Synthesis of β-Thiolated Amino Acids: Investigation Toward the Total Chemical Synthesis of Lasso Peptide Microcin J25

Microcin J25 (MccJ25) is of special interest due to its "lariat" topology. The lasso architecture is thought to be responsible for its remarkable thermal stability (100°C for 30 min incubation) and potency against Gram-negative bacteria (i.e., MBC of ~4.75 µM against E. coli strain DH5α). This naturally occurring lasso peptide is formed via post-translational modifications (PTMs), including leader peptide removal and macrolactam cyclization between the N-terminus and 8-Glu side chain. Since the discovery of MccJ25 in 1992, synthetic endeavors toward the total chemical synthesis of MccJ25 have remained elusive. Herein, we investigated the chemical synthesis of MccJ25 utilizing β-thiol amino acids as the chemical tools to prestaple and rigidify the peptide backbone through disulfide linkages. Although the proposed chemical strategy failed to afford the desired lasso configuration, synthetic routes toward Fmoc-SPPS compatible, stereoselective β-thiol amino acids via thiazoline derivatives were developed. In addition, chemical/biochemical literature synthesis of MccJ25 and its analogs, as well as the synthesis of β-thiol amino acids, are summarized within.