Peptide coupling methods derived from onium salts based on 1-hydroxybenzotriazole (HOBt) and
1-hydroxy-7-azabenzotriazole (HOAt) are becoming incorporated in synthetic strategies more
frequently than the classical carbodiimide methods. We have correlated the reactivity of various
onium salts derived from HOXt (X = A, B), with the structure of the reagents in question. Thus,
we confirmed that the aza derivatives are more reactive than the parent benzotriazole derivatives
in both activation and coupling. In addition, the activation step is determined by the structure of
the carbon skeleton. Thus, pyrrolidino derivatives appear to be reagents of choice relative to the
piperidino analogues or those derived from trialkylamines. Furthermore although phosphonium
salts are slightly less reactive than the corresponding aminium/uronium salts, the former should
be used for the activation of hindered species, since the latter may lead to the formation of guanidino
derivatives.
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