Total synthesis of 10-deoxymethynolide and narbonolide.

A flexible and convenient approach was developed for the synthesis of 10-deoxymethynolide (1) and narbonolide (2), which are aglycones of the methymycin and the pikromycin families of macrolide antibiotics. These lactones are produced by pikromycin polyketide synthase from Streptomyces venezuelae. Polyketide lactones, 10-deoxymethynolide and narbonolide, which contain 12- and 14-membered rings, respectively, were synthesized efficiently. These target lactones were retrosynthetically divided into three parts and assembled by using an asymmetric aldol reaction, the Yamaguchi esterification, and ring-closing metathesis. The ring-closing metathesis reaction catalyzed by the second-generation Grubbs catalyst is particularly efficient in preparing these macrocyclic polyketide lactones.