A One-Pot Procedure for the Preparation ofN-9-Fluorenylmethyloxycarbonyl-α-amino Diazoketones from α-Amino Acids

Abstract

The study describes a new "one-pot" route to the synthesis of N-9-fluorenylmethyloxycarbonyl (Fmoc) α-amino diazoketones. The procedure was tested on a series of commercially available free or side-chain protected α-amino acids employed as precursors. The conversion into the title compounds was achieved by masking and activating the α-amino acids with a single reagent, namely, 9-fluorenylmethyl chloroformate (Fmoc-Cl). The resulting N-protected mixed anhydrides were reacted with diazomethane to lead to the α-amino diazoketones, which were isolated by flash column chromatography in very good to excellent overall yields. The versatility of the procedure was verified on lipophilic α-amino acids and further demonstrated by the preparation of N-Fmoc-α-amino diazoketones also from α-amino acids containing side-chain masking groups, which are orthogonal to the Fmoc one. The results confirmed that tert-butyloxycarbonyl (Boc), tert-butyl ((t)Bu), and 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl (Pbf), three acid-labile protecting groups mostly adopted in the solution and solid-phase peptide synthesis, are compatible to the adopted reaction conditions. In all cases, the formation of the corresponding C-methyl ester of the starting amino acid was not observed. Moreover, the proposed method respects the chirality of the starting α-amino acids. No racemization occurred when the procedure was applied to the synthesis of the respective N-Fmoc-protected α-amino diazoketones from L-isoleucine and L-threonine and to the preparation of a diastereomeric pair of N-Fmoc-protected dipeptidyl diazoketones.