Synthesis of Sequential Polypeptides Containing O‐Phospho‐L‐Serine

The chemistry of phosphoserine [Ser(P)] containing peptides and polypeptides was extensively investigated to explore a new biomineralization material science. The selective cleavage of the O,O′‐diphenyl phospho‐protecting groups of Ser(PO₃Ph₂) was examined using hydrogenolysis catalysts. Among the catalysts examined, only PtO₂ in 50% trifluoroacetic acid (TFA)/AcOH successfully cleaved the protecting group of Ser(PO₃Ph₂) to give Ser(P). Based on these characteristic new findings, Ser(P)‐containing dipeptides such as Gly‐Ser(P), Ala‐Ser(P), Ser‐Ser(P), Asp‐Ser(P), Glu‐Ser(P), and Lys‐Ser(P), and tetrapeptide [Asp‐Ser(P)]₂ were synthesized by a facile method. When we used the Ser(PO₃Ph₂) residues at the C terminals, the amino functional groups of amino acids and peptides can be coupled by the unsymmetric mixed anhydride using isobutyl chloroformate but cannot be by the symmetric anhydride method using dicyclohexylcarbodiimide. Neither unsymmetric mixed anhydride nor symmetric anhydride can be coupled with p‐nitrophenol at their C terminals. High‐molecular‐weight sequential polypeptides containing Ser(P) such as poly[Ser(P)‐Xaa] (Xaa: Gly, Ala, Ser, Lys, Asp, Glu) and poly[Gly‐Ser(P)‐Gly] were first synthesized by the polycondensation of the di‐ and tripeptide p‐nitrophenyl active esters, followed by the quantitative elimination of the diphenyl protecting groups by PtO₂ in TFA/AcOH. The new strategy to synthesize Ser(P)‐containing peptides and model proteins may help the development of hybrid formulations of marine and biomimetic protein minerals.