| The total synthesis of phorboxazole B is described.{09}The C3-C17 bis-oxane cores of phorboxazoles A and B were synthesized in >98% enantiomeric excess by the technique of two-directional synthesis followed by desymmetrization using a Pd(0)-mediated, chiral-ligand controlled double cycloetherification. The bis-oxane core of phorboxazole B was elaborated to fully functionalized C1-C17 and C3-C17 subunits by careful manipulation of conformational preferences and functional group proximity effects. The C20-C32 subunit of phorboxazoles A and B was constructed via a hetero Diels-Alder reaction to afford the first reported catalytic enantioselective synthesis of this segment of the phorboxazoles: A fully protected C33-C39 lactone was assembled in 4 steps from Brassard's diene utilizing a diastereoselective hetero Diels-Alder reaction. The C20-C32 and C33-C39 subunits were joined and taken to a complete C46-C18 subunit in 11 steps. Finally, several avenues to complete the total synthesis of phorboxazole B were explored, ultimately resulting in a 28 step longest linear sequence (55 total steps) to synthetic phorboxazole B. |
