Iodine-catalyzed green and efficient synthesis of secondary and tert-esters of N-acetyl-protected amino acids

Abstract

Esterification of amino acids is a critical transformation in synthetic and peptide chemistry. In this study, a green and effective I₂-catalyzed method was developed for the esterification of N-acetyl protected amino esters and their hydrolysis. It is an environmentally friendly protocol that uses a less amount of catalyst, and does not require strong mineral acid or metal-based reagents, making it especially appealing as a synthesis protocol in synthetic and peptide chemistry. Primary and secondary esters were synthesized effectively in excellent yield, while tert-butyl esters were obtained in up to 80% yield using 4 mol% I₂ and 0.02 mg (0.55 × 10⁻³ mol%) of DMAP as a co-catalyst. In addition to ester formation, the system enables selective de-esterification of tert-butyl esters using a minimum amount of I₂ (0.03 mg) with 100% conversion to corresponding N-acetylated amino acids. This dual catalytic approach of I₂ in both the introduction and deprotection sequences introduces a practical and sustainable alternative to conventional acid-mediated processes. This strategy highlights the versatility of I₂ as an inexpensive, metal-free, and environmentally benign catalyst, and may inspire further exploration of Lewis acid-based catalysis in green amino acid and peptide chemistry.