Efectos del enlace mecánico en la organocatálisis con aminas secundarias entrelazadas y la reactividad de rotaxanos derivados de glutaconamida

Abstract

This Doctoral Thesis is structured in two different projects, from which three scientific publications in the form of articles derive, two corresponding to one of the projects, and the third and last article, corresponding to the second project. GOALS The general goal of this Thesis consists of the development and study of interlocked systems based on [2]rotaxanes assembled by hydrogen bonds with benzylic amides. The reactivity in confined spaces of new organic functionalities present in these systems will be studied and new interlocked organocatalysts, useful in aminocatalysis, will be designed. METHODOLOGY AND RESULTS The experimental development of this Doctoral Thesis has been carried out in the laboratories of the Department of Organic Chemistry, in the Faculty of Chemistry of the University of Murcia. Furthermore, different structural elucidation techniques have been used to determine the compounds obtained; such as Nuclear Magnetic Resonance Spectroscopy (NMR), Infrared Spectroscopy (IR), High Resolution Mass Spectrometry (HRMS) and Single Crystal X-ray Diffraction (SCXRD). For the development of the first project, a series of mechanically interlocked systems that have one or two succinamides as binding sites were synthesized. The presence of an acyclic secondary amine allows these systems to be evaluated as organocatalysts in transformations generally catalyzed by amino acids. In the case of a system with two binding sites, the displacement dynamics was studied and the displacement speed was calculated, observing greater catalytic activity for this system than for the one with a single binding zone. Furthermore, the speed of the translational movement of the ring was related to the variation of its substituents, and therefore to the catalytic capacity through the kinetic study of a Michael addition between crotonaldehyde and acetylacetone, using these systems as catalysts. For the development of the second project, a series of mechanically interlocked systems with glutaconamides as binding site were synthesized. These systems were tested as starting materials under basic conditions to obtain new derivative products, obtaining the allylic oxidation product, through aerobic oxidation through the corresponding anion and molecular oxygen. In the case of non- interlocked templates, the formation of the allylic anion and its subsequent nucleophilic attack on its oxidized derivatives (generated in situ), prevents the reaction from stopping in this intermediate, initially forming the Michael addition product. Finally, after a new intramolecular nucleophilic attack, a cyclic and dimeric species is formed as a hydroxycyclohexene structure. On the other hand, the presence of the mechanical bond in the interlocked systems, in addition to increasing the yields in allylic oxidation, prevents the subsequent Michael addition, preventing the reaction from progressing and the respective dimers from forming. This effect allows these intermediates to be isolated, and can subsequently be used in an intramolecular photochemical cyclization to obtain, in a divergent way, their corresponding cyclic interlocked derivatives, a hydroxy-β-lactam and an oxazolidinone. CONCLUSIONS 1. Two templates containing one and two succinamide stations have been synthesized, with a secondary amine as the catalytic site, and two dibenzylamine stoppers, used to catalyze the Michael addition of acetylacetone to crotonaldehyde. Subsequently, these templates have been used in the preparation of their corresponding [2]rotaxanes of benzylic amides. 2. The catalysis studies revealed a greater activity of the interlocked systems with respect to that of their corresponding free axes, producing activation due to the presence of the mechanical bond. Rotaxane with two succinamide stations shows greater catalytic activity due to the translational movement of the ring allowing the activation of the reaction substrates. 3. A series of interlocked catalysts ([2]rotaxanes) have been synthesized using the thread that has two succinamide stations and modifying the electronic properties of the substituents of the macrocycle. Catalysis studies of the Michael addition of acetylacetone to crotonaldehyde with these systems have allowed us to find a linear relationship between the value of the parameter σm and the reaction rate. Furthermore, for the lowest values of said parameter, the best conversions are obtained and the translation movements of the ring are faster. 4. A series of axes derived from glutaconamides and their corresponding [2]rotaxanes of benzylic amides have been synthesized, which were obtained as a mixture of their geometric isomers E and Z. 5. The allylic oxidation of glutaconamides has been carried out using potassium phosphate as a base, obtaining the corresponding α-ketoamides in the case of using interlocked substrates, and a dimeric species with a hydroxycyclohexene structure when the nude axes are used as substrates. 6. The allylic oxidation of the [2]rotaxanes and the axes has been carried out using selenium dioxide as an oxidant. During this transformation it has been shown that the protective effect of the mechanical bond stabilizes the oxidation product (α-ketoamides), and increases the transformation yield in the case of using interlocked glutaconamides as starting material. 7. Interlocked α-ketoamides have been used in a type II Norrish/Yang cyclization obtaining interlocked hydroxy-β-lactams and oxazolidinones in different proportions depending on the reaction conditions used.