A Novel Family of Onium Salts Based Upon Isonitroso Meldrum's Acid Proves Useful as Peptide Coupling Reagents

A new family of uronium salts (HTMU, HMMU, and HDmPyMU) based on isonitroso Meldrum's acid (HONM) are reported as stand‐alone coupling reagents. Amide bond formation with the use of these reagents occurred more quickly than that with other uronium salts as a result of the presence of a neighboring group effect with a cyclic structure. Thus, these novel onium salts were often more effective in the acylation of poor nucleophiles and in the control of optical purity than related Oxyma‐ and benzotriazole‐based reagents. Among the HONM derivatives, HMMU showed the best performance in reducing racemization and assembling demanding sequences such as the Aib‐ACP decapeptide or analogues of Leu‐enkephalin pentapeptide. Furthermore, the scope and limitations of the use of HONM as an additive in combination with carbodiimides is discussed. A new family of uronium salts (HTMU, HMMU, and HDmPyMU) has been successfully synthesized from the sodium salt of isonitroso Meldrum's acid (HONM). The dimethylmorpholino analogue HMMU especially shows promising results in reducing racemization and enhancing coupling extension with poor nucleophiles.