Preparation of 4-[Bis(<i>tert</i>-butoxy)phosphorylmethyl]-<i>N</i>-(fluoren-9-ylmethoxycarbonyl)-DL-phenylalanine. A Hydrolytically Stable Analogue of<i>O</i>-Phosphotyrosine Potentially Suitable for Peptide Synthesis

Abstract

Sodium methoxide catalyzed aldol condensation of ethyl α-azidoacetate with 4-[bis-(tert-butoxy)phosphorylmethyl]benzaldehyde (4) provides methyl α-azido-4-[bis(tert-butoxy)phosphorymethyl]cinnamate (5), which undergoes facile hydrogenation in the presence of 10% palladium on carbon to yield methyl 4-[bis(tert-butoxy)phosphorylmethyl]-DL-phenylalaninate (6). Hydrolysis of the methyl ester by brief treatment 1N sodium hydroxide in dioxane, followed by reaction with 1-benzotriazolyl 9-fluorenylmethyl carbonate (Fmoc-OBT) at pH 8 cleanly provides 4-[bis(tert-butoxy) phosphorylmethyl]-N-Fmoc-DL-phenylalanine (3), an orthogonally protected derivative potentially suitable for utilization in the synthesis of peptides containing a hydrolytically stable mimetic of O-phosphotyrosine.