Total Synthesis of Mycoplanecin A

Abstract

The first total synthesis of mycoplanecin A, a potent antitubercular macrocyclic depsipeptide natural product targeting the DnaN sliding clamp, is described. Interesting key steps are the synthesis of the two trans 4-alkylated-L-prolines via an iterative Matteson homologation and an O→N acyl shift observed during the fragment coupling of the building blocks. The challenging macrocyclization of the globally deprotected linear precursor was accomplished under optimized high-temperature, high-dilution conditions. This work provides chemical access to mycoplanecin A, enabling further biological investigation and analogue development against the important pathogen Mycobacterium tuberculosis.