A calix[4]arene with acylguanidine units as an efficient catalyst for phosphodiester bond cleavage in RNA and DNA model compounds

• Published in: Organic & biomolecular chemistry 2019-08, Vol.17 (32), p.7482-7492
• Main Authors: Salvio, Riccardo, Volpi, Stefano, Folcarelli, Tommaso, Casnati, Alessandro, Cacciapaglia, Roberta
• Format: Article
• Language: English
• Subjects: Acceleration; Acidity; Additives; Calixarenes; Calixarenes - chemistry; Carbonyl compounds; Carbonyl groups; Carbonyls; Catalysis; Catalysts; Cleavage; Computer Simulation; Conformation; Density Functional Theory; Deoxyribonucleic acid; DNA; DNA - chemistry; Guanidine; Guanidines - chemistry; Hydrolysis; Kinetics; Mathematical analysis; Molecular Conformation; NMR; Nuclear magnetic resonance; Organophosphates - chemistry; pH effects; Phenols - chemistry; Phosphodiester bonds; Reaction mechanisms; Ribonucleic acid; RNA; RNA - chemistry; Scaffolds
• ISSN: 1477-0520; 1477-0539
• DOI: 10.1039/c9ob01141b

A calix[4]arene scaffold, blocked in the cone conformation and decorated at the upper rim with two acylguanidine units, effectively catalyzes the cleavage of phosphodiester bonds of HPNP and BNPP under neutral pH conditions. The catalyst performance is discussed in terms of acceleration over background hydrolysis and effective molarity (EM). The combination of potentiometric acid-base titrations with pH-rate profiles for HPNP and BNPP cleavage in the presence of 2 ·2HCl additives points to a marked synergic action of an acylguanidine/acylguanidinium catalytic dyad in 2 H + , via general base-electrophilic bifunctional catalysis. Acceleration factors over background larger than 3 orders of magnitude are obtained. The connection of the guanidine/guanidinium dyad to the calixarene scaffold by means of carbonyl joints has a double advantage: (i) the acidity of the guanidinium moiety is enhanced by the electron-withdrawing carbonyl group and maximum conversion into the catalytically active form 2 H + occurs at almost neutral pH, lower than the pH needed for the monoprotonated form 1 H + devoid of carbonyl groups; (ii) the EM value for HPNP cleavage with 2 H + is definitely higher than that with 1 H + , suggesting a highly preorganized catalyst that perfectly fits in a strainless ring-shaped transition state in the catalyzed process. DFT calculations also provide useful insights into the reaction mechanisms and transition states. Conjugated carbonyl units in a calixarene scaffold provide the right amount of flexibility for catalysis with a minimum entropic cost.