A Second-Generation Total Synthesis of (+)-Phorboxazole A

A highly convergent second-generation synthesis of (+)-phorboxazole A has been achieved. Highlights of the synthetic approach include improved Petasis−Ferrier union/rearrangement conditions on a scale to assemble multigram quantities of the C(11−15) and C(22−26) cis-tetrahydropyrans inscribed with the phorboxazole architecture, a convenient method to prepare E- and Z-vinyl bromides from TMS-protected alkynes utilizing radical isomerization of Z-vinylsilanes, and a convergent late-stage Stille union to couple a fully elaborated C(1−28) macrocyclic iodide with a C(29−46) oxazole stannane side chain to establish the complete phorboxazole skeleton. The synthesis, achieved with a longest linear sequence of 24 steps, proceeded in 4.6% overall yield.