Ricerc@Sapienza

Benzazetidines are a class of N‐heterocycles potentially very interesting for a variety of purposes, including biological applications and drug design. In the past, their high ring strain has hampered the development of trustable, general, and efficient synthetic methodologies for their preparation. In this review article, the aim is to disclose all the literature contributions about the synthesis of these compounds and the study of their reactivity, from the early examples to the most recent synthetic approaches.

In the last twenty years, N-heterocyclic carbenes (NHCs) have been extensively studied for their application as organocatalysts in stereoselective synthesis as well as ligands for transition metals-promoted synthetic methodologies. Derived mainly from azolium salts, NHCs have demonstrated exceptional versatility in their generation usually performed by deprotonation or reduction (chemical or electrochemical).

This thesis explores the applications of organocatalysis and its combination with metal catalysis for the enantioselective synthesis of novel oxygen- and nitrogen-containing heterocycles. The developed procedures rely on both covalent- and hydrogen-bounding organocatalysis and metal coordination catalysis. The first project focused on the development of an efficient asymmetric synthesis of new 4-amino-isochromanones starting from anilines and 2-formylbenzoates.

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.

The organocatalyzed addition of several malonates to 1,4-benzoquinones affords benzofuranones bearing a quaternary stereocenter with good enantioselectivity. This reaction is an intramolecular desymmetrization since it proceeds through the formation of an arylated achiral malonate that cyclizes to give the reaction product. The addition rate of the quinone dramatically affects the reaction yield which was originally low.

This Account describes from a personal point of view the possible strategies to tackle and optimize non-covalent organocatalyzed reactions. When chemical intermediates are covalently bound, predictive mechanicistic pictures can be depicted. In contrast, there are several organocatalyzed transformations (e.g. those employing Cinchona alkaloids) for which optimization is essentially based on a trial-and-error approach. The experience of authors is that these reactions can be tackled with a rational approach employing DoE, Design of Experiment.