The Design And Application Of Novel Rosin-derived Amine Thiourea Bifunctional Catalytic System In Asymmetic Synthesis: Drug-lead Synthesis Of Chiral Unnatural Amino-acids And Bioactive Molecules

Organocatalysis is defined as the acceleration of chemical reactions with a substoichiometric amount of organic molecules, which do not contain an active metal reaction center. The operational simplicity, ready availability of these mostly inexpensive bench-stable catalysts, which are incomparably more robust than enzymes or other bioorganic catalysts makes organocatalysis an attractive method for the synthesis of complex structures. In contrast to any other system developed earlier, organocatalytic reactions provide a rich platform for multicomponent, tandem, or domino-type multistep reactions, allowing the increase of the structural complexity of the product in a highly stereocontrolled manner. Moreover, there is no risk of metal leakage and also no expensive recovery process is required in the waste treatment. Such protocols are increasingly finding application in the synthesis of both biologically active natural products and important synthetic compounds. Nowadays, the environmentally friendly "green" aspect of this chemistry coupled with the sustainability of the catalysts is considered widely for replacing metal-based reactions. Hydrogen bonding acts as an ubiquitous glue to sustain the intricate architecture and functionality of proteins, nucleic acids and many supramolecular assemblies, and thus is responsible for the structure of much of the world around us. Rapid progress in other areas of organocatalysis, which occurred contemporaneously with early developments in chiral hydrogen-bond-donor catalysis, rendered chemists keenly aware of the potential of simple organic molecules in asymmetric catalysis. Although the concept of hydrogen donor catalysts has been widely accepted, information about the mechanism is quite limited.A key goal of the synthesis of chiral catalysts is to both maximize the efficiency of using readily available materials and minimize the generation of waste. With the continuous development of asymmetric synthesis, in the past few decades, organic chemists have made great effort to develop effective asymmetric catalysts and a variety of large number of chiral organocatalysts have been reported. The current synthetic strategy often relies on the derivatization of the available chiral pool of the natural organic products, which limits the number of accessible derivatives. However, they are almost always rooted in a very few "core structure " of natural chiral pool. For example:natural amino acid structure, Cinchona alkaloid and glycosides, etc. Based on the current application can be used for asymmetric synthesis of chiral catalysts pool is still very limited, the discovery and development of new chiral pool sources, will become very urgent and important. If a resource-rich, low cost, renewable source can be successfully applied to asymmetric catalysis, which will greatly promote the development of the field.Although the natural rosin with excellent structural backbone and well-defined stereocenters is abundant in nature, its easily available derivatives have rarely been developed in the synthesis of efficient catalysts for asymmetric catalytic reactions to date. Starting from commercially available natural rosin derivatives, a class of bifunctional rosin-derived amine thiourea catalysts were designed and synthesized. These rosin-derived chiral thiourea catalysts have successfully applied to asymmetric catalysis firstly, and have been shown to serve as effective catalysts for organocatalytic process by the investigation of the efficacy of the thiourea catalysts in comparison with other thiourea catalysts reported. The powerful asymmetric catalytic activity has been proved firstly for the application in asymmetric catalysis in the future.We found that this new types of rosin-derived chiral thiourea catalysts showed excellent catalytic activities in many catalytic asymmetric organic reactions through our research (Michael addition reaction, Mannich reaction, Henry reaction, aldol reactions, Friedel-Crafts reaction, inverse-electron-demand Diels-Alder reaction, Michael/cyclization reaction, Michael/acyl transfer reaction, Morita-Baylis-Hillman reaction, and more step cyclization reaction). In my research work, encouraged by these elegant advances and the establishment of novel efficient catalytic system, a variety of new optically active non-natural amino acids had been synthesized by using asymmetric synthesis strategy. Especially the use of the doubly stereocontrolled asymmetric synthesis approach could facilitate to achieve the efficient synthesis of a variety of new optically active non-natural amino acids with different configurations (non-naturalα- orβ-prolines, non-naturalα-amino acids, non-naturalβ-amino acids, non-naturalγ-amino acids, non-naturalβ-hydroxy-α-amino acids, hydroxy-substituted non-naturalβ-amino acids, and other no-natural chiral amino acids), including several types of non-natural amino acids are the first synthesis. The research greatly promoted the study of peptide drugs. Furthermore, drug-lead synthesis through rapid construction of chiral molecular complexity around the biologically relevant framework using a highly efficient strategy is a key goal of organic synthesis. Furthermore, it remains a great challenge to develop an efficient and convenient strategy to access these optically active natural alkaloids and related analogues for further biological studies, thereby contributing to the development of new therapeutic agents. In my work, based on the establishment of novel efficient catalytic system, the highly efficient and convenient strategies that allow rapid construction of several kind of optically active natural alkaloids, related analogues and biologically relevant frameworks have been presented.