An improved approach to the synthesis of N-acyl-alpha,alpha-dialkyl glycines and their esters and amides using Ugi’s four-component reaction

Abstract

Owing to steric hindrance, syntheses of and reactions with alfa,alfa-dialkylglycines are very slow; thus, most methods of peptide synthesis are of little use to handle these compounds when the alfa-alkyl groups are larger than methyl. Ugi’s four-component reaction is appropriate to synthesise these amino acids [1], but for peptide synthesis it presents two drawbacks, i.e. (i) peptide isonitriles racemise above –20 ºC and (ii) an unavoidable alkyl group in the reaction product needs to be cleaved [2]. Reactions with alfa,alfa-dialkylglycines are too slow to allow performing them at –20 ºC. Isonitriles have been devised to allow mild cleavage of the amide bond at the C-terminus of the Ugi adduct, but in alfa,alfa-dialkylglycine derivatives the amide bond generated by the isonitrile is sufficiently labile [3] to allow mild cleavage. Thus, as shown in the scheme below, we devised a simple and fairly efficient approach to routine synthesis of peptides containing alfa,alfa-dialkylglycine residues, using commercially available reagents.