Review: 246 refs.

Here we present a new formulation of the recently introduced OxymaPure additive for peptide bond formation, in which the N‐hydroxylamine group is replaced by a potassium salt. The complete suppression of its acidity converts K‐Oxyma into the most suitable coupling choice when peptides are assembled on highly acid‐labile solid‐supports. The coupling efficiency and diminished prospects for epimerization are conserved relative to OxymaPure. In addition, K‐Oxyma displays excellent solubility in a variety of organic solvents and undergoes safer decomposition than classical 1‐hydroxybenzotriazole additives.

The methodology for peptide bond formation is undergoing a continuous evolution where the main actors are being renewed. In recent years, coupling reagents based on the Oxyma scaffold, such as the uronium salt COMU, has been a groundbreaking contribution to the field. The advantages of COMU over classic benzotriazole-based reagents (HATU, HBTU, HCTU, TBTU) were proven in terms of solubility and coupling efficiency in bulky junctions in our groups and others. However, some aspects of the use of COMU need to be revised and improved, such as the stability of commercial samples in organic solvents, which hampers the compatibility with long synthesis in automated synthesizers. In this review, an overview of the main features and suggestions to improve the use of COMU are presented, along with a discussion on the best conditions for its use in microwave-assisted peptide robots.