1. Lewis acid catalysed methylation of N-(9H-fluoren-9-yl)methanesulfonyl (Fms) protected lipophilic α-amino acid methyl esters
Antonella Leggio, Danila Alò, Emilia Lucia Belsito, Maria Luisa Di Gioia, Emanuela Romio, Carlo Siciliano, Angelo Liguori J Pept Sci. 2015 Aug;21(8):644-50. doi: 10.1002/psc.2777. Epub 2015 Apr 28.
This work reports an efficient Lewis acid catalysed N-methylation procedure of lipophilic α-amino acid methyl esters in solution phase. The developed methodology involves the use of the reagent system AlCl3/diazomethane as methylating agent and α-amino acid methyl esters protected on the amino function with the (9H-fluoren-9-yl)methanesulfonyl (Fms) group. The removal of Fms protecting group is achieved under the same conditions to those used for Fmoc removal. Thus the Fms group can be interchangeable with the Fmoc group in the synthesis of N-methylated peptides using standard Fmoc-based strategies. Finally, the absence of racemization during the methylation reaction and the removal of Fms group were demonstrated by synthesising a pair of diastereomeric dipeptides.
2. A one-pot procedure for the preparation of N-9-fluorenylmethyloxycarbonyl-α-amino diazoketones from α-amino acids
Carlo Siciliano, Rosaria De Marco, Ludovica Evelin Guidi, Mariagiovanna Spinella, Angelo Liguori J Org Chem. 2012 Dec 7;77(23):10575-82. doi: 10.1021/jo301657e. Epub 2012 Nov 16.
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.
3. An efficient and highly selective deprotection of N-Fmoc-alpha-amino acid and lipophilic N-Fmoc-dipeptide methyl esters with aluminium trichloride and N,N-dimethylaniline
M L Di Gioia, A Leggio, A Le Pera, C Siciliano, A Liguori, G Sindona J Pept Res. 2004 Apr;63(4):383-7. doi: 10.1111/j.1399-3011.2004.00104.x.
A novel procedure for the deprotection of the carboxyl group of amino acid methyl esters is presented. The process is carried out by the reagent system aluminium trichloride/N,N-dimethylaniline that can successfully be applied to unblock the carboxyl moiety either of N-Fmoc-protected amino acid methyl esters and N-Fmoc-protected short dipeptide methyl esters. The chiralities of the optically pure amino acid or peptide precursors are maintained totally unchanged.