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

摘要

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