Marine organisms have provided numerous secondary metabolites with important biological activities and structural diversity, which serve as excellent candidates for investigation of new drugable molecules with high pharmacological potential. Among these marine secondary metabolites, a significant number of polyketide macrolides have been isolated from sponges, algae, dinoflagellates, and other marine invertebrates, and their structural novelty has attracted attentions from the synthetic communities. From a chemical structure point of view, the highly oxygenated nature and stereochemical elaboration, are the key features of polyketide macrolides. In continuation of our group’s synthetic work, we were interested in the tetrahydrofuran (THF)-containing amphidinolactone B, a novel 26-membe...[ Read more ]

Marine organisms have provided numerous secondary metabolites with important biological activities and structural diversity, which serve as excellent candidates for investigation of new drugable molecules with high pharmacological potential. Among these marine secondary metabolites, a significant number of polyketide macrolides have been isolated from sponges, algae, dinoflagellates, and other marine invertebrates, and their structural novelty has attracted attentions from the synthetic communities. From a chemical structure point of view, the highly oxygenated nature and stereochemical elaboration, are the key features of polyketide macrolides. In continuation of our group’s synthetic work, we were interested in the tetrahydrofuran (THF)-containing amphidinolactone B, a novel 26-membered macrolide isolated in 2007. The macrolide core of amphidinolactone B contains a highly functionalized THF moiety, a trisubstituted C‒C double bond, and four hydroxy groups. Besides the fascinating molecular architecture, amphidinolactone B exhibits moderate cytotoxicity as well. To the best of our knowledge, total synthesis of amphidinolactone B has not been reported since its isolation except for a synthesis of the C1‒C7 acid fragment by our group. Thus, determination of the stereochemistry of amphidinolactone B in synthetic manner becomes a major goal in our work, especially for the undefined configuration of C6. As a continuation of our group’s unpublished total synthesis of (2R,6R,9S)- and (2R,6S,9S)-stereoisomers, this thesis work mainly focuses on the synthesis of (2S,6R,9S)- and (2S,6S,9S)-stereoisomers of amphidinolactone B, in which a multimodule assembly strategy is adopted. Three key fragments were prepared and assembled via Yamaguchi esterification, B-alkyl Suzuki‒Miyaura cross-coupling, and ring-closing metathesis (RCM).

Given in Chapter 1 are the general background of amphidinolactone B, including isolation, structural elucidation, and bioactivity. It is followed by a brief discussion on total synthesis of the structurally related amphidinolide B, D, G, and H congeners by other groups. Moreover, the results of total synthesis of (2R,6R,9S)- and (2R,6S,9S)-stereoisomers of amphidinolactone B in our group and the planned studies in this thesis work are presented.

Determination of the stereochemistry of the C13‒C19 THF fragment is summarized in Chapter 2. Following the established synthetic route, a repeated synthesis of the C13‒C19 THF fragment was achieved, which involves an acid-catalyzed intramolecular hydroalkoxylation for construction of the highly functionalized THF ring. The stereochemistry of the newly generated quaternary stereogenic center and the configuration of the trisubstituted double bond in the hydroalkoxylation product were confirmed. The stereochemistry of the C15 chiral center was first clarified by the NOE technique and then the absolute configuration was fully confirmed by the X-ray structural analysis of the ferrocenecarboxylate of the THF fragment.

Preparation of the (2S,6R)- and (2S,6S)-C1‒C7 acid fragments are presented in Chapter 3. According to the previously developed synthetic route, two new C1‒C7 carboxylic acid fragments with (2S,6R)- and (2S,6S)-configuration were synthesized from a common C6,C7-diol, which was derived from a vinyl iodide and a known alkyl iodide by B-alkyl Suzuki‒Miyaura cross-coupling reaction. In order to address some shortcomings in the previous synthetic route, an alternative synthetic strategy featuring an asymmetric alkylation was attempted. Evans alkylation and Myers alkylation were investigated for the introduction of the C2 chirality.

The results of total synthesis of (2S,6R,9S)- and (2S,6S,9S)-stereoisomers are compiled in Chapter 4. Thus, the C13‒C15 alcohol fragment and the C8‒C12 alkyl iodide fragment were repeatedly synthesized and the macrolides were smoothly assembled via Yamaguchi esterification, B-alkyl Suzuki‒Miyaura cross-coupling, and RCM. However, both (2S,6R,9S)- and (2S,6S,9S)-stereoisomers did not match with the natural form by comparison of the NMR data. The collected NMR data of the newly synthesized (2S,6R,9S)- and (2S,6S,9S)-stereoisomers in combination with the previously synthesized (2R,6S,9S)- and (2R,6R,9S)-stereoisomers indicate that the absolute configuration of C23 of amphidinolactone B might be different from that of amphidinolide B, D, G, and H congeners. Further synthetic efforts are required to address this issue.

The main experimental procedures, the characterization data of major compounds, and the cited references are found at the end of the thesis. The copies of original ¹H, ¹³C NMR, and HMBC spectra of key compounds are given in Appendix.