title: α-N-Protected dipeptide acids: a simple and efficient synthesis via the easily accessible mixed anhydride method using free amino acids in DMSO and tetrabutylammonium hydroxide.
abstract: The importance of dipeptides both in medicinal and pharmacological fields is well documented and many efforts have been made to find simple and efficient methods for their synthesis. For this reason, we have investigated the synthesis of α-N-protected dipeptide acids by reacting the easily accessible mixed anhydride of α-N-protected amino acids with free amino acids under different reaction conditions. The combination of TBA-OH and DMSO has been found to be the best to overcome the low solubility of amino acids in organic solvents. Under these experimental conditions, the homogeneous phase condensation reaction occurs rapidly and without detectable epimerization. The present method is also applicable to side-chain unprotected Tyr, Trp, Glu, and Asp but not Lys. This latter residue is able to engage two molecules of mixed anhydride giving the corresponding isotripeptide. Moreover, the applicability of this protocol for the synthesis of tri- and tetrapeptides has been tested. This approach reduces the need for protecting groups, is cost effective, scalable, and yields dipeptide acids that can be used as building blocks in the synthesis of larger peptides.
authors.affiliation: Dipartimento di Chimica, Fisica e Ambiente, Università di Udine, Via del Cotonificio 108, I-33100 Udine, Italy. giancarlo.verardo@uniud.it
authors.forename: G
authors.initials: G
authors.lastname: Verardo
authors.forename: A
authors.initials: A
authors.lastname: Gorassini
mesh_terms: D000596:Amino Acids / Q000737:chemistry*; D000812:Anhydrides / Q000737:chemistry*; D002851:Chromatography, High Pressure Liquid; D004121:Dimethyl Sulfoxide / Q000737:chemistry; D004151:Dipeptides / Q000138:chemical synthesis* / Q000737:chemistry; D005449:Fluorenes / Q000737:chemistry; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry; D000644:Quaternary Ammonium Compounds / Q000737:chemistry
chemical_list: D000596:Amino Acids; D000812:Anhydrides; D004151:Dipeptides; D005449:Fluorenes; D010455:Peptides; D000644:Quaternary Ammonium Compounds; C009405:tetrabutylammonium; D004121:Dimethyl Sulfoxide