Facile Approach to Enantiomerically Pure α-Amino Ketones by Friedel−Crafts Aminoacylation and Their Conversion into Peptidyl Ketones

Abstract

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.

Liquid chromatographic enantioseparation of aryl?-amino ketones on a crown ether-based chiral stationary phase

“…Sulphuric acid (H 2 SO 4 ) was from Matsunoen Chemicals (Osaka, Japan) and perchloric (HClO 4 ) and acetic acid (CH 3 COOH) were from Junsei Chemicals (Tokyo, Japan). Racemic and optically active α-amino ketones 2-13 were prepared from corresponding racemic and optically active α-amino acids via the known procedure (Itoh et al, 1992;Gioia et al, 2001).…”

“…Previously, various efforts have been devoted to the development of effective methods for the synthesis of optically active aryl α-amino ketones including cathinone (2) (Itoh et al, 1992;Gioia et al, 2001). Efforts have also been devoted to the chromatographic resolution of racemic cathinone.…”

Liquid chromatographic direct resolution of aryl α-amino ketones on a residual silanol group-protecting chiral stationary phase based on optically active (3,3′-diphenyl-1,1′-binaphthyl)-20-crown-6☆

“…1) prepared from the corresponding ␣-amino acids were available from a prior study [18]. Injection samples were prepared by dissolving each of racemic and optically active aryl ␣-amino ketones (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14) in water (usually 2.5 mg/ml). The usual injection volume was 3.0 l. For the loading capacity study, the same chromatography system with a 500 l sample loop was used and the injection sample was prepared by dissolving 5.0 mg of racemic cathinone (3) in 1.0 ml of water.…”

“…CSP 2 was applied to the resolution of cathinone (3) and its analogue aryl ␣-amino ketones (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14). The chromatographic results on CSP 2 are summarized and compared to those on CSP 1 in Table 1.…”

“…Several effective methods have been developed for the synthesis of optically active aryl ␣-amino ketones [7,8]. For the exact determination of the enantiomeric composition of optically active compounds, liquid chromatographic chiral stationary phase (CSP) methods are known to be the most accurate and convenient and, consequently, various CSPs have developed and applied to the resolution of racemic compounds [9,10].…”