Synthesis of Casein-Related Peptides and Phosphopeptides. VII. The Efficient Synthesis of Ser(P)-Containing Peptides by the Use of Boc-Ser(PO3R2)-OH Derivatives

Abstract

A new approach to the synthesis of Ser(PO3R2)-containing peptides by using five protected Boc-Ser(PO3R2)-OH (R=phenyl, ethyl, methyl, benzyl, t-butyl) derivatives is described. The five Boc-protected derivatives are prepared by a simple three-step synthetic procedure which features the use of either (A) diphenyl or dialkyl phosphorochloridate/pyridine, or (B) dialkyl N,N-diethylphosphoramidite/1H-tetrazole-m-chloroperoxybenzoic acid for the phosphorylation of the serine hydroxy group. The five derivatives were utilized in the Boc mode of peptide synthesis with the use of the mixed-anhydride coupling procedure, and led to the synthesis of the protected tripeptides, Boc-Glu(OBzl)-Ser(PO3R2)-Leu-OBzl, in high yield and purity. In peptide deprotection studies, the phenyl and benzyl phosphate protecting groups were readily removed from the protected Ser(PO3Ph2) and Ser(PO3Bzl2) tripeptides by hydrogenolysis and gave Glu-Ser(P)-Leu in near quantitative yield. The t-butyl phosphate groups were cleaved from the Ser(PO3But2) dipeptide by mild acidolysis and gave Ser(P)-Leu in quantitative yield. However, attempts to cleave the ethyl or methyl phosphate groups by acidolytic or silylitic treatment of the Ser(PO3Et2) and Ser(PO3Me2) tripeptides resulted in decomposition of the O-phosphoseryl residue.