Synthesis of Monobactam Antibiotic LYS228
Process Development for the Synthesis of a Monobactam Antibiotic – LYS228.
Org. Process Res. Dev. 2020;
15 May 2020 (online)
Key wordsLYS228 - monobactam antibiotic - asymmetric synthesis - [2+2] cycloaddition - Staudinger β-lactam synthesis
LYS228 is a monobactam antibiotic that inhibits cell-wall synthesis in Gram-negative bacteria through covalent modification of the active-site serine of penicillin-binding protein 3. It is active in vitro and in vivo against Enterobacteriaceae, and it is stable to most serine-β-lactamases and all metallo-β-lactamases profiled to date.
The key step in the manufacturing process for LYS228 depicted is the asymmetric Staudinger β-lactam synthesis involving a [2+2] cycloaddition of a ketene derived from C with aldimine B derived from (S)-glyceraldehyde acetonide A (C. Hubschwerlen, J.-L. Specklin Org. Synth. 1995, 72, 14). For the discovery synthesis, see: Bioorg. Med. Chem. Lett. 2018, 28, 7748.