Studies on Enantioselective Stetter and Aza-Benzoin Reactions Catalyzed by Bis(amino)cyclopropenylidenes (BACs)

Abstract

NHC catalysis is one of the main pillars of organocatalysis. Its importance has been built upon the reversal of polarity (umpolung) of aldehydes. This catalytic activity profile has led to some of the most important methodologies in synthetic chemistry. One area that is significantly influenced by NHC catalysis is the preparation of motifs with 1,2 and 1,4 functional groups relationships. To this end, there have been several challenges to be addressed by NHC catalysis such as chemo-, regio-, and stereoselectivity. One of the known strategies that has been widely used by organic chemists to tackle these challenges is the catalyst design. Depending on the nature and requirements of a reaction, efficient NHC catalysts have been designed and their efficacy tested. Nevertheless, there are several challenges that have not been successfully addressed yet. It was hypothesized that chiral bis(amino)cyclopropenylidenes (BACs) could address some of these challenges. This thesis showcases a series of novel competent catalysts that were designed and prepared to address enantioselectivity in the synthesis of 1,4-dicarbonyl compounds using the Stetter reaction. Use of rigid BAC catalysts proved to be effective. Different aromatic and heteroaromatic aldehydes as well as various chalcone derivatives were used as reaction partners in the Stetter reaction. Moderate to excellent enantioselectivities (55 to 94% ee) were obtained, showing a significant improvement over previous studies using chiral NHCs (up to 78% ee). The usefulness of chiral BACs was further demonstrated in the enantioselective 1,6-conjugate addition using p-quinonemethide as the Michael acceptor. Good enantioselectivity was obtained (76% ee) using this reactant. The origin of the enantioselectivity in the Stetter reaction was studied using density functional theory (DFT). The transition states and intermediates of key steps in the reaction mechanism were modeled and their energies were calculated. The computational results show that R enantiomer is slightly preferred, which is consistent with the experimentally obtained results. Nevertheless, the energy difference between two pathways leading to each enantiomer was found to be too small (0.2 kcal/mol), and cannot be used to explain the enantiomeric excess that was observed in experiment (90% ee). Chiral BACs were also tested in the aza-benzoin reaction. It was demonstrated that chiral BACs show a much better reaction scope than chiral NHCs in the case of aromatic and heteroaromatic aldehydes, with 43-80% ee and 54-100% yield.