Reexamination of sodium-liquid ammonia reduction in the peptide chemistry†

Abstract
Sodium-liquid ammonia reduction has been used for over 50 years for removal of benzyl-type protecting groups in peptide chemistry. Up until now a definitely blue end-point has generally been accepted for detection of the completion of reaction. Systematic investigation with model compounds has revealed that this is not only unnecessary for the complete removal of the protecting groups, but also that the application of Na in excess results in many undesired transformations which can simply be suppressed or even eliminated by optimizing the Na consumption. Cleavage of tert-butyloxycarbonyl group and N-C.alpha. bond, reduction of carboxamide groups to carbinol derivatives, transpeptidation and formation of a hydantoin derivative were observed in model experiments by using Na in excess.