Facile approach to enantiomerically pure alpha-amino ketones by Friedel-Crafts aminoacylation and their conversion into peptidyl ketones.
In this article we describe a versatile and straightforward preparative approach to chiral aryl alpha-amino ketones via a Friedel-Crafts-type reaction of stable and enantiomerically pure N-Fmoc protected L-amino acid chlorides with toluene in the presence of aluminum trichloride. The developed methodology provided aryl alpha-amino-p-methylphenyl ketones, which can be obtained and isolated as free bases or recovered as their N-acetyl derivatives, after treatment with acetic anhydride in chloroform at room temperature, subsequent to the Lewis acid induced removal of the 9-fluorenylmethoxycarbonyl protecting group. The Friedel-Crafts-like process and the cleavage of the amino function masking group can selectively be performed since, as verified in all cases, the alpha-aminoacylation step occurred with kinetics that were faster than those required to remove the N-protection. The presented approach was also explored as a facile and useful synthetic tool for the preparation of optically pure ketone di- and tripeptides. These compounds can be obtained in exceptionally overall yields without need of chromatographic purification. Moreover, either aryl alpha-amino ketones or modified di- and tripeptides, in all cases, can be isolated in very high chemical and optical purity without recourse to resolution of diastereomeric mixtures, since the chiralities of the asymmetric amino acid educts were completely conserved throughout the entire process.
Di Gioia
M L
ML
Dipartimento di Chimica, Università degli Studi della Calabria, Via Ponte P. Bucci, Cubo 15/C, I-87030 Arcavacata di Rende (CS), Italy.
Leggio
A
A
Liguori
A
A
Napoli
A
A
Siciliano
C
C
Sindona
G
G
D004151:Dipeptides / Q000138:chemical synthesis; D007659:Ketones / Q000138:chemical synthesis* / Q000737:chemistry; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism
D004151:Dipeptides; D007659:Ketones; D010455:Peptides