Synthesis of Casein-Related Peptides and Phosphopeptides. IX. A Modified Method for the Synthesis of Ser(P) Peptides by Using Ppoc-Ser(PO₃bzl₂)-OH

Abstract

Benzyl phosphate groups were found to be sensitive to acid conditions, and a stability study with dibenzyl isobutyl phosphate under various acid conditions is described. While extensive acidolytic debenzylation of the dibenzyl phosphorotriester occurred on treatment with either 4 M hydrogen chloride/ dioxan or 50% trifluoroacetic acid/dichloromethane, only minor benzyl loss occurred with the use of formic acid or 1 M hydrogen chloride/acetic acid. Minimization of benzyl phosphate loss during the synthesis of a Ser(PO₃Bzl₂)-containing tripeptide was effected by the use of 98% formic acid (or 1 M hydrogen chloride/acetic acid) for the cleavage of the Boc group from Boc -Ser(PO₃Bzl₂)- Leu-OBzl . In an alternative procedure, the protected 2-phenylisopropyloxycarbonyl derivative, Ppoc -Ser(PO₃Bzl₂)-OH was prepared by an efficient four-step procedure and was used in a solution-phase peptide synthesis for the high yielding preparation of Boc-Glu ( OBzl )-Ser(PO₃Bzl₂)- Leu-OBzl . The protected Ser(PO₃Bzl₂) tripeptide was deprotected by palladium- catalysed hydrogenolysis in formic acid and gave Glu -Ser(P)-Leu in near-quantitative yield.