Novel Stereoselective Intramolecular Processes for the Generation of New Molecular Entities

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The present doctoral thesis is devoted to the study of novel stereoselective intramolecular reactions as synthetic tools for the generation of complex New Molecular Entities. Along its three chapters, the focus is put, in the first place, on intramolecular 1,3-dipolar cycloadditions with novel fluorinated substrates and, in the second place, on new organocatalysed tandem sequences. In Chapter 1, the synthesis of three families of fluorinated polycyclic isoxazolidines is described by means of an intramolecular nitrone cycloaddition reaction of unprecedented ortho-substituted α-trifluoromethyl styrenes. The trifluoromethyl group plays an important role in the regioselectivity of the process and it is able to invert the regioisomeric outcome of the reaction compared to the non-fluorinated case. Additionally, combining an organocatalytic step for the convenient functionalisation of the nitrone precursors with a subsequent cycloaddition event, enantiopure derivatives are accessible. Complementary computational calculations allow for a deeper understanding of the regio- and diastereoisomeric reaction outcome. In Chapter 2, an asymmetric synthesis of fluorinated polycyclic proline derivatives was developed by means of an intramolecular dipolar cycloaddition between a homochiral in situ generated azomethine ylide and a trifluoromethyl-substituted alkene, ensuring high levels of regio- and diastereoselectivity. Again, theoretical calculations correctly predict the drop of selectivity observed when a non-fluorinated alkene was used. Finally, in Chapter 3, a novel tandem organocatalysed cycloaromatisation/intramolecular Friedel-Crafts alkylation sequence is reported, leading to the synthesis of a new family of annulated pyrrole derivatives in moderate to good yields. An asymmetric approach was developed using chiral, non-racemic Brønsted acid organocatalysts, obtaining moderate levels of enantioselectivity.
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