Study On Total Synthesis Of Micromonospolide B

Total synthesis of complex natural products facilitates advancement in synthetic methodologies and strategies. This thesis research deals with study on total synthesis of Micromonospolide B, a new member of the plecomacrolides, exhibiting strong inhibitory activity against gastrulation. The latter is one of the fundamental events in embryogenesis.Chapter 1 outlines the structures and biologic activities of the plecomacrolides. It is followed by an overview on the known strategies used in the literature for total synthesis of bafilomycin A₁, which shares the same macrolactone core with Micromonospolide B. A new synthetic strategy employing 1,3-diene-ene ring-closing metathesis (RCM) is proposed for formation of the 16-membered macrolactone in this thesis work.Chapter 2 describes the known strategies reported in the literatures on assembling the C21-C23 stereotriad of bafilomycin A₁, and new results on synthesis of the C18-C28 fragment of Micromonospolide B. The key steps applied for construction of the desired stereotriad are the anti-selective aldol reaction of Abiko's chiral propionate, Sharpless asymmetric epoxidation, and regioselective epoxide ring opening.Chapter 3 briefly introduces the up-to-date development of RCM, and application in total synthesis of natural products. It is followed by the discussion in detail on the synthetic route established for construction of the 16-membered tetraenoic lactone with the (Z)-double bond at C12-C13. The C3-C12 fragment is coupled with the C13-C17 fragment via aldol reaction. The resultant seco intermediate is then cyclized via 1,3-diene-ene RCM to form the (12Z)-geometric isomer. Finally the double bond at C2-C3 is formed by aβ-elimination, enabling a synthesis of (12Z)-16-membered tetraenoic lactone.Chapter 4 gives a brief introduction to application of cross metathesis (CM) in total synthesis of natural products, followed by presenting the results of two synthetic routes designed for preparation of (10E, 12E)-1,3-diene. The first route is attempted according to 1,3-diene-ene CM, and another is attempted by using CM-HWE olefination sequence. However, the both are not satisfactory.The experimental section compiles the main synthetic procedures, the characterization data for the key compounds and the cited references. Copies of the original ¹H and ¹³C NMR spectra are found in the Appendix.