The diisopropylcarbodiimide/1-hydroxy-7-azabenzotriazole system: Segment coupling and stepwise peptide assembly

For a group of model peptide segments, coupling reactions carried out via s olution or solid phase techniques have demonstrated the advantages of the s ystem DIC/HOAt over DIC/HOBt and in addition for systems involving other se lected carbodiimides and substituted HOBt derivatives bearing electron-with drawing substituents. Very little, if any, loss of configuration occurred i n DCM regardless of the additive used, although the relative order of effic iency was similar in solvents such as DMF in which more extensive epimeriza tion resulted. In application of DIC/HOAt to stepwise peptide assembly by s olid phase techniques, it was found that the hindered pyridine base collidi ne enhanced the step involving preactivation of the carboxylic acid residue in contrast to the normal situation in which bases such as DIEA, NMM, or n on-hindered pyridine bases inhibit this step. These results led to developm ent of a stepwise procedure for peptide assembly in which collidine is adde d to enhance activation and subsequently DIEA is added to enhance coupling, (C) 1999 Elsevier Science Ltd. All rights reserved.