Synthesis and application of silylated pyrrolidines : enantioselective organocatalytic synthesis of alpha-trifluoromethyl alpha-amino acid derivatives and copper catalyzed multicomponent reactions
The work presented in this thesis focuses on the synthesis and application of silylated pyrrolidines, chiral phosphoric acid catalyzed Friedel-Crafts reactions to form quaternary trifluoromethylated amino acid derivatives and copper-catalyzed four-component reactions towards functionalized imidates. First, various silylated pyrrolidines were obtained in high yields by asymmetric synthesis. Enantiopure (S)-2-(diphenylmethylsilyl)pyrrolidine was furnished after recrystallization of its HCl salt and the absolute configuration was confirmed by X-ray crystal structure analysis. The application of these Lewis base structures, bearing a silyl group directly attached to the pyrrolidine, in asymmetric Michael-type addition reactions has been demonstrated. The catalyzed enantioselective addition of propanal and butanal to nitroolefins resulted in the desired nitro aldehydes in high yields (up to 99%), diastereoselectivities (up to 97:3 dr) and enantioselectivities (up to 95.5:4.5 er). The second part of this work describes the first Brønsted acid catalyzed Friedel-Crafts reaction to form quaternary amino acids that bear a trifluoromethyl moiety. Trifluoropyruvate imines were selected as substrates for this purpose. These imines were activated by a catalytic amount of TRIP and reacted with a wide variety of indole derivatives to afford the desired compounds in high yields (up to 99%) and enantioselectivities (up to 97.5:2.5 er). The absolute configuration of a representative example was determined by comparison of theoretical and experimental ECD spectra. The deprotection of the 6-chloro derivative with trifluoroacetic acid yielded the free amino ester. In addition to indole derivatives, pyrrole could be used as substrate for this Friedel-Crafts reaction. However, more investigations are necessary to obtain higher yields and enantioselectivities in that case. The last project of this thesis describes the development of copper-catalyzed multicomponent reactions. Terminal alkynes, tosyl azide, methanol and nitroolefins reacted in the presence of triethylamine as base and catalytic amount of copper(I) iodide to form functionalized imidates in one-pot. A wide variety of terminal alkynes and nitroolefins were tolerated to give the desired adducts in high yields (up to 74%) with moderate diastereoselectivities (up to 66:34 dr). The course of this transformation was studied by NMR spectroscopic experiments. Interestingly, an intramolecular example was discovered that led to the formation of a 1,2-dihydroisoquinoline derivative
