EXPLORING DIFFERENT ORGANOCATALYTIC STRATEGIES FOR THE STEREOSELECTIVE SYNTHESIS OF CHIRAL NITROESTERS

Among unnatural α-amino acids, α,α-disubstituted amino acids are key biological scaffolds with many specific roles and properties that have made them increasingly attractive in the fields of organic chemistry, biochemical research and drug discovery. Structurally, they have unique properties, and this represents an important feature for their use in the design of new pharmaceutically active compounds as well as intermediates for the study of pathological pathways and the role of peptides and their applications in the treatment of the same pathologies they are involved in. Furthermore, their utility as chiral frameworks are critical and so, enantioselectivity plays a key role in their pharmaceutical activity. However, there are limited examples in the literature of highly enantioselective synthetic approaches for these compounds or their precursors, that result in sufficient enantioselectivity suitable for their peptidomimetic applications. The global objective of this PhD thesis is to discover unprecedented synthetic strategies for the synthesis of α,α-disubstituted-α-amino acids and/or their precursors, focusing on the stereoselective reactions and employing known and also newly designed organocatalysts, including chiral phase transfer catalysts. To achieve our goals, two main strategies will be studied: o The enantioselective conjugate addition of nitroesters to α,β-unsaturated ketones mediated by Cinchona derived thiourea or squaramide catalysts, for the construction of nitroesters bearing a quaternary stereocenter. o An alternative strategy that started from easily available ketones, converted to tetrasubstituted nitroolefins, which would be organocatalytically reduced to afford enantioeneriched nitroalkanes, featuring two stereocenters, as highly functionalized starting materials for a further alkylation step to generate a quaternary stereocenter In summary, new synthetic approaches for the generation of α,α disubstituted α amino acids, using organocatalysis were studied. A reproducible strategy for the synthesis of tetrasubstituted nitroalkenes was successfully developed, and enantioselective organocatalyzed reductions performed, to afford the functionalized nitroalkanes. However, several challenges were found in the further alkylation step, and despite trying different variations to the process, the synthesis of a α,α disubstituted α amino acid derivative was not accomplished, following this route. The reactivity of the new synthetized tetrasubstituted nitroalkenes was also studied. Unfortunately, it was only possible to obtain the Michael adduct 136, after long reaction times in comparison with their trisubstituted analogues. The organocatalyzed conjugate addition of nitroesters 118, 130 to unsaturated ketones 120, 125 to get enantiopure nitroesters 123,126,131,132 bearing a quaternary stereocenter, which were obtained with good to moderate yields. These compounds are not extensively reported in literature, in some cases they are only reported as a racemic mixture, so to the best of our knowledge, for the first time it was demonstrated that it is possible to do this transformation in an enantioselective manner.