Biocatalytic Synthesis of Pikromycin, Methymycin, Neomethymycin, Novamethymycin, and Ketomethymycin

A biocatalytic platform that employs the final two monomodular type I polyketide synthases of the pikromycin pathway in vitro followed by direct appendage of d-desosamine and final C–H oxidation(s) in vivo was developed and applied toward the synthesis of a suite of 12- and 14-membered ring macrolide natural products. This methodology delivered both compound classes in 13 steps (longest linear sequence) from commercially available (<i>R</i>)-Roche ester in >10% overall yields