Ricerc@Sapienza

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 mild and efficient palladium catalyzed [3+2] cycloaddition of vinyl aziridines and indane-1,3-diones has been realized. The resulting spiropyrrolidines were provided in excellent yields and, with the introduction of the leucine-derived phosphine ligand, moderate to good enantio- and diastereoselectivities.

The d and l amino acid mediated enantioselective intramolecular aldol reaction of 4-((1-methyl-2,6-dioxo-cyclohexyl)methyl)-pent-4-enal 1 leading, after dehydration, to (-)-(R) and (+)-(S) 4a-methyl-3-methylene-5-oxo-2,3,4,4a,5,6,7,8-octahydro-naphthalene-1-carbaldehyde 2 was explored. It was found that (-)-(R) carbaldehyde 2 is enantioselectively formed in the presence of l-amino acids while (+)-(S) carbaldehyde 2 is enantioselectively formed in the presence of d-amino acids. (-)-(R) Carbaldehyde 2 was then transformed into (+)-22.

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.