Novel 5’-Substituted Cinchona-Derived Organocatalysts: Synthesis, Reactivity, and Dual Activation Potential

This work presents the synthesis of three little-investigated types of asymmetric cinchona organocatalysts. The cinchona moiety is considered one of the privileged chiral skeletons, and one of its well-known modifications involves attaching H-bond donor catalyst moieties at the C9 position. In our study, we aimed to introduce different types of H-bond donor functional groups, namely squaramide and thiourea, at the relatively unexplored 5’-position of the quinoline ring. Our goal was to compare the performance of these novel catalysts with those that are already established. Our test reaction was a pharmaceutically relevant Michael addition reaction, ultimately producing an intermediate for baclofen. The results indicated that the new substitution at the 5’-position did not yield significant advantages in terms of either yield (34%–97%) or enantiomeric excess (0%–18%). Additionally, we synthesised a unique type of asymmetric organocatalyst that incorporates both an H-bond donor and an enamine catalyst moiety, allowing for two different activation mechanisms. This innovative catalyst was also used in the synthesis of warfarin, resulting in lower yields (4%–26%) but promising enantiomeric excess values (13%–60%).