Ring Expansion of Thiolactams via Imide Intermediates: An Amino Acid Insertion Strategy

The Ag-I-promoted reaction of thiolactams with N-Boc amino acids yields an N-(alpha-aminoacyl) lactam that can rearrange through an acyl transfer process. Boc-deprotection results in convergence to the ring-expanded adduct, thereby facilitating an overall insertion of an amino acid into the thioamide bond to generate medium-sized heterocycles. Application to the site-specific insertion of amino acids into cyclic peptides is demonstrated.

Automated summary

The reaction of thiolactams with N-Boc amino acids promoted by Ag-I results in the formation of N-(alpha-aminoacyl) lactam, which can rearrange through an acyl transfer process. Deprotection of Boc leads to the ring expansion adduct, allowing for the insertion of an amino acid into the thioamide bond to generate medium-sized heterocycles. This method is demonstrated for the site-specific insertion of amino acids into cyclic peptides.