tert-Butylethylcarbodiimide as an Efficient Substitute for Diisopropylcarbodiimide in Solid-Phase Peptide Synthesis: Understanding the Side Reaction of Carbodiimides with OxymaPure

• Published in: Organic process research & development Vol. 26; no. 10; pp. 2894 - 2899
• Main Authors: Manne, Srinivasa Rao, Akintayo, Damilola Caleb, Luna, Omar, El-Faham, Ayman, de la Torre, Beatriz G., Albericio, Fernando
• Format: Journal Article
• Language: English
• Published: American Chemical Society 21-10-2022
• Subjects: oxadiazine; oxadiazole; racemization; carbodiimides; OxymaPure
• ISSN: 1083-6160; 1520-586X
• DOI: 10.1021/acs.oprd.2c00220

The undesired reaction between carbodiimides (peptide coupling reagent) and OxymaPure (peptide coupling additive), which takes place in very low extension during peptide bond formation, is dependent on the steric hindrance around the carbodiimide backbone. Carbodiimides containing tertiary substituents on N such as di-tert-butylcarbodiimide do not activate the carboxylic group properly; the presence of secondary substituents such as in the case of diisopropylcarbodiimide (DIC) leads to the formation of oxadiazole and HCN; finally, primary substituents render an adduct of oxadiazine and no formation of HCN. tert-Butylethylcarbodiimide (TBEC), which is a hybrid of primary and tertiary substituents, leads to the formation of oxadiazine with no concomitant formation of HCN. Furthermore, TBEC outperforms DIC in terms of yield and minimization of racemization as it is demonstrated herein.