Peptides as catalysts for asymmetric 1,4-addition reactions of aldehydes to nitroolefins

Abstract

Within this thesis, the development of peptides as highly efficient catalysts for asymmetric conjugate addition reactions of aldehydes to nitroolefins is described. The tripeptide TFA*H-Pro-Pro-Asp-NH2 1 was originally developed and established as an efficient catalyst for asymmetric aldol reactions. Based on insight gained from conformational analysis it was predicted that 1 and closely related peptides may also serve as catalysts for asymmetric 1,4-addition reactions. Indeed, TFA*H-D-Pro-Pro-Asp-NH2 21 proved to be a highly effective catalyst for asymmetric conjugate addition reactions of aldehydes to nitroolefins. A broad scope of different substrate combinations including aliphatic and aromatic nitroolefins as well as linear, ?-branched and aromatic aldehydes reacted readily in the presence of as little as 1 mol% of 21 to the desired ?-nitroaldehydes in high yields (82-99 %), high diastereoselectivities (syn:anti = 4:1->99:1) and very high enantioselectivities (88-98 % ee). Thus, 21 proved to be significantly more active and applicable to a broader substrate scope compared to other amine based catalysts that had previously been developed for 1,4- addition reactions of aldehydes to nitroolefins. In addition, the peptidic catalyst 21 also offered solutions to other challenges encountered with the other amine based catalysts and allowed for using only a small excess of the aldehyde providing the products within a reasonable reaction time. Analysis of the structural and functional prerequisites for high catalytic efficiency within catalysts 21 led then to the establishment of the closely related peptide TFA*H-D-Pro-Pro- Glu-NH2 56 as an even more effective catalyst for conjugate addition reactions of aldehydes and nitroolefins including the functionalised ?-nitroacrolein dimethylacetal (up to quant. yields, syn:anti ratio up to >99:1, up to 99 % ee). Even nitroethylene, the simplest of all nitroolefins, reacts readily with functionalised and non-functionalised aldehydes. The derivatisation of the corresponding products offered a new entry into the synthesis of monosubstituted ?2-amino acids, previously only accessible by using chiral auxiliaries. Extensive kinetic studies allowed for further insight into the reaction mechanism and led to the establishment of improved reaction conditions. Only as little as 0.1 mol% of 56 was required for the corresponding reactions, which is the lowest catalyst loading that has been achieved for enamine catalysis to date. A further benefit of the peptidic catalyst is that, in contrast to many other organocatalysts, no additives are necessary to obtain the desired products in very high yields and selectivities. Further conformational studies indicated that peptide 56 is more rigid than usual tripeptides but still bear a significant degree of conformational freedom. Therefore, the right degree of flexibility might be the key to the effectiveness of peptides as asymmetric catalysts. These studies demonstrate the high potential of short peptides as efficient catalysts and establish a basis for further investigations. These may include the application of peptides as catalysts for other 1,4-addition reactions using different Michael donors (e.g. ketones, malonates, nitroalkanes) and Michael acceptors (e.g. ?,?-unsaturated aldehydes and ketones, ?-disubstitued nitroolefins). Also new challenging transformations such as e.g. ?-alkylation of aldehydes or complex cascade reactions might become accessible by using peptides as catalysts.