Pd-catalyzed site-selective C(sp2)-H chalcogenation of amino acids and peptides using a picolinamide auxiliary

Chalcogenated amino acids/peptides have recently been considered as therapeutic drug candidates. This report describes a handy synthetic method for the Pd-catalyzed picolinamide-directed site-selective C(sp(2))-H chalcogenation of alpha-amino acids and peptides with diaryl disulfide and diselenide reagents. A variety of alpha-amino acids, benzylamines and phenethyl amines were chalcogenated in moderate to good yields with good selectivity. Importantly, this synthetic methodology has provided a late-stage peptide chalcogenation, for the first time to the best of our knowledge. Also, wide substrate scopes with sensitive functionalities, late-stage drug modification, various postsynthetic utilities including easy removal of the directing group, and synthesis of indoline were demonstrated as a result of systematic investigations carried out to assess the practical utility of the methodology. Hence, this synthetic methodology could be applied to the chalcogenation of target-specific aromatic amino acid and peptide derivatives for the development of therapeutic drug candidates.

Automated summary

This study presents a convenient synthetic method for the Pd-catalyzed picolinamide-directed site-selective C(sp(2))-H chalcogenation of alpha-amino acids and peptides. It has been successfully applied to the synthesis of a variety of alpha-amino acids, benzylamines, and phenethyl amines with moderate to good yields and good selectivity. Moreover, it allows for late-stage peptide chalcogenation and offers wide substrate scopes and various postsynthetic utilities.