Adiciones 1,4-conjugadas a deshidroalaninas quirales para la síntesis de aminoácidos no naturales

Abstract

This Doctoral Thesis is focused on the reactivity of different serine-derived bicyclic chiral dehydroamino acids, developed in the research group in which this work has been carried out (QuiBi at University of La Rioja). α,β-Dehydroamino acids are a type of electrophiles widely employed in 1,4-conjugate additions with nucleophiles of different nature to obtain unnatural amino acids. However, their chiral version that would allow access to such enantiomerically pure amino acids is still considered a synthetic challenge. Previously, the reactivity of a chiral cyclic dehydroalanine against sulfur nucleophiles (S-nucleophiles) has been studied, allowing the access to cysteine derivatives of high biological interest. Therefore, based on this works, in this Thesis we intend to expand this methodology to different nucleophiles that open the door to the synthesis of different enantiopure unnatural amino acids. Specifically, in Chapter 3, a study of the Michael-type addition reaction with N-, Se- and C-nucleophiles has been developed. Thanks to this methodology, derivatives of α,β-diamino acids and bis-α-amino acids can be obtained, among which histidinoalanine, which is related to cellular aging, can be highlighted. On the other hand, β-seleno-α-amino acids can also be obtained, which present great interest thanks to their antiviral and anticancer activities. In this case, we can highlight the synthesis of a mimetic derivative of the Tn antigen, which show better antibody molecular properties thanks to the incorporation of selenium in the glycosidic bond. Finally, unnatural amino acids substituted at the β-carbon with other groups can be obtained through C-C bonds, although this synthesis is rather limited due to the need of employing nucleophiles with sufficiently acidic hydrogens susceptible to deprotonation. Therefore, in Chapter 4, a new type of reactivity based on the 1,4-addition reactions is presented; however, in this case we employed radicals to form C-C bonds, which is known as the Giese reaction. Moreover, these radicals are generated by blue light photocatalyzed reactions. This reactivity allows the synthesis of interesting unnatural amino acids. For instance, a Se-protected derivative of selenohomocysteine to be used in native chemical ligation is described. In addition, an amino acid bearing an alkyne group susceptible to click reactions with azides is also obtained, which can be used in bioconjugation chemistry. In Chapter 5, the synthesis of different compounds isotopically labelled with deuterium is discussed. The preparation and use of these derivatives is a booming field of research, since deuterium-labelled drugs retain their biological activity and are also more stable against degradation, which implies the use of lower doses. In addition, deuterium labelling of various compounds allows them to be traced by different techniques, such as nuclear magnetic resonance. Finally, Chapter 6 presents the work carried out during the Doctoral Thesis in parallel to the main thread of this report. This work focuses, by one hand, on the synthesis and reactivity of cyclic sulfamidates derived from serine or α-methylserine against carbohydrates, and by other hand, on the study and characterization of compounds derived from isoserine by means of nuclear magnetic resonance experiments and X-ray diffraction analysis.