Peptide Catalyzed Conjugate Addition Reactions of Aldehydes to Nitroolefins - Mechanistic Insights and Transformation of Bifunctional Substrates

Abstract

The conjugate addition reaction between aldehydes and nitroolefins belongs to an active field of organocatalyzed reactions. Accordingly, highly enantio- and diastereoselective methodologies relying on secondary amine organocatalysts have been established. In the context of this thesis we investigated the secondary amine-catalyzed conjugate addition reaction of aldehydes to nitroolefins. Despite intensive research on the mechanism, the role of the intermediate generated by the carbon-carbon formation is still under debate. The structure of such an intermediate is thought to be either an iminium nitronate- or a 1,2-oxazine N-oxide species. We show in Chapter 3 that a nitronate model system allows identification of nitronates by UV/Vis spectroscopy. Under preparative conditions, a novel characteristic band was identified alongside established ones. By computational studies we demonstrated that the newly observed excitation belongs to the intermediate formed by the carbon-carbon bond formation. We monitored this intermediate in situ and showed that the structure of the secondary amine catalyst as well as the nature of the solvent significantly influence its stabilization. Since alkylating substrates are prone to deactivate secondary amine catalysts, the application of these substrates is a major challenge in the field. In Chapter 4 we address this issue and show that in the secondary amine-catalyzed conjugate addition reaction of aldehydes to nitroolefins nitroacrylates alkylate the catalyst reversibly. We demonstrate that the release of the alkylated catalyst becomes rate limiting and a complementary mechanistic scenario is observed when using nitroacrylates. Further we show how sterically demanding nitroacrylates reduce the alkylation rate of the catalyst, and then use such bulky substrates to achieve faster reaction rates. We identified a cocatalyst that led to even faster reaction rates and allowed use of only 500 ppm of a peptidic catalyst to prepare various substrates in good yields, diastereoselectivities and enantiomeric excesses. Further we demonstrate in Chapter 5 that combining the peptide-catalyzed conjugate addition reactions of aldehydes to nitroacrylates with subsequent cinchona-catalyzed additions of thioenolates allows the synthesis of tricyclic natural product derivatives (tetraponerines). We developed a synthetic route for the transformation of ester-substituted γ-nitroaldehydes formed in peptide-catalyzed conjugate addition of aldehydes to nitroacrylates to a chiral imine building block. We demonstrate that this imine reacts with thioenolates in the presence of a cinchona alkaloid catalyst to form a tetraponerine core structure (annulated 5-6-5 ring), which bears up to seven stereogenic centers.