The study describes a new "one-pot" route to the synthesis of N-9-fluorenylmethyloxycarbonyl (Fmoc) alpha-amino diazoketones. The procedure was tested on a series of commercially available free or side-chain protected alpha-amino acids employed as precursors. The conversion into the title compounds was achieved by masking and activating the alpha-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 alpha-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 alpha-amino acids and further demonstrated by the preparation of N-Fmoc-alpha-amino diazoketones also from alpha-amino acids containing side chain masking groups, which are orthogonal to the Fmoc one The results confirmed that tert-butyloxycarbonyl (Boc), tert-butyl (Bu-t), 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 alpha-amino acids. No racemization occurred when the procedure was applied to the synthesis of the respective N-Fmoc-protected alpha-amino diazoketones from L-isoleucine and L-threonine and to the preparation of a diastereomeric pair of N-Fmoc-protected dipeptidyl diazoketones.

A one-pot procedure for the preparation of N-9-fluorenylmethoxycarbonyl-alpha-amino diazoketones

LIGUORI, Angelo
2012

Abstract

The study describes a new "one-pot" route to the synthesis of N-9-fluorenylmethyloxycarbonyl (Fmoc) alpha-amino diazoketones. The procedure was tested on a series of commercially available free or side-chain protected alpha-amino acids employed as precursors. The conversion into the title compounds was achieved by masking and activating the alpha-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 alpha-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 alpha-amino acids and further demonstrated by the preparation of N-Fmoc-alpha-amino diazoketones also from alpha-amino acids containing side chain masking groups, which are orthogonal to the Fmoc one The results confirmed that tert-butyloxycarbonyl (Boc), tert-butyl (Bu-t), 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 alpha-amino acids. No racemization occurred when the procedure was applied to the synthesis of the respective N-Fmoc-protected alpha-amino diazoketones from L-isoleucine and L-threonine and to the preparation of a diastereomeric pair of N-Fmoc-protected dipeptidyl diazoketones.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/20.500.11770/148067
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