Iriomoteolide-13a is a novel 22-membered macrolide containing one hexahydrofuro[3,2-b]furan (fused bis-THF) ring, one tetrahydropyran (THP) ring, two tetrahydrofuran (THF) rings, three one-carbon branches, and three hydroxy groups, two of which are belonged to two hemiacetals. The subunits of the bis-THF ring and the fused bis-THF ring are unique among the members of the family of iriomoteolides. Iriomoteolide-13a exhibits potent cytotoxicity against human cervix adenocarcinoma HeLa cells (IC₅₀ = 0.5 μg/mL). We initiated a total synthesis program to establish a reliable and flexible chemical synthesis strategy toward iriomoteolide-13a with the aim to confirm its proposed structure and to offer access to analogous.

In Chapter 1, the prior efforts on total synthesis of iriomoteol...[ Read more ]

Iriomoteolide-13a is a novel 22-membered macrolide containing one hexahydrofuro[3,2-b]furan (fused bis-THF) ring, one tetrahydropyran (THP) ring, two tetrahydrofuran (THF) rings, three one-carbon branches, and three hydroxy groups, two of which are belonged to two hemiacetals. The subunits of the bis-THF ring and the fused bis-THF ring are unique among the members of the family of iriomoteolides. Iriomoteolide-13a exhibits potent cytotoxicity against human cervix adenocarcinoma HeLa cells (IC₅₀ = 0.5 μg/mL). We initiated a total synthesis program to establish a reliable and flexible chemical synthesis strategy toward iriomoteolide-13a with the aim to confirm its proposed structure and to offer access to analogous.

In Chapter 1, the prior efforts on total synthesis of iriomoteolides and the methodologies used for construction of bis-THF and fused THF rings are briefly described. These synthetic studies are useful and inspirational for our synthesis planning. The target molecule was disconnected into the C1(C4)–C15 and C16–C30 fragments according to allylation reactions to form the C15–C16 bond. It would be followed by the macrocyclic ring formation such as macrolactonization reaction and ring-closing metathesis (RCM), respectively, after suitable manipulation of the C3 hemiacetal hydroxy group or the C21-OH group.

Chapter 2 presents the results of synthesis of the C1–C15 fragment of iriomoteolide-13a. A novel approach to the C4–C11 THF intermediate was established via an epoxide ring-opening cyclization under the Pd(0) catalysis conditions. The absolute stereochemistry of the trisubstituted THF fragment was confirmed by X-ray single crystal structural analysis (XRD analysis). The C11 position of the C4–C11 THF intermediate was then transformed into the corresponding thioester. The latter was coupled with a chiral four-carbon alkyl iodide using the recently reported Kishi’s Zr/Ni-mediated one-pot ketone synthesis protocol. The resultant C11–ketone was stereoselectively reduced with the assistance of the C9-OH group to secure the C9,C11-anti-diol subunit. On the other hand, three carbons were attached to the C4 olefinic carbon of the C4–C11 THF intermediate via a sequence of cross metathesis (CM), base-mediated alkene isomerization, Cu(I)-catalyzed borylation of α,β-unsaturated ester, and two-stage oxidation to install the β-keto ester functionality.

Chapter 3 compiles the results of the synthesis of the C16–C30 bis-THF-containing fragment. Intramolecular S_N2 reaction and syn-oxypalladation reaction were explored to construct the key bis-THF ring subunit. The C21-OH group was masked as the ester of 3-butenoic acid by esterification under the influence of AgClO₄ and the resultant 3-butenoate functionality could be considered as the C1–C3 moiety for an alternative macrocyclic ring formation via RCM reaction. Different methods for introducing the allylsilane functionality were explored, and finally, haloboration reaction of the terminal alkyne group was first carried out and it was followed by protodeboronation to form the 2-iodoalk-1-ene. The latter was subjected to Kumada coupling reaction with TMSCH₂MgCl to furnish the corresponding allylsilane functionality of the C16–C30 fragment.

Chapter 4 is dealt with various fragment-coupling strategies for the C15–C16 bond formation between the synthesized C1(C4)–C15 and C16–C30 fragments. The Sakurai reaction was first attempted but it did not form the desired coupling compound presumably due to formation of the protodesilylation byproduct. 3-Chloro-2- chloromethylprop-1-ene (methallyl dichloride) was then used as a three-carbon linchpin (C16–C18) to react first with the C19–C30 aldehyde using the chiral silane mediated allylation reaction under the modified Leighton protocol. Then, the C16–C30 allyl chloride, after installation of the bis-THF ring and confirmation of stereochemistry by XRD analysis, was subjected to the second indium-mediated allylation reaction with the C4–C15 aldehyde to form the seco C4–C30 advanced intermediate possessing a but-3-enoyloxy substituent at C21. The latter was examined for RCM reaction between the but-3-enoyloxy substituent and the C4 olefinic carbon in the presence of Grubbs 2nd generation catalyst; unfortunately, the desired macrocyclic product was not detected presumably due to competitive RCM reaction with the C17-methylene moiety. At this stage, the fully elaborated C1–C30 linear precursor was assembled from the indium-mediated coupling reaction of the C16–C30 allyl chloride with the C1–C15 aldehyde. Macrolactonization was initially attempted but hydrolysis of 3-TESO-substituted methyl ester and the C21-acetate moieties failed to give the corresponding acid with a free hydroxy group at C21 (n-Bu₃SnOH, PhMe, 85 ºC, 24 h). Finally, an intramolecular transesterification of C21-OH group with the β-keto methyl ester was performed at 130 ºC for 2 h in PhMe in a sealed vial to furnish the macrolactone in 70% yield. The resultant macrolactone was transformed into iriomoteolide-13a after conventional selective desilylation, oxidation state manipulation, and acetal formation. The ¹³C NMR data of our synthesized sample do not match with those of the natural product despite the fact that all stereogenic centers, except for C11 and two acetal carbons at C3 and C15, were confirmed by XRD analysis. It is apparent that the proposed structure of iriomoteolide-13a was wrongly assigned.

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 XRD analysis data of the compounds 229 and 357a are given in Appendix.