Convergent Synthesis of the Minimal Macrolide Antibiotic Narbomycin

Macrolide antibiotics are a class of structurally diverse polyketides including essential medicines like erythromycin and azithromycin. Structurally minimal macrolides such as narbomycin lack much of the functionality common to other members of the class and exhibit a distinct mode of action wherein they completely inhibit bacterial growth despite only moderate inhibition of global protein synthesis. Unfortunately, lack of availability of these natural products has prevented a thorough investigation of their unusual mechanisms of action. Here we report a 10-step synthesis of narbomycin enabled by a Liebeskind-Srogl fragment coupling, a novel macrolactonization by direct displacement of an Evans auxiliary, and a stereoselective late-stage enone reduction. In addition to accessing the natural product, the route enables access to C8,19-unsaturated variants which could in principle serve as useful precursors for late-stage functionalization by conjugate addition.