Synthetic fermentation of β-peptide macrocycles by thiadiazole-forming ring-closing reactions

Abstract

Macrocyclic β-peptides were efficiently prepared using a thiadiazole-forming cyclization reaction between an α-ketoacid and a thiohydrazide. The linear β-peptide precursors were assembled from isoxazolidine monomers by α-ketoacid-hydroxylamine (KAHA) ligations with a bifunctional initiator – a process we have termed ‘synthetic fermentation’ due to the analogy of producing natural product-like molecules from simpler building blocks. The linear synthetic fermentation products underwent Boc-deprotection/thiadiazole-forming macrocyclization under aqueous, acidic conditions to provide the cyclic products in a one-pot process. This reaction sequence proceeds from easily accessed initiator and monomer building blocks without the need for additional catalysts or reagents, enabling facile production of macrocyclic β-peptides, a relatively underexplored structural class.