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 sodium in excess results in many undesired transformations which can simply be suppressed or even eliminated by optimizing the sodium consumption.
Cleavage of tert. ‐butyloxycarbonyl group and N‐Cα bond, reduction of carboxamide groups to carbinol derivatives, transpeptidation and formation of a hydantoin derivative have been observed in model experiments by using sodium in excess.
Basic conditions (e.g. piperidinolysis), used for the removal of the N~-9-fluorenylmethyloxycarbonyl group, lead to significant cleavage of side-chain benzyl esters of peptides containing benzylaspartyl residues both in solution and solid-phase syntheses; the intermediate imide derivative is slowly transformed to a mixture of piperidides.Recently a synthesis of thymosin-a, onp-nitrobenzhydrylamine resin was reported,l using benzyl esters for protection of sidechain carboxy groups. The temporary N"-9-fluorenylmethoxy-carb0ny1~9~ (Fmoc) protecting group was removed by piperidinolysis. During the purification of the crude thymosin-cc,, fractions corresponding to minor peaks in the elution profile obtained from DEAE-Sephadex A-25 column chromatography were shown to contain materials which could not be completely digested with leucine-aminopeptidase, suggesting that undesired reactions may have occurred during the synthesis.Knowing the general base-sensitivity of p-esters of aspartyl pep tide^^-^ we have examined the possibility that the repeti-
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