Mechanochemical Synthesis of Dipeptides Using Mg‐Al Hydrotalcite as Activating Agent under Solvent‐Free Reaction Conditions

Abstract

Given the high demand for green and sustainable synthetic methods for the formation of amides and peptidic bonds, herein we report the efficient, solvent‐free mechanochemical synthesis of dipeptides from N‐protected amino acids and amino acid methyl ester hydrochlorides in the presence of 1‐hydroxybenzotriazole (HOBt) and N‐ethyl‐N′‐[3‐(dimethylamino)propyl]carbodiimide hydrochloride (EDC) as coupling reagents, and using Mg‐Al hydrotalcite‐like minerals as green activating agent. From commercial Mg‐Al hydrotalcite (HT‐S), we obtained its calcined (HT‐C) and reconstructed (HT‐R) modifications, which were evaluated as activating heterogeneous bases in amidation reactions, replacing commonly used toxic and/or corrosive bases (e.g., NEt3, iPr2NEt and NaOH). As a practical application of this strategy, various α,α‐, α,β‐ and β,β‐dipeptides were prepared in good to excellent yields. Under optimized reaction conditions (vibrating mill at 25 Hz for 75 min) HT‐S and HT‐R showed higher activity (89 % yield of the desired peptide) compared with HT‐C (57 % yield). The present protocol offers several advantages, including the use of readily available reagents and inexpensive materials, easy workup, simple recovery and recyclability of the hydrotalcite activator, and short reaction times.

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

“…[34] On the one hand, replacing DMAP and MeNO 2 with NaH 2 PO 4 and EtOAc, respectively,p rovedv iable.S econdly,t he authors utilized Oxyma as an additive to suppress racemization of the amino acid partners. [37] This new work included the use of 1-hydroxybenzotriazole (HOBt; 27)n ot only as an additive to activate 26 and 28 butalso to inhibit racemization of the activated amino acids. Not only did this new approache nable the preparation of as many as 20 examples, it also included the extension of this methodology to the mechanosynthesis of tri-and tetrapeptides.…”

“…Not only did this new approache nable the preparation of as many as 20 examples, it also included the extension of this methodology to the mechanosynthesis of tri-and tetrapeptides. [37] An important feature of this mechanochemical peptideb ondf ormation was the use of hydrotalcite as ar ecyclable base, which, in combination with the EDC/HOBt coupling agents, gave the dipeptides in 70-89 %y ield after 1.25 ho fm illinga t 25 Hz (Scheme 6). [37] This new work included the use of 1-hydroxybenzotriazole (HOBt; 27)n ot only as an additive to activate 26 and 28 butalso to inhibit racemization of the activated amino acids.…”

“…[34,36] In 2017, Landeros and Juaristi reportedt he application of the mechanochemicalc arbodiimide coupling strategy to prepareaseries of a,a-, b,a-, and b,b-dipeptides. [37] This new work included the use of 1-hydroxybenzotriazole (HOBt; 27)n ot only as an additive to activate 26 and 28 butalso to inhibit racemization of the activated amino acids. Despite HOBt being considered as an explosophore, [38] no problemswiththe use of this additive by ball-milling were reported.…”

Thermal and Mechanical Stability of Immobilized Candida antarctica Lipase B: an Approximation to Mechanochemical Energetics in Enzyme Catalysis.

“…[26] Furthermore, CALB as N435 has shown remarkable stability and recyclability under rough chemical conditions. [27,28] Recently, as part of our interest in the development of more sustainable synthetic methodologies, [29][30][31][32] and considering previous reports using proteins mechanically activated through the High-Speed Ball-Milling technique, [33,34] we were able to carry out various stereoselective biotransformations. [35,36] Gratifyingly, CALB partially retains activity after the harsh mechanochemical conditions provoked by the collisions inside the milling-jar, and proved to be stable enough to carry out its catalytic function, affording highly enantioenriched products.…”