Organocatalysis and catalyst aggregation: a study using the asymmetric synthesis of benzofuranones as a test reaction

Abstract

A common problem encountered in enantioselective organocatalysis is the aggregation of the catalyst, which can result in a relevant decrease of the efficiency and selectivity of the process. In the asymmetric synthesis of chiral benzofuranones, recently reported by us, we noted a remarkable increase of the reaction yield upon the addition of one of the reagents in a portionwise manner rather than in a single addition. We investigated this phenomenon by several experimental techniques such as 1D and 2D NMR experiments, UV-Vis spectroscopy, circular dichroism and dynamic light scattering. In addition, we studied the kinetic profile of this reaction using a simple numerical model and carried out in silico investigations. All these different approaches point to the conclusion that in the reaction medium a supramolecular polymerization/aggregation phenomenon, based on weak interactions, occurs and such a process is promoted by a quinone, which is one of the reagents of the benzofuranone synthesis. The portionwise mode of addition is a known strategy which can improve the performance of many synthetic procedures and this strategy is commonly adopted on account of empirical experience. However, our results provide an explanation, based on a chemical kinetic model, of the reason why the portionwise addition affects in such a dramatic way the yield of the benzofuranone synthesis catalyzed by Cinchona alkaloids.

Rational Design of an Organocatalyst for Peptide Bond Formation

“…The plot of product concentration versus time [ 8a ] n t reveals a first-order dependence on catalyst 8a . Diselenide 8a is a dimer, and urea-based organocatalysts often show a tendency to form higher-order aggregates, − but our analysis suggests that only one molecule of reduced 8a (or any of its intermediates) is involved in the rate-determining step of the reaction.…”

Green Chemistry Meets Asymmetric Organocatalysis: A Critical Overview on Catalysts Synthesis

“…The bifunctional nature of thiourea‐based organocatalysts can represent a limitation for the catalytic activity itself, since H‐bonded aggregates can be formed in dependence of concentration and temperature. [209] In order to prevent self‐aggregation of the catalyst, Song and co‐workers introduced squaramide based dimeric Cinchona alkaloids 124 . [210a] These compounds can be easily accessed by the one‐step reaction of dimethyl squarate 123 with one of the 9‐amino‐(9‐deoxy)‐ epi ‐Cinchona alkaloids (Scheme 55 a).…”

Organocatalytic Synthesis of Benzazetidines by Trapping Hemiaminals with Protecting Groups

“…In the course of our recent research work on the development of new organocatalytic synthetic procedures, we succeeded in reversibly trapping, with the aid of protecting groups, the hemiaminal function affording a benzazetidine scaffold. Benzazetidines are compounds containing a highly strained benzo-fused four-membered azetidine motif. − These small and strained N-heterocycles are potentially promising for applications in drug design and biomedical research. , However, the synthesis of benzazetidine and their reactivity remain largely unexplored because of the scarcity of effective synthetic methodologies toward this class of compounds − ,− which stems from their relative instability. ,, They also attract interest because, in the family of the fused four-membered N -heterocycles, the fused β-lactams account for the largest share of research efforts and, consequently, there is a lack of diversity among these compounds in the literature.…”