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

摘要

The study describes a new “one-pot” route tonthe synthesis of N-9-fluorenylmethyloxycarbonyl (Fmoc) α-namino diazoketones. The procedure was tested on a series ofncommercially available free or side-chain protected α-aminonacids employed as precursors. The conversion into the titlencompounds was achieved by masking and activating the α-namino acids with a single reagent, namely, 9-fluorenylmethylnchloroformate (Fmoc-Cl). The resulting N-protected mixednanhydrides were reacted with diazomethane to lead to the α-namino diazoketones, which were isolated by flash columnnchromatography in very good to excellent overall yields. The versatility of the procedure was verified on lipophilic α-amino acidsnand further demonstrated by the preparation of N-Fmoc-α-amino diazoketones also from α-amino acids containing side-chainnmasking groups, which are orthogonal to the Fmoc one. The results confirmed that tert-butyloxycarbonyl (Boc), tert-butyl (tBu),nand 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl (Pbf), three acid-labile protecting groups mostly adopted in the solutionnand solid-phase peptide synthesis, are compatible to the adopted reaction conditions. In all cases, the formation of thencorresponding C-methyl ester of the starting amino acid was not observed. Moreover, the proposed method respects the chiralitynof the starting α-amino acids. No racemization occurred when the procedure was applied to the synthesis of the respective NFmoc-nprotected α-amino diazoketones from L-isoleucine and L-threonine and to the preparation of a diastereomeric pair of NFmoc-nprotected dipeptidyl diazoketones.