sequence of Meyer−Schuster rearrangement−asymmetric dihydroxylation (AD) to build the C20−C22 keto diol unit. Synthesis of the C13−C19 dienyl iodide was firstly illustrated as the common intermediate which was used for synthesis of the functionalized THF fragment of amphidinolactone B in our group’s prior study. Then, the C13−C19 dienyl iodide was converted into the propargyl alcohol, and its gold-catalyzed Meyer−Schuster rearrangement, along with few other substrates, was examined with failure. The second synthetic route was successfully developed by using the Horner–Wadsworth–Emmons (HWE) olefination of the C13−C21 keto phosphonate. The resultant enone was subjected to AD to afford the keto diol unit of the C13−C26 fragment.

Chapter 3 summarizes the results on synthesis of the C7−C12 alkyl iodide fragment, assembling reactions of the fragments, and completion of the total synthesis of amphidinolide B4. The Yamaguchi esterification was used to joint the known C1–C6 acid with the C13–C26 alcohol fragment. This was followed by formation of the C12−C13 bond with the C7–C12 alkyl iodide via the B-alkyl Suzuki coupling using our Pd(OAc)2–Aphos-Y catalyst system. After the C7–C9 allylic alcohol was transformed into the corresponding vinyl epoxide, the RCM reaction was performed by using Grubbs second generation catalyst to form the C6–C7 (E)-double bond with closure of the macrolactone core. Finally, global desilylation using TASF furnished amphidinolide B4 whose structure was confirmed by NMR spectral data and high-resolution mass analysis.

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