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 app roach to chiral aryl alpha -amino ketones via a Friedel-Crafts-type reactio n of stable and enantiomerically pure N-Fmoc protected L-amino acid chlorid es with toluene in the presence of aluminum trichloride. The developed meth odology provided aryl alpha -amino-p-methylphenyl ketones, which can be obt ained 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-fluorenylmethoxycarbo nyl protecting group. The Friedel-Crafts-like process and the cleavage of t he amino function masking group can selectively be performed since, as veri fied in all cases, the oc-aminoacylation step occurred with kinetics that w ere faster than those required to remove the N-protection. The presented ap proach was also explored as a facile and useful synthetic tool for the prep aration of optically pure ketone di- and tripeptides. These compounds can b e obtained in exceptionally overall yields without need of chromatographic purification. Moreover, either aryl alpha -amino ketones or modified di- an d tripeptides, in all cases, can be isolated in very high chemical and opti cal purity without recourse to resolution of diastereomeric mixtures, since the chiralities of the asymmetric amino acid educts were completely conser ved throughout the entire process.