The family of maltepolides A−E is the secondary metabolites, originated from soil-dwelling Gram-negative myxobacterium Sorangium cellulosum So ce1485, which exhibit cytostatic activity against L929 mouse fibroblast cell lines with IC₅₀ values ranging from 4.6 to 39 μM. Of the maltepolide family, maltepolides A and E are also potential inhibitors for kinesin Eg5 as the effect of morphological changes in the dividing transformed PtK₂ cells resembles that of monastrol. Maltepolide E features a 20-membered macrolactone and two vinylic epoxide moieties in its core and side chain, respectively. It is the only congener in the family that possesses a vinylic epoxide moiety in the core and it was confirmed to be the parent structure for the entire family. Transformation of maltepolide E into oth...[ Read more ]

The family of maltepolides A−E is the secondary metabolites, originated from soil-dwelling Gram-negative myxobacterium Sorangium cellulosum So ce1485, which exhibit cytostatic activity against L929 mouse fibroblast cell lines with IC₅₀ values ranging from 4.6 to 39 μM. Of the maltepolide family, maltepolides A and E are also potential inhibitors for kinesin Eg5 as the effect of morphological changes in the dividing transformed PtK₂ cells resembles that of monastrol. Maltepolide E features a 20-membered macrolactone and two vinylic epoxide moieties in its core and side chain, respectively. It is the only congener in the family that possesses a vinylic epoxide moiety in the core and it was confirmed to be the parent structure for the entire family. Transformation of maltepolide E into other congeners is achieved by adjusting the pH value in suitable solvents. Several synthetic studies towards fragments of maltepolides as well as the total synthesis of maltepolide C were reported by several research groups. The spectral data of the synthetic maltepolide C were found deviated to those of the natural maltepolide C. One of the two MeO groups gave 0.84 ppm difference in the ¹³C NMR spectrum, suggesting the proposed structures of natural and synthetic maltepolide C are not the same. Moreover, the synthesized C19-truncated maltepolides A, B, and E by Dai’s group confirmed that the C15-OMe on the core is correctly assigned for the natural product. The above-mentioned discrepancy in ¹³C NMR data seams concerned with the MeO group on the side chain of maltepolide C.

The current thesis research focuses on total synthesis of maltepolide E and its congeners. After a brief introduction of maltepolides and prior synthetic studies in Chapter 1, our approach towards total synthesis of maltepolide E and the accomplished results are presented and discussed in Chapters 2 and 3. The main focus of Chapter 2 describes the synthesis of the three key fragments, i.e. C1−C8 acid fragment, C9−C19 aldehyde fragment and C20−C24 terminal alkyne fragment. Synthesis of the C1–C8 acid is achieved with the modified procedures to obtain the C5-OTBS-protected acid fragment while synthesis of the C9−C19 aldehyde fragment features an asymmetric CBS reduction of γ,δ-epoxy-α,β-enone to secure the requisite stereochemistry of the C15-OH group. The γ,δ-epoxy-α,β-enone is prepared from Horner–Wadsworth–Emmons olefination of an epoxy aldehyde with β-keto phosphonate. The latter is prepared by a modified approach using addition of LiCH₂P(O)(OMe)₂ with a β-PMBO-substituted aldehyde followed by oxidation of the β-OH group. The modification suppresses a severe β-elimination of the PMBO group and furnishes high yield of the β-keto phosphonate. During synthesis of the C20−C24 alkyne fragment, a well-known 1,4-O,O-silyl migration was observed, which may likely account for the discrepancy in ¹³C NMR of the MeO group between the synthetic and the natural maltepolide C. as reported in the literature

Completion of total synthesis of maltepolide E as well as maltepolides A and B is presented in Chapter 3 featuring the Yamaguchi esterification and the 1,3-diene−ene RCM reaction as the key steps to assemble the macrolactone core. Selective desilylation among three different silyl ethers (C5-OTBS, C22-OTES, C23-OTBDPS) in the molecules is accomplished after careful investigation. The spectral data of the synthetic maltepolide E as well as maltepolides A and B are found identical to those of the natural products. The longest linear sequence is twenty-five steps with overall yields of 0.93% for maltepolide E, 0.19% for maltepolide A, and 0.096% for maltepolide B.

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