Preparation Of A Cinnamide Library And Total Syntheses Of Stereoisomers Of Marine Macrolide Iromoteolide-1a

Exploration on formation of C-C bond and strategy for assembling molecular skeleton is a main research area in synthetic organic chemistry and it plays an important role in total synthesis of complex natural products and in construction of libraries of bioactive compounds in a speedy and efficient manner. This thesis research covers two topics:(a) construction of a cinnamide compound library based on establishment of "one-pot" Wittig reaction of a-bromoacetamides in aqueous media; and (b), as the main effort of the thesis work, total synthesis of stereoisomers of the proposed marine macrolide Iriomoteolide-la.Chapter 1 briefly introduces the structural characteristics of Amphidinolides which are the marine macrolides of the same biological origin as Iriomoteolides, and the accomplishments made by our research group in total synthesis of Amphidinolide T2, X, and Y. It is followed by description about the structures of Iriomoteolide-la,-1b,-1c, and 3a, a summary on the updated progress in total synthesis of the proposed Iriomoteolide-la/-lb by the researchers all over the world, and the discrepancy among the proposed structures of Iriomoteolide-la/-lb with the synthetic samples. A tunable "four-module" coupling approach is proposed for total synthesis of the stereoisomers of the proposed Iriomoteolide-1a using ring-closing metathesis (RCM) as the key step for assembling the 20-membered macrocycle, targeting for uncovering the structural mystery of the natural product.As an initial phase of the thesis work, given in Chapter 2 are some bioactive natural products possessing a cinnamide subunit, and a summary of the new results on "one-pot" aqueous Wittig reaction of a-bromoacetamides, including the data on optimization of reaction conditions, the scope of substrates, and synthesis of the library of about 70 cinnamides.Chapter 3 briefly addresses on alkene RCM reaction, the commonly used RCM initiators, and selected examples of RCM used in total synthesis of natural products. The known syn- and anti-selective Abiko-Masamune asymmetric aldol reaction is applied for synthesis of the (18S,19R)-C17-C23 alkyl iodide fragment and three stereoisomers of the C1-C6α,β-unsaturated acid fragment possessing (2E,4R,5S),(2E,4S,5R),及(2E,4S,5S) absolute configuration, respectively. Configuration of the trisubstituted double bond is controlled via Michael addition of Me2CuLi to the alkynoate. The key results on total synthesis of three (2E,4R,5SS,18SS,19R), (2E,4S,5R,18S,19R), and (2E,4S,5S,18S,19R) stereoisomers of Iriomoteolide-la and (2E,4S,5R,18S,19R)-Iriomoteolide-lb are compiled. These macrolides are synthesized via the sequence of the B-alkyl Suzuki-Miyaura cross-coupling, the indium-mediated aldehyde allylation, and the RCM reaction.Chapter 4 presents the results on total synthesis of (2E,4R,5S,18R,19S), (2E,4S,5S,1R,19S), and (2Z,4R,5S,18R,19S) via the same "four-module" coupling approach. In this case, the anti-aldol subunit in the (18R,19S)-C17-C23 alkyl iodide fragment is prepared via Sharpless asymmetric allylic epoxidation and epoxide ring opening with Me2CuLi. Although all the synthesized stereoisomers of the proposed Iriomoteolide-la/-lb in this thesis work do not match with the structures of the natural products, the gathered structural information should be valuable for future work on these marine macrolides.The experimental section including the synthetic procedures and full characterization data for all new compounds, the cited references, and the copies of selected original NMR spectra are found at the end of the thesis.