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

Terrence R. Burke Jr; Pamela Russ; Benjamin Lim

doi:10.1055/s-1991-26636

Synthesis 1991; 1991(11): 1019-1020
DOI: 10.1055/s-1991-26636

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

Terrence R. Burke, Jr.^* , Pamela Russ, Benjamin Lim

^*Laboratory of Medicinal Chemistry, Developmental Therapeutics Program, Division of Cancer Treatment, Building 37, Rm 5C06, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA

Abstract

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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.

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