Synthesis of secondary difluoromethylphosphonate-contaning amino acid and its biological examination

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Phosphorylation and dephosphorylation of proteins serve as post-translational modifications that are critical for intracellular signal transudation. Therefore, nonhydrolyzable phosphoamino acid mimetic-containing peptides have gained much attention as useful agents for exploring signaling events. Among various nonhydrolyzable phosphoamino acid analogs, those employing the difluoromethylene unit (CF2) as a replacement for the phosphoryl ester oxygen have shown particular utility. We have already achieved the synthesis of CF2-substituted pTyr and pSer mimetics; however, synthesis of 2-amino-4, 4-difluoro-3-methy1-4-phosphonobutanoic acid (F2Pmab) as a CF2-substituted pThr mimetic was lacing. In this study, we accomplished the preparation of racemic protected F2Pmab by CeCl3-mediated conjugate addition of diethyl difluoromethylphosphonate anion onto a nitroalkene. Furthermore, we accomplished the stereoselective synthesis of all four F2Pmab isomers by applying Cu-mediated coupling reaction of (diethylphosphonodifluoromethyl) -zinc bromide with β-iodo-α, β- unsatureted carboxylic acid derivatives, followed by diastereoselective hydrogenation and amination with the aid of a chiral auxiliary. The protected amino acid derivative was successfully incorporated into peptides using a two-step deprotection methodology consisting of high acidic-and low acidic reagents. For high acidic reagents, 1 M TMSOTf-thioanisole in TFA system was used, and 0.3 M