N-Acyl Benzotriazole Derivatives for the Synthesis of Dipeptides and Tripeptides and Peptide Biotinylation by Mechanochemistry

Abstract

An eco-friendly methodology for preparing Fmoc-, Z-, and Boc-Nprotected dipeptides and tripeptides is described, from the corresponding Nprotected-α-aminoacyl benzotriazoles and α-amino acid derivatives, with different Cterminal functionalities such as esters or amides, using vibrational ball-mill (VBM). The reactivity of a β-amino ester was also investigated. In some cases, the coupling was achieved by liquid-assisted grinding (LAG). α,αand one α,β-dipeptide were obtained in good to excellent yields mainly by precipitation in water, resulting in an improved environmental impact compared to classical peptide synthesis in solution, as shown by green metric calculations. The method was extended to the biotinylation, via an aminohexanoyl spacer, of the pentapeptide RGDfV, which contains the well-known integrins recognition site arginine−glycine−aspartic acid (RGD) motif.

The effect of ball mass on the mechanochemical transformation of a single-component organic system: anhydrous caffeine

“…Mechanochemical methods have been used in the synthesis and preparation of a broad range of molecules and materials [2][3][4][5]. Many examples are now available where mechanical treatment has been shown to be a method providing access to novel molecular materials or has been used to enhance the selectivity and the rates of product formation [6][7][8][9]. In recent years, attention has largely turned towards the use of mechanical treatment as a tool for synthesis of new organic and coordination compounds, including pharmaceuticals, as well as for control of their polymorphism [10][11][12][13][14].…”

Peptide synthesis: ball-milling, in solution, or on solid support, what is the best strategy?

“…Indeed, liquid reaction mixtures enable efficient agitation when using a conventional batch reactor equipped with either magnetic stirring bar or impeller, and automated handling such as pumping and filtration. Since Lamaty and co-workers have shown in their seminal work that peptide synthesis could be performed in a ball-mill (BM) [9], various solvent-free or solvent-less peptide synthesis strategies have been developed [10][11][12][13][14][15][16][17]. While these approaches enable to circumvent the use of toxic solvents and bases [18][19][20], no comparison between ballmilling and conventional approaches was performed, discussed and communicated.…”

From Synthesis of Amino Acids and Peptides to Enzymatic Catalysis: A Bottom‐Up Approach in Mechanochemistry

“…[40] Commercially available amino acid benzotriazole derivatives reacted in ab all mill with a-aminoe sters 21, aamino amides 34,a nd HCl·b-ala-OtBu 35 (Scheme8). [40] Commercially available amino acid benzotriazole derivatives reacted in ab all mill with a-aminoe sters 21, aamino amides 34,a nd HCl·b-ala-OtBu 35 (Scheme8).…”

“…Similarly,Colacino and co-workersused activated a-aminoacyl benzotriazole derivatives 33 in mechanochemical peptide synthesis. [40] Commercially available amino acid benzotriazole derivatives reacted in ab all mill with a-aminoe sters 21, aamino amides 34,a nd HCl·b-ala-OtBu 35 (Scheme8). Additionally,d ipeptides [TFA·H-aa 1 -aa 2 -(OMe/NH 2 )] could be coupled with 33 to prepare tripeptidesi ng ood yields.…”

“…The advantages of the mechanochemical peptidec oupling were put into practice during the synthesis of the more complex biotinylated peptide 38.A fter extended millingt imes, the reaction of 36 and the solid-phase made peptide 37 gave product 38 in 36 %y ield (Scheme 8, bottom). [40] Activation of the carboxylic acid functionality in aamino acids has also been achieved by using 2,4,6trichloro-1,3,5-triazine (TCT) with catalytic amounts of PPh 3 . [41] Pattarawarapan's team reported the preactivation of N-protected amino acids 26 with TCT followed by the addition of the a-amino acid ester salts 21.…”