Peptide-Catalyzed Stereoselective Conjugate Addition Reactions of Aldehydes and Ketones to Maleimides

This thesis describes the development of peptidic catalysts for stereoselective conjugate addition reactions of aldehydes and ketones to maleimides. In addition, mechanistic aspects of this conjugate addition were investigated and structural aspects of peptidic catalysts of the general H-DPro-Pro-type were studied. From a collection of tripeptides, H-DPro-Pro-Asn-NH2 was found to catalyze the conjugate addition reaction between aldehydes and unprotected maleimide in a highly stereoselective manner with only 5 mol% of the catalyst required. The obtained products were derivatized to corresponding pyrrolidine, lactam, lactone, and peptide-like compounds by two-step procedures without loss of optical purity. Interestingly, peptide H-DPro-Pro-Asn-NH2 bearing two amide functional groups in the third position, gave significantly higher stereoselectivities and conversions than peptides bearing an acidic moiety. This contrasts with previous findings, where peptides bearing a suitably positioned acidic moiety were found to be optimal for the conjugate addition of aldehydes to β-monoand α,β-disubstituted nitroolefins. Various aliphatic and functionalized aldehydes, which could potentially lower reactivity or stereoselectivity by hydrogen-bonding to the catalyst, were successfully reacted with maleimide. Initial mechanistic investigations showed that significantly lower conversions were obtained with N-protected maleimides. X-ray crystallographic, computational, and NMR-spectroscopic studies suggested a dual hydrogen bonding interaction between the asparagine side chain of the catalyst and the substrate to be important for the observed high stereoselectivities. In further mechanistic studies non-linear effects were not found, but product inhibition was shown to significantly slow the reaction down. NMR-spectroscopic and mass spectrometric studies revealed an enamine as a highly likely nucleophilic species and a cyclobutane as resting state. In the second part of this thesis, H-Pro-Pro-Asp-NHC12H25 was found to be a highly reactive and selective catalyst for the conjugate addition reaction between aldehydes and C-substituted maleimides. Only 1 – 5 mol% of the catalyst were necessary in order to obtain the products in good yields and excellent regioand stereoselectivity. In case of C-substituted maleimides, a suitably positioned acidic moiety in the third position of the peptide was important for obtaining high stereoselectivity. Furthermore, an aliphatic chain at the C-terminus of the peptide improved its solubility in the optimal solvent 1,4-dioxane, which enhanced the catalysts reactivity without affecting stereoselectivity. A range of electron rich and electron poor aromatic substituents were