Asymmetric Synthesis of Phorboxazole B—Part I: Synthesis of the C20-C38 and C39-C46 Subunits

The total synthesis of the antitumor marine macrolide phorboxazole B (1) has been realized. The phorboxazoles are representative of a new structural class of macrolides and are among the most cytostatic natural products known: inhibiting the growth of tumor cells at nanomolar concentrations. Key fragment couplings include a highly selective double stereodifferentiating aldol reaction, a metalated-oxazole alkylation, and an oxazole-stabilized Wittig olefination. Following macrocyclization, a highly stereoselective chelation-controlled addition of a side-chain alkenyl metal species provides the full carbon framework of phorboxazole B.