Synthesis of Chiral TFA-Protected α-Amino Aryl-Ketone Derivatives with Friedel–Crafts Acylation of α-Amino Acid N-Hydroxysuccinimide Ester

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.

Synthesis of TFA-protected α-Amino Acid Chloride via a Vilsmeier Reagent for Friedel–Crafts Acylation

“…Optically active D-Ile and L-/D-allo-Ile were first protected by TFA groups, resulting in TFA-D-Ile (D-2) and TFA-L-/D-allo-Ile (L-/D-5). Similar to our previously reported study [11], during N-terminal protection by TFA, only the α-proton signal of L-/D-2 in 1 H-NMR (δ = 4.69 ppm, Supplementary Material) could be observed. No trace of L-/D-5 (δ = 4.77 ppm) was detected, ensuring that the chirality retention of N-TFA isoleucine derivatives was suitable for use in the next reaction (Fig.…”

“…3). Although L-/D-3 and L-/D-6 showed high reactivity for acylation of benzene at room temperature, but they are unsuitable for storage and prone to hydrolysis which in opposite with previously reported study by utilization of Nhydroxysuccinimide ester [11].…”

“…The activation of the C-terminal of N-protected amino acids has been extended into the synthesis of N-protected amino aryl-ketone via Friedel-Crafts acylation [2][3][4][5][6][7][8][9]. In recent studies, only a few N-protected amino acid derivatives containing a good leaving group, such as N-protected N-(αaminoacyl)benzotriazole [10] and N-trifluoroacetyl (TFA)protected α-amino N-hydroxysuccinimide ester [11,12,13], have been utilized as acyl donors in Friedel-Crafts acylation to give moderate yields of N-protected amino aryl-ketone with chirality retention.…”

“…Isoleucine and its diastereomer alloisoleucine are important natural α-amino acids that possess two chiral centers in their structure. We previously reported on the activation of the C-terminal of TFA-protected isoleucine or its diastereomer allo-isoleucine derivatives via an N-hydroxysuccinimide ester for the Friedel-Crafts acylation of arenes [11]. Based on this previous work, the utilization of isoleucine (and allo-isoleucine) derivatives appeared to offer a convenient method for the detection by 1 H-NMR of any nonequivalent signals corresponding to optical loss at the α-position.…”

Synthesis, In Silico and In Vitro Evaluation of Antimicrobial and Toxicity Features of New 4-[(4-Chlorophenyl)sulfonyl]benzoic Acid Derivatives

“…The N -protected α-amino ketones are also versatile building blocks in the synthesis of various potential biologically active compounds, including 1,3-oxazoles and 2-oxazolines [ 33 , 51 ]. Therefore, over time several methodologies have been reported for their synthesis, the primary method being the Friedel–Crafts aminoacylation reaction of various aromatic compounds with N -acyl-α-amino acids, N -protected α-amino acyl chlorides, α-amino acid anhydrides, or 1,3-oxazol-5(4 H )-ones in the presence of Lewis acids or Brönsted acids as catalysts [ 33 , 52 , 53 , 54 , 55 , 56 ]. Also, some functionalized derivatives were obtained by reaction of enolizable cyclic 1,3-dicarbonyls with 1,3-oxazol-5(4 H )-ones [ 57 ].…”