Total Synthesis Of Amphidinolide X Based On Stereochemical Influence By Remote Exocyclic Functionalities In Ring-Closing Metathesis

Amphidinolide X, a 16-membered cytotoxic macrodiolide, and its (12Z)-isomer have been synthesized via ring-closing metathesis (RCM) for assembling the C12-C13 trisubstituted double bond.Chapter 1 introduces the development of olefin metathesis catalysts, and the factors which influence the reactivity and E/Z selectivity of RCM, especially on the aspect of formation of trisubstituted double bonds. The structures of amphidinolides and the retrosynthetic bond disconnection used in the Furstner's total synthesis of amphidinolide X were briefed. It is followed by the presentation of our RCM strategy tackled under the current thesis research.Chapter 2 describes the synthesis of the C13-C22 tetrahydrofuran fragment appended with a hydroxy group at C17. It is a common structural subunit applicable for total synthesis of amphidinolide X and Y via the RCM approach. The oxygenated chiral quaternary carbon at C19 was assembled by the asymmetric dihydroxylation in high enantioselectivity and the tetrahydrofuran ring was constructed by an acid-catalyzed 5-endo ring-opening cyclization of the epoxide possessing a vinyl moiety. The latter could be also used to facilitate a B-alkyl Suzuki-Miyaura cross-coupling reaction for the introduction of the C13 olefinic carbon.Chapter 3 presents the synthesis of the C1-C12 acid fragments possessing an (8R)-and (8S)-TBDPSO group, respectively. The anti-methyl homoallylic alcohol was prepared by anti-selective aldehyde crotylation using the chiral boron and silicon reagents. A modified microwave heating procedure was also established for selective cleavage of the a,β-unsaturated methyl ester in the presence of the C6 ester moiety.Chapter 4 compiles the results of our studies on RCM toward formation of the trisubstituted double bond. Influence on the stereochemical outcome of the RCM by remote exocyclic groups appended at C8 was observed for the first time. (12Z)-Amphidinolide X was synthesized in 85% isolated yield as the sole isomer from the C8-keto substrate in the presence of 20 mol% of the Grubbs second generation catalyst. In contrast, the (8R)-TBDPSO-substituted substrate afforded a 29:71 mixture of amphidinolide X and (12Z)-isomer in 50% and 65% combined yield, respectively, by using 20 mol% of the Grubbs second generation catalyst and the corresponding indenylidene ruthenium complex. The latter was found to suppress formation of the substituted styrene byproduct associated with use of the benzylidene ruthenium complex. This work represents an example of using a bulky TBDPSO group at the remote exocyclic C8 position to partially facilitate formation of the trisubstituted (12E)-alkene embedded in the 16-membered macrodiolide ring.The experimental section, characterization of all new compounds, cited references, and copies of original ¹H and ¹³C NMR spectra are found at the end of the thesis.