Total Synthesis of Narbonolide and Biotransformation to Pikromycin

An improved total synthesis of narbonolide and its biotransformation to pikromycin is reported. This total synthesis utilized an intramolecular Nozaki−Hiyama−Kishi coupling that significantly improved macrocyclization yields (90−96%) and allowed for differentiation of the C3- and C5-oxidation states. A pikAI deletion mutant of Streptomyces venezuelae was used to biotransform synthetic narbonolide to pikromycin by glycosylation and oxidation in vivo. This integration of synthetic chemistry and engineered biotransformations holds great promise for the synthesis of novel macrolide analogues of biological interest.