The Design,Development And AppIication Of Two Concepts For Asymmetric Organocatalysis

The systematic study on asymmetric organocatalysis is described in this thesis. We aimed at solving some long-standing problems in this research field. The thesis is divided into three parts.Part1:The design, development and application of the concept of "Asymmetric Organocatalytic Relay Cascades":The application of asymmetric organocatalytic cascade reactions in the synthesis of complex molecules with multiple stereocenters is one of the fast moving fronts. However, despite the important advances in this research field, there are still many limitations. At present, most of organocascade reactions are designed based on the mature strategy of iminium/enamine catalysis as well as a few cases involving bifunctional base/acid catalysis. Furthermore, the controlled synthesis of diastereomers is a long-standing, yet unsolved problem. Another but not the last problem is many important molecules could not been constructed with a single catalyst. To this end, the concept of "Asymmetric Organocatalytic Relay Cascades" was developed as one of effective ways for solving these challenging problems. This new concept has been successfully applied in the synthesis of fully substituted piperidines and polysubstituted cyclohexanes. Different diastereomers could be readily accessed in high enantiomeric excess by changing the combination of catalysts used in the cascade reaction. Notably, the exploration of intermolecular H-bonding and covalent bond relay catalysis makes important complementation to the current limitations. This concept provides a potentially useful method for the design and synthesis of complex molecules.Part2:The design, development and application of the concept of "Hydrogen-Bond-Mediated Supramolecular Iminium Catalysis":As the third discipline in the field of asymmetric catalysis, organocatalysis has been recognized as important as metal catalysis and biocatalysis. As a result, this research field has received a great deal of attention and being extensively explored. Iminium, enamine and H-bond catalysis are three fundamental activation modes in this research field. Based on these new activation modes, many valuable reactions have been increasingly developed and successfully applied in the synthesis of medicinal agents and natural products. However, the current research in the field of asymmetric organocatalysis has been hampered by several limitations, such as long reaction time, high catalyst loading, low reactivity and so on. To this end, we designed and developed a new concept termed as "Hydrogen-Bond-Mediated Supramolecular Iminium Catalysis" for solving these long-standing challenge problems in iminium catalysis. We find this concept could be applied to iminium catalysis. Another advantage of this concept is that the stereocontrolling ability of the modularly designed supramolecular iminium catalysts will be powerful since they can be easily fine-tuned by simple modification or replacement of any of the components; as a consequence, a library of diverse catalysts could be used to make a wide range of supramolecular iminium catalysts enantioselective, while special tailored complex catalysts are avoided. Hence, this concept is important to the field asymmetric catalysis involving iminium or H-bond catalysis.Part3:The application of cascade reactions in natural products synthesis and drug discovery:Natural products and drug molecules synthesis as a driving force for cascade reactions discovery is a promising research field which has been extensively investigated. More specifically, despite the high efficiency, there are few organocascade reactions have been applied in the synthesis of natural products and drug molecules. Thus, the further development of this challenging yet promising research field is of great importance. To this end, we developed an efficient cascade reaction for the construction of the skeleton of Lycorine-type alkaloids. The total synthesis of a-Lycorane has been accomplished. Moreover, we developed a highly efficient cascade reaction for synthesis of drug-related trifluoromethylated furans.