SYNTHESIS OF O-PHOSPHOSERINE-CONTAINING PEPTIDES BY SOLUTION-PHASE AND SOLID-PHASE METHODS

The preparation of Ser(P)-containing peptides is described by the use of either (a) a 'global phosphite-triester phosphorylation' approach which uses dialkyl N,N- dialkylphosphoramidites or by (b) a more general approach which utilizes protected Boc-Ser(PO3R2)-OH derivatives in the Boc mode of solution or solid phase peptide synthesis. In the first approach, a protected Ser-containing peptide is synthesized and phosphorylated using dibenzyl or di-t-butyl N,N-diethylphosphoramidite/1H-tetrazole followed by oxidation of the resultant 'phosphite-triester' intermediate. The cleavage of benzyl phosphate groups is effected by hydrogenolysis while t-butyl phosphate groups are cleaved by mild acidolytic treatment. In the second and more efficient approach, various Boc-Ser(PO3R2)-OH derivatives are prepared from Boc-Ser-OH by a high yielding three step route using either the phosphorotriester or 'phosphite-triester' phosphorylation procedures. The benzyl derivative, Boc-Ser(PO3Bzl2)-OH, has been used for the synthesis of Ser(PO3Bzl2)-containing peptides followed by a final palladium-catalyzed deprotection step. However, this derivative has restricted use in peptide synthesis due to the susceptibility of benzyl phosphate groups to acidolytic treatments used for Boc-cleavage. The phenyl derivative, Boc-Ser(PO3Ph2)-OH, has been used for the synthesis of several complex Ser(PO3Ph2)-containing peptides with complete cleavage of the phenyl groups effected by platinum oxide-mediated hydrogenation. This derivative has also been used in solid phase methodology for the synthesis of various simple Ser(P)-containing peptides.