Asymmetric synthesis of phorboxazole B - Part II: Synthesis of the C1-C19 subunit and fragment assembly

Abstract

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 maong the most cytostatic natural products known: inhibiting the growth of tumor cells at nanomolar concentrations. Key fragment couplings inlucde a highly selective double stereodiffentiating aldol reaction, a metalated-oxazole alkylation, and an oxazole-stabilized Wittig olefination. Following macrocyclization, a highly stereoseclective chelation-controlled addition of a side-chain alkenyl metal species provides the full carbon framework of phorboxazole B.