The total synthesis of (-)-discodermolide

A highly convergent and stereocontrolled total synthesis of ($-$)-discodermolide (1), antipode of potent immunosuppressive and antimitotic (+)-discodermolide, is described in this thesis. Chapter one summarizes the interesting biological activities of (+)-discodermolide and the pursuits of several research groups towards its total synthesis. Chapter two details the effort of the Smith group in this venture. Our recognition of the recurring stereochemical triad in ($-$)-1 suggested retrosynthetic disconnections of ($-$)-discodermolide at C(14,15) and C(8,9) into fragments A, B and C, and their preparations from the common precursor.* The coupling of fragments A and B to form the trisubstituted Z olefin ($-$)-38 was accomplished utilizing a Pd(0) catalyzed cross coupling reaction.* Further elaboration of ($-$)-38 to the desired C(9) iodide and corresponding Wittig reagent revealed an interesting conformational phenomenon. Steric strain present in the C(9,14) segment results in a close contact between olefinic C(13) and primary C(9). Therefore, substitution of an EWG (electron withdrawing group) at C(9) is complicated by a novel intramolecular cyclization.* Despite this challenge, iodination of the alcohol was successfully carried out in a less polar solvent system. Preparation of the Wittig reagent was then achieved by heating (80$\sp\circ$C) the iodide with excess PPh$\sb3$ under neat conditions. This latter transformation was further optimized recently using high pressure.* Subsequent Wittig reaction between ($-$)-55 and fragment C provided cis olefin ($-$)-60, which upon further elaboration completed the total synthesis of ($-$)-discodermolide.* ftn*Please refer to the dissertation for diagrams