Abstract
Chiral N-protected α-amino aryl-ketones are one of the useful precursors used in the synthesis of various biologically active compounds and can be constructed via Friedel–Crafts acylation of N-protected α-amino acids. One of the drawbacks of this reaction is the utilization of toxic, corrosive and moisture-sensitive acylating reagents. In peptide construction via amide bond formation, N-hydroxysuccinimide ester (OSu), which has high storage stability, can react rapidly with amino components and produces fewer side reactions, including racemization. This study reports the first synthesis and utilization of N-trifluoroacetyl (TFA)-protected α-amino acid-OSu as a potential acyl donor for Friedel–Crafts acylation into various arenes. The TFA-protected isoleucine derivative and its diastereomer TFA-protected allo-isoleucine derivative were investigated to check the retention of α-proton chirality in the Friedel–Crafts reaction. Further utilization of OSu in other branched-chain and unbranched-chain amino acids results in an adequate yield of TFA-protected α-amino aryl-ketone without loss of optical purity.
Highlights
Chiral N-protected α-amino aryl-ketone are usually used as a precursor in the synthesis of various biologically active compounds [1,2]
We demonstrated the utility of optically active isoleucine, which has two chiral centers in the molecules, and its diastereomer allo-isoleucine to identify chilarity of the Friedel–Crafts acylation product’s α-proton by nuclear magnetic resonance (NMR)
As for chiral N-protected α-amino aryl-ketone synthesis, especially the reaction involving direct acylation of α-amino acids, the product’s chirality is commonly determined by complexation with a chiral shift reagent [7]. This racemic α-amino aryl-ketone can be detected by the appearance of two separated proton signals by NMR
Summary
Chiral N-protected α-amino aryl-ketone are usually used as a precursor in the synthesis of various biologically active compounds [1,2]. The α-amino acid chloride [1,2,7,8] is widely used as an acyl donor to undergo Friedel–Crafts acylation due to its reactivity. This acyl donor is unstable, sensitive to moisture and difficult to handle [9]. It should be used instantly and cannot be stored. Α-amino acid anhydride can be employed as an acylating agent and can be used to obtain the α-amino aryl-ketone without the N-protecting group
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