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.

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In this work, a series of α‐amino acids (L‐Phe, D‐Phe, L‐Trp) and several α,β‐dipeptides (H2N‐L‐Val‐N‐Bn‐β‐Ala‐COOH and H2N‐L‐Leu‐N‐Bn‐β‐Ala‐COOH) intercalated into hydrotalcite (Mg/Al, x=0.333) were prepared by high speed ball milling (HSBM) assisted rehydration/reconstruction methods, followed by sonication and mechanical stirring. All organic‐inorganic hybrid samples were characterized by powder X‐ray diffraction (XRD) and FTIR‐ATR spectroscopy. The catalytic activity of the resulting hydrotalcite‐supported materials (natural and hybrid) was evaluated in the asymmetric Michael addition reaction of α,α‐disubstituted‐aldehydes to N‐substituted‐maleimides. Pristine (HTS), calcined (HTC) and water‐reconstructed (HTR‐l) hydrotalcite‐derived materials exhibited very low catalytic activities, affording racemic mixtures of the anticipated Michael adduct. By contrast, hybrid materials showed better activities, especially HTR‐α‐amino acid catalysts afforded Michael products in up to 94 % yield and with rather high enantioselectivity (enantiomeric ratio (e.r.) up to 99 : 1) at room temperature under neat reaction conditions. The effect of solvents and Brønsted basic or acidic additives was evaluated using the best hybrid catalyst, HTR‐L‐Phe. In addition, recycling and reuse of the catalyst (up to 4 cycles) and large‐scale experiments was successfully carried out.

Knowledge accumulated in the field of organocatalysis led to the design and synthesis of three novel and efficient organocatalysts for the stereoselective aldol and Michael reactions in the presence of water.

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