The present review offers an overview of nonclassical (e.g., with no pre- or in situ activation of a carboxylic acid partner) approaches for the construction of amide bonds. The review aims to comprehensively discuss relevant work, which was mainly done in the field in the last 20 years. Organization of the data follows a subdivision according to substrate classes: catalytic direct formation of amides from carboxylic and amines ( section 2 ); the use of carboxylic acid surrogates ( section 3 ); and the use of amine surrogates ( section 4 ). The ligation strategies (NCL, Staudinger, KAHA, KATs, etc.) that could involve both carboxylic acid and amine surrogates are treated separately in section 5 .

A mild, practical, and simple procedure for peptide-bond formation is reported. Instead of activation of the carboxylic acid functionality, the reaction involves an unprecedented use of activated α-aminoesters. The method provides a straightforward entry to dipeptides and was effective when a sensitive cysteine residue was used, as no epimerization was detected in this case. The applicability of this method to iterative peptide synthesis was illustrated by the synthesis of a model tetrapeptide in the challenging reverse N→C direction.

5-Substituted-3-(alkoxycarbonyl)alkyl-hydantoin derivatives were prepared by mechanochemistry from amino esters or dipeptides, via a 1,1'-carbonyldiimidazole-mediated one-pot/two-step cyclization reaction involving amino acid unsymmetrical urea A and carboxy-imidazolyl-dipeptide ester B intermediates. Comparative experiments in solution were also performed. The successful preparation of an antibacterial agent precursor was also investigated.