Terrestrial and marine microorganisms provide a valuable source of structurally diverse and biologically active secondary metabolites. As introduced in Chapter 1, maltepolide A–F are a family of polyketide-derived 20-membered macrolides isolated from the fermentation broth of myxobacterium Sorangium cellulosum So ce1485. Most of maltepolides show moderate cytostatic activity on L929 mouse fibroblast cell lines with IC₅₀ values of 4.6–39 μM. Maltepolide A and E cause unique morphological changes in the dividing transformed PtK₂ cells with the phenotype closely resembling the effect of monastrol which is known as an inhibitor of the kinesin Eg5. Maltepolides possess either a THF moiety or a hydroxy vinyl epoxide within the macrocyclic core and the side chain appended at C19 contai...[ Read more ]

Terrestrial and marine microorganisms provide a valuable source of structurally diverse and biologically active secondary metabolites. As introduced in Chapter 1, maltepolide A–F are a family of polyketide-derived 20-membered macrolides isolated from the fermentation broth of myxobacterium Sorangium cellulosum So ce1485. Most of maltepolides show moderate cytostatic activity on L929 mouse fibroblast cell lines with IC₅₀ values of 4.6–39 μM. Maltepolide A and E cause unique morphological changes in the dividing transformed PtK₂ cells with the phenotype closely resembling the effect of monastrol which is known as an inhibitor of the kinesin Eg5. Maltepolides possess either a THF moiety or a hydroxy vinyl epoxide within the macrocyclic core and the side chain appended at C19 contains either a vinyl epoxide or a corresponding epoxide ring-opening moiety by H₂O/MeOH. It has been demonstrated that maltepolide E is the common precursor of the entire family. Total synthesis of the proposed structure of maltepolide C and synthesis of the related fragments have been reported but the structure of maltepolide C is confirmed incorrect. The main theme of this thesis work aims at establishment of a viable synthetic strategy for assembling maltepolide E possessing two sets of labile vinyl epoxide moieties, one at C11–C14 within the core and the other at C20–C23 on the side chain. In order to simplify our synthetic planning, this thesis work focuses on synthesis of the truncated maltepolide E without the C20–C24 side chain via 1,3-diene–ene ring-closing metathesis (RCM). After brief introduction of the reported examples of 1,3-diene–ene RCM in total synthesis in Chapter 1, our strategic consideration and the retrosynthetic analysis of the maltepolide E core are presented.

Synthesis of the TBS-protected C1–C8 acid fragment and the C9–C19 alcohol fragment are compiled in Chapter 2. Of particular note are the DDQ-mediated over-oxidation of a dienyl alcohol in the synthesis of the C1–C8 acid fragment and the failed gold-catalyzed Meyer–Schuster rearrangement of the epoxy propargylic alcohol in an attempted installation of the C11–C15 epoxy (E)-enone subunit. Fortunately, the latter could be accessed by the HWE olefination of the epoxy aldehyde. Assembling of the maltepolide E core is described in Chapter 3 via esterification between the C1–C8 acid and the C9–C19 alcohol followed by RCM with exclusive formation of the (E)-C8–C9 double bond. It is delighted to found that upon releasing the C17-OH group, the truncated maltepolide E along with the truncated maltepolide A and B are obtained and fully characterized.

Finally, a separate part of the thesis work on synthesis of the novel chiral 2-amido arenol-derived methacrylates is recorded in Chapter 4. The SmI₂-mediated reductive coupling of these chiral methacrylates with trimethylacetaldehyde affords the α,γ-disubstituted γ-butyrolactone in a moderate yield (55%) with excellent diastereomeric ratios (trans:cis = 98:2–99:1) but low enantioselectivities (40.6–46.5% ee).

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 GC chromatogram, comparisons figures of the ¹³C NMR data of the truncated maltepolide A, B, and E with the natural products, and ¹H and ¹³C NMR spectra of the key compounds are given in Appendix.