Work

Convergent Synthesis of the Minimal Macrolide Antibiotic Narbomycin

Year: 2026

Type: article

Abstract: 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.

Source: Journal of the American Chemical Society

DOI: 10.1021/jacs.6c12688

Authors: Quinn Edmondson, Cecilia Panfil, Jasmine K. Keyes, Andrew K. Ecker, Nicholas S. Settineri, Ian B. Seiple

Institutions: University of California, San Francisco, Scripps Research Institute, Lawrence Berkeley National Laboratory, University of California System

Language: English

Topic: Organic Chemistry Synthesis Methods

Subfield: Organic Chemistry

Field: Chemistry

Domain: Physical Sciences

Open Access status: green

Funders: Camille and Henry Dreyfus Foundation, National Institutes of Health, National Institute of General Medical Sciences

Awards: G5527247144, Modular synthesis of antibiotic and anticancer classes of natural products, Scripps Research Translational Chemical Biology