New applications of Ester/Amide surrogates in organic synthesis

Abstract

Masked esters/amides are scaffolds endowed with a great potential in the field of organic synthesis. This PhD project has been conceived, in the context of non-covalent organocatalysis, with the aim to exploit unsaturated (a) and saturated (b) masked esters/amides (Figure A) as starting materials to accomplish the synthesis of different classes of organic compounds in a one-pot fashion.Masked esters/amides (Figure A) exhibit some important features which make them valid substrates for organocatalytic one-pot sequences. Firstly, the presence of a nitrogen-based heterocycle renders them more reactive if compared with esters or amides: the heterocycle “steals” electron density from the molecule, resulting in an enhanced electrophilicity at the β position of reagent a or an enhanced acidity of α-proton in type b substrates. Secondly, nitrogen atoms of the heterocycle offer to these substrates more possibilities of interaction with an organocatalyst through further H-bonds formation. This provides a major rigidity in the transition state and a subsequent increase in the stereochemical outcome of the reaction. Finally, another important property of these compounds, due to the ability of the aza-heterocycle as leaving group, is the possibility to obtain ester or amide functionality through simple treatment with alcohols or amines via typical addition/elimination mechanism (hence the name “ester/amide surrogates”). We tried to achieve the stereocontrolled formation of carbon-carbon and carbon-heteroatom bonds to obtain cyclic compounds of different nature and size (such as benzothiazepines and bicyclic pyrazolidinones) and non-cyclic compounds, such as imines, β-aminoalcohols and nitrones. In this doctoral thesis, the first stereoselective cascade sulfa-Michael/lactamization sequence for the synthesis of cis- and trans-2,3-diaryl substituted 1,5-benzothiazepines has been developed, starting from α,β-unsaturated N-acylpyrazoles and 2-aminothiophenols. The two steps are promoted by catalytic amounts of a readily available bifunctional thiourea and p-toluenesulfonic acid, respectively. Our work provides access to both N unprotected diastereoisomers of the product with satisfactory results (Scheme A). Moreover, we demonstrated that these products can be easily elaborated to prepare libraries of compounds for biological tests. [edited by Author]