En Route to a Heterogeneous Catalytic Direct Peptide Bond Formation by Zr-Based Metal–Organic Framework Catalysts

Abstract

Peptide bond formation is a challenging, environmentally and economically demanding transformation.Catalysis is key to circumvent current bottlenecks. To date, many homogeneous catalysts able to provide synthetically useful methods have been developed, while heterogeneous catalysts remain largely restricted to the studies addressing the prebiotic formation of peptides. Here, the catalytic activity of Zr6-based metalorganic frameworks (Zr-MOFs) towards the peptide bond formation is investigated using the dipeptide cyclization as a model reaction. Unlike previous catalysts, Zr-MOFs largely tolerate water, and reactions are carried out under ambient conditions. Notably, the catalyst is recyclable and no additives to activate COOH group are necessary, which are common limitations of previous methods. In addition, broad reaction scope tolerates substrates with bulky and Lewis basic groups. The reaction mechanism was assessed by intermolecular peptide bond formation. While intrinsic challenges associated with the catalyst structure and water removal limit a more general intermolecular reaction scope under current conditions, the results suggest that further design of Zr-MOF catalysts could render these materials broadly useful as heterogeneous catalysts for this challenging transformation.

Enhancing the Catalytic Activity of MOF‐808 Towards Peptide Bond Hydrolysis through Synthetic Modulations

“…[1][2][3][4][5][6][7][8][9][10] MOFs based on metal-oxo clusters of Lewis acid metals such as Zr(IV), Hf(IV), and Ce(IV) as secondary building units have emerged as powerful heterogeneous catalysts, as they are intrinsically reactive, and the high coordination numbers of these metals result in a variety of possible reaction types. [11] In our recent works we have been leveraging the intrinsic reactivity of these MOFs, in particular Zr 6 O 8 -based MOFs (Zr-MOFs) to develop them as heterogeneous nanozymes for selective hydrolysis [12][13][14][15][16][17] and formation [18] of peptide bonds, also with biomolecules as complex as proteins. [19] Materials with potential biological applications are at the forefront of medicine, biology, environmental and material chemistry fields, [20][21][22] and the versatility of MOFs is attracting increasing attention in the area due to their modular and robust structures that can be easily designed, and tuned for specific uses while preserving the practical advantages of heterogeneous systems (e. g. recyclability, easy separation from reaction mixture…).…”

MOF nanoparticles as heterogeneous catalysts for direct amide bond formations

“…However, the conditions reported here are milder in terms of tempera-ture (60 °C) and MOF loading (5 mol%), which is half of the loading reported. 28 A higher yield can be obtained when the reaction time is increased to 72 h, obtaining a ca. 37% yield with the Zr-NDC catalyst, while no product is detected in the absence of a catalyst (see Fig.…”

“…34 For the synthesis of N-benzyl-2-phenylacetamide from the reaction between phenylacetic acid and benzylamine, Francisco de Azambuja et al obtained a 14% yield of amide product after 24 h in the presence of UiO-66 (10 mol%) in ethanol at 80 °C. 28 This is associated with a reaction rate of ca. Mechanism for the direct amide bond formation at ultra-small Zr-MOF nanoparticles…”

“…[22][23][24][25] These MOFs are also the preferred systems in acid-catalyzed direct amidation reactions between carboxylic acids and amines. [26][27][28] On the one hand, Timofeeva et al considered either the sulphated cluster or the pore sizein the case of sulfonated MOF-808 or UiO-66, respectively 27 as key factors for the formylation of aniline under solvent-free/MeOH room temperature conditions (see Scheme 1a).…”

“…On the other hand, UiO-66 was also recently employed as a heterogeneous catalyst by de Azambuja, Parac-Vogt and co-workers for the reaction between benzylamine and phenylacetic acid (see Scheme 1b). 28 Zr-dicarboxylate MOFs of the UiO-66 isoreticular series (see Fig. 1) are commonly investigated in catalysis due to the fact that the Zr 6 O 4 (OH) 4 secondary building unit (SBU) can be maintained while linkers with slight microscopic variations in the composition, such as the presence of substitutions on the aromatic ring, can be incorporated, resulting in significant changes in the macroscopic properties of the final MOF, such as the hydrophobicity, pore size or catalytic activity.…”