Total Synthesis of Malacidin A by β‐Hydroxyaspartic Acid Ligation‐Mediated Cyclization and Absolute Structure Establishment
Zhenquan Sun, Zhuo Shang, Nicholas Forelli, Kathy Hiu Laam Po, Sheng Chen, Sean F. Brady, Xuechen Li
Abstract
The development of novel antibiotics is critical to combating the growing emergence of drug-resistant pathogens. Malacidin A is a new member of the calcium-dependent antibiotic (CDAs) family with activity against antibiotic-resistant pathogens. Its mode of action is distinct from classical CDAs. However, the absolute structure of malacidin A has not been established. Herein, the total syntheses of malacidin A and its analogues are reported by a combination of Fmoc-based solid-phase peptide synthesis (SPPS) and β-hydroxyaspartic acid ligation-mediated peptide cyclization. The total synthesis enabled us to establish the absolute configuration of malacidin A, which is in agreement with those for natural malacidin A confirmed by advanced Marfey's analysis in our study.