Synthesis and Application of Fmoc-O-[bis(dimethylamino)pbosphono]-tyrosine, a Versatile Protected Phosphotyrosine Equivalent

摘要

The discovery of SH2 domains in proteins and their interactions with phosphotyrosine motifs in signal trans-duction pathways presents an opportunity to develop new anticancer therapeutic agents. To understand protein-protein interactions that propagate signal transduction at the molecular level, the use of phosphotyrosine-concdining peptides has become the favored approach owing to their well-defined structures and their increasing ease of synthesis. Recently, we reported the synthesis of the (methyldiphenylsilyl)ethyl (MDPSE)-protected Fmoc-phosphotyrosine derivative and its use to make phosphopeptidea, all in good yields and high purity. In this paper, we describe the development of a different and perhaps more versatile building block, Fmoc-O-[bis-(dimethylamino)phosphono]tyrosine (8), for .the preparation of peptides containing phosphotyroshie or one of its analogs. The chemistry underlying the O-[bis(dimeth-ylamino)phosphono]tyrosine protection strategy was mod-eled upon hydrolytic lability of the P-N bond under acidic conditions.