HOMO-raising strategies in aminocatalysis, from Enamine to Tetraenamine

Abstract

In this Master Thesis two different HOMO-raising strategies in aminocatalysis - enamine activation and tetraenamine activation were studied. For the tetraenamine activation concept, it was rationalized that the condensation between 2-(cyclohepta-1,3,5-trien 1-yl)acetate and the TMS-protected diraylprolinol ether aminocatalyst would provide the desired tetraenamine intermediate. The novelty of this concept was further explored by the studied of the [4+2]-cycloaddition between the tetraenamine intermediate formed and a series of 3- olefinic oxindoles, benzofuranone and benzothiophenone. The corresponding cycloaddition products were obtained bearing four stereocenters including a spiro-carbon with yields between 51 and 93%. The reaction also proved to be both diastereo- and enanteoselective with the dr ranging between 86:14 and >95:5 and ee between 50 and 99%. Furthermore, the isolated cycloadducts were subjected to several transformations including an oxidation reaction under Dess-Martin conditions, which produced a highly substituted cyclohexanone and a selective bromination of the triene system of the cycloadduct which occurred with total regioselective control. In this project, mechanistic studies were also performed allowing the isolation and/or characterization of a series of intermediates namely the tetraenamine, which allowed a mechanistic proposal that was then supported by computational calculations. In this Thesis was also explored the well known enamine activation concept. It was intended to perform a Michael reaction between a series of aldehydes and vinyl sulfones catalyzed by a bifunctional H-bond directing aminocatalyst. For this purpose isovaleraldehyde and phenyl acetaldehyde were tested with methyl vinyl sulfone, phenyl vinyl sulfone and trifluoromethy lvinyl sulfone in the presence of either a squaramide based aminocatalyst or a TMS-protected diraylprolinol ether aminocatalyst. Despite the several attempts and modifications of the reaction conditions no reactivity was observed which could be explained by the lack of activation of the Michael acceptor(i.e. the vinyl sulfones). The results obtained suggest that new catalytic systems should be explored in order to perform the conjugate addition of aldehydes to vinyl sulfones.