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Total Synthesis of Malacidin A by β‐Hydroxyaspartic Acid Ligation‐Mediated Cyclization and Absolute Structure Establishment
Author(s) -
Sun Zhenquan,
Shang Zhuo,
Forelli Nicholas,
Po Kathy Hiu Laam,
Chen Sheng,
Brady Sean F.,
Li Xuechen
Publication year - 2020
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.202009092
Subject(s) - total synthesis , absolute configuration , chemistry , ligation , antibiotics , stereochemistry , peptide , combinatorial chemistry , mode of action , biochemistry , biology , microbiology and biotechnology
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.