Novel Strategies for the Activation of Nucleophiles and Electrophiles in Asymmetric Organocatalysis

Resumen

The importance of chiral compounds has been demonstrated with the Thalidomide case. The use of this drug by the pharmaceutical industry in the late sixties was a huge tragedy given the unknown effects of each enantiomer administered to the population. Therefore, asymmetric synthesis has been located at the forefront of the methodologies to obtain selectively enantioenriched substrates. In particular, asymmetric catalysis has been considered one of the best tools for gaining chiral products by using catalytic amount of molecules that can be recovered once the reaction is finished. In this context, organocatalysis stands out from the rest because it is a more sustainable strategy since catalysts are fully organic frameworks. The importance of this approach has been recognized with the Nobel Prize this year 2021 to Benjamin List and David MacMillan, for the development of asymmetric organocatalysis. Since the year 2000, numerous activation modes have been described that, together with the design of catalysts, have permitted the development of plenty organic reactions of high interest. They can be classified depending on the interaction between the substrates and the catalyst, giving rise to covalent and non-covalent catalysis. The former includes aminocatalysis and N-heterocyclic carbene catalysis, in which an intermediate is formed in the reaction. Thus, enamine, dienamine, trienamine, tetraenamine, iminium-ion and its variants, and Breslow intermediates can be generated in situ. On the other hand, non-covalent catalysis involves ion pairing and hydrogen bonding. The latter has been recognized as one of the best strategies because the possibility of using chiral bifunctional catalysts has enabled good results in terms of reactivity and selectivity of the processes. Thiourea and squaramide derivatives stand out from the rest along with Brønsted bases, achieving very efficient organocatalysts in this area. Throughout this PhD Thesis we have developed different substrate activation strategies to carry out asymmetric organocatalytic reactions. In Chapters 2 (part A and part B) and 3, the power of the hydroxyl group placed at the ortho position of the aromatic ring of the corresponding imines appears to be a great solution for the limitations found in some organic transformations – regarding reactivity and selectivity enhancement – using non-covalent chiral organocatalysts for the construction of pyrrolidines, amino acid derivatives and diamines. On the other hand, in Chapter 4, BODIPY core is able to activate a double bond for the [4+2]-cycloaddition reaction via trienamine.