Pd-catalyzed site-selective C(sp(2))-H chalcogenation of amino acids and peptides using a picolinamide auxiliary

• Published in: ORGANIC CHEMISTRY FRONTIERS Vol. 10; no. 5; pp. 1252 - 1262
• Main Authors: Bag, Raghunath, Sharma, Nagendra K.
• Format: Journal Article
• Language: English
• Published: CAMBRIDGE Royal Soc Chemistry 28.02.2023; Royal Society of Chemistry
• Subjects: Amines; Amino acids; Chemistry; Chemistry, Organic; Drug development; Methodology; Organic chemistry; Palladium; Peptides; Physical Sciences; Reagents; Science & Technology; Selectivity; Substrates; DIRECTING GROUP; FUNCTIONALIZATION; UNACTIVATED C(SP)-H BONDS; PALLADIUM; ACTIVATION; INTERMOLECULAR SILYLATION; ARYLATION; SULFENYLATION; ARYL; C-H BONDS
• ISSN: 2052-4129; 2052-4110; 2052-4110
• DOI: 10.1039/d2qo01876d

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.