Total synthesis of natural products is the Holy Grail of chemical science. Not only does it serve for structural elucidation, but also as an enabling endeavor for the discovery of new fundamental transformations and concepts in chemistry and their application to chemical biology and other disciplines. Mycolactone A–G are a family of polyketide-derived 12-membered macrolides that are produced by different strains of Mycobacterium ulcerans. They are causally involved in the pathology associated with M. ulcerans infections in humans, commonly known as Buruli ulcer (BU). All mycolactones share the same 12-membered macrolactone core but possess different polyene side chains. Construction of the core has been reported, featuring installation of the C14–C20 vinyl iodide fragment onto t...[ Read more ]

Total synthesis of natural products is the Holy Grail of chemical science. Not only does it serve for structural elucidation, but also as an enabling endeavor for the discovery of new fundamental transformations and concepts in chemistry and their application to chemical biology and other disciplines. Mycolactone A–G are a family of polyketide-derived 12-membered macrolides that are produced by different strains of Mycobacterium ulcerans. They are causally involved in the pathology associated with M. ulcerans infections in humans, commonly known as Buruli ulcer (BU). All mycolactones share the same 12-membered macrolactone core but possess different polyene side chains. Construction of the core has been reported, featuring installation of the C14–C20 vinyl iodide fragment onto the preformed 12-membered ring lactone subunit via Negishi or Suzuki–Miyaura cross-coupling. Attempts for assembling the fully functionalized mycolactone core via ring-closing metathesis (RCM) failed due to exclusive formation of the cyclohexene byproducts by connecting C9 with C14. Iriomoteolides are another family of macrolides with structural diversity and complexity; many of them show significant cytotoxicity. However, the structures of iriomoteolide-1a, -1b, and -1c are yet correctly elucidated despite of considerable synthetic efforts. This thesis work focuses on total synthesis of the fully functionalized mycolactone core and a stereoisomer of iriomoteolide-1b by applying the powerful ring-closing metathesis (RCM) protocols.

A brief introduction of the structures of mycolactones and iriomoteolides, and the reported synthesis of these macrolides is given in chapter 1. It is followed by an overview of progress in RCM and its application in total synthesis. These serve as the background information for the proposed research in this thesis work.

Chapter 2 discusses B-alkyl Suzuki–Miyaura cross-coupling reaction and our results on the evaluation of an efficient and reliable Pd(OAc)₂–Aphos-Y catalyst system for “9-MeO-9-BBN variant” of B-alkyl Suzuki–Miyaura cross-coupling reaction with alkenyl halides. The hemilability of Aphos-Y ligand enables its efficient role in the catalytic cycle as dppf and Ph₃As do under the Johnson protocol. The substrate scope has been examined for the construction of C(sp³)–C(sp²) bond with densely functionalized coupling partners. Application of the Pd(OAc)₂–Aphos-Y catalyst system in the total synthesis of mycolactone E and iriomoteolide-1a and -1b stereoisomers has been achieved in this work.

Chapter 3 summarizes our results on total synthesis of mycolactone core via relay RCM (RRCM) of the fully functionalized seco-precursors and total synthesis of mycolactone E. The substrates for chemoselective uploading of the ruthenium carbene species onto C8 rather than C9 were designed and synthesized. The effects of catalyst, temperature, and substrate structure on RRCM were studied in detail, leading to a reasonable mechanistic rationale and a high-yielding synthesis of the fully functionalized mycolactone core. Total synthesis of mycolactone E was accomplished using the C1'–C15' acid fragment synthesized in our lab. A concentration-dependent ¹³C NMR profile in acetone-d₆ was observed for mycolactone E, presumably arising from hydrogen bonding network associated with the four hydroxyl groups.

Chapter 4 describes the synthesis of the stereoisomers of iriomoteolide-1a and -1b with reassigned (11E)-geometry for iriomoteolide-1b. An unexpected effect of trace metal impurity on the indium-mediated allylation of aldehydes was observed. The base-mediated isomerization of the stereoisomer of iriomoteolide-1a into the stereoisomer of iriomoteolide-1b was confirmed by HPLC analysis to prefer (11E)-geometry.

The main experimental procedures, the characterization data of major compounds, and the cited references are found at the end of the thesis. Copies of original ¹H and ¹³C NMR spectra of key compounds and tables for comparisons of our ¹³C NMR data for the mycolactone core and mycolactone E with the reported values are given in Appendix.