The Facile Synthesis of 2-(Fluorenylmethoxycarbonylamino)-4-(O′,O″-dimethylphosphono)-L-butanoic Acid {Fmoc-Abu(PO₃Me₂)-OH}

2-(Fluorenylmethoxycarbonylamino)-4-((O′,O″-dimethylphosphono)-L-butanoic acid (8) was prepared in high yield by an improved seven-step procedure which involved sodium borohydride reduction of Boc-Asp-OBu-t 1, TEMPO-catalysed hypochlorite oxidation of the alcohol 2 and phosphonylation of the aldehyde 3 with dimethyl trimethylsilylphosphite followed by in situ hydrolysis of the silyl group. Homolytic deoxygenation of the 3-hydroxy-4-dimethylphosphonate derivative 4 was effected by its treatment with phenyl chlorothionoformate/4-dimethylaminopyridine followed by treatment of the resultant xanthate 5 with tris(trimethylsilyl)silane/2,2′-azobisisobutyronitrile. The Boc and tert-butyl groups were cleaved from Boc-Abu(PO₃Me₂)-OBu-t 6 by acidolytic treatment with trifluoroacetic acid and the Fmoc group was finally introduced using fluorenylmethoxycarbonylsuccinimide to give Fmoc-Abu(PO₃Me₂)-OH 8 as a white foam in 50% overall yield.