Reacción aza-Michael intramolecular organocatalítica sobre enonas y derivados de ácido: nuevas estrategias

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2016
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10/01/2017
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Abstract
For the creation of carbon-nitrogen bonds and to access b-amino carbonylic compounds, together with the Mannich reaction, the aza-Michael reaction is considered one of the more appealing methodologies. It consists on the conjugate addition of a nucleophilic nitrogen source to an a,b-unsaturated system. This reaction has acquired a special relevance in its intramolecular version as it conducts to the formation of nitrogen heterocycles in a very straightforward manner. Furthermore, when the activated olefin contains prochiral centers, there are generated one or more stereogenic centers through the addition process. Thus, the asymmetric version of this transformation would allow the preparation of stereoselective functionalized nitrogen-containing compounds. Whereas the conjugate addition of chiral amines to electronic deficient olefins has been the most employed strategy among the asymmetric aza- Michael reactions, the emergence of catalytic variants came late. Likewise, the asymmetric version of the intramolecular aza-Michael reaction has practically remained unexplored, being just organocatalyzed processes the few described examples. The main constraint of the organocatalytic enantioselective aza-Micheal reaction is that the Michael acceptors are generally a,b-unsaturated aldehydes. The greater difficulty that implies the generation of the corresponding iminium ion with ketones has made the catalysis with these substrates a more compromised task. In this way, the use of primary amines, where the kinetic for the formation of the iminium intermediate is more favorable, has enabled a more efficient use of this transformation in its intermolecular version. Similarly, the employment of a,b-unsaturated esters as Michael acceptors is not very extended and even less within the organocatalysis field. In this cases the activation process will always be through hydrogen bondings, since the ester group is not enough reactive as to form the iminium salt observed with aldehydes and ketones. Due to this poor reactivity of the conjugated esters, there have been developed a great variety of synthetic equivalents that either show an enhanced reactivity as electrophiles or they facilitate the activation process and the formation of a more stable transition state through their hydrogen-bonding acceptors. Taking the aforementioned into account and given the relevance of the asymmetric synthesis in organic chemistry, the objectives of the present PhD Thesis are focused on one hand, in the design of more general methodologies of organocatalytic enantioselective intramolecular aza-Michael reactions (IMAMR) for a,b-unsaturated ketones and esters; and on the other hand, in the application of those methodologies to the synthesis of structures of high interest, such as sultams. The starting materials required to study the IMAMR are prepared through a cross-metathesis (CM) reaction between the a,b-unsaturated carbonylic compounds and the corresponding properly protected amines. The latter will be in turn obtained following procedures similar to those described in the literature. Once with the IMAMR substrates in hand, there will be studied the reaction conditions (solvent, temperature, catalyst, additive, …) to execute the intramolecular addition in an enantioselective fashion. In conclusion, there have been developed several highly enantioselective protocols for the preparation of nitrogen heterocycles containing b-amino carbonylic motifs, applying chiral organocatalysts to activate a,b-unsaturated ketones and ester surrogates in the intramolecular aza-Michael reaction. Moreover, it has been achieved the application of one of these methodologies for the preparation of bicyclic sultams with a structural composition not described to date.
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