The Synthetic Studies On Asymmetric Total Synthesis Of (+)-Biotin And Related Reactions

Based on the new methodologies in the field of current asymmetric catalysis, this thesis mainly focused on the investigation of new synthetic strategy to fulfill the stereospecific total synthesis of biotin and many results of this research present a good promise in both academia and industry. In the first part, the asymmetric synthetic route to (+)-biotin were developed by utilizing chiral Lewis base-catalyzed enantioselective alcoholysis of meso-cyclic anhydride as the key step. In the following part, an enantioselective desymmetrization of meso-thioanhydride strategy has been investigated to fulfill the stereocontrolled total synthesis of (+)-biotin.In chapter 1, the significant progress of asymmetric total synthesis of (+)-biotin has been briefly reviewed. The investigation of new synthetic method to fulfill the enantioselective desymmetrization of meso-cyclic anhydride in optically pure form along Hoffmann Roche lactone-thiolactone route developed by Goldberg and Sternbach in 1949 is the new direction and challenge to complete the stereocontrolled total synthesis of (+)-biotin.In chapter 2, a range of chiral bifunctional thiourea and sulfonamide organocatalysts derived from cinchona alkaloid were screened the catalytic reaction activity in the asymmetric alcoholysis of meso-cyclic anhydride in the total synthesis of (+)-biotin. The bifunctional sulfonamide quinine derivatives (QN-SA) showed highly reactive and stereoselectivity in the preparation of (4S,5R)-halfester under the optimum reaction conditions. To account for the observed stereochemical outcome of this reaction, a transition state model was proposed. In addition, we improved the preparation of the cyclic anhydride and the ionic hydrogenation for reducing the tertiary hydroxyl group of thiolactol.In chapter 3, we designed a novel desymmetrization strategy for the stereospecific total synthesis of (±)-biotin from the commercially available cis-1, 3-dibenzyl-2-imidazolidone-4,5-dicarboxylic acid. The key step in the sequence involve a concise and efficient desymmetrization reaction of meso-thioanhydride with carbon-based nucleophile. Investigation of the structurally diverse set of chiral ligands and organocatalysts to fulfill the enantioselective desymmetrization of meso-thioanhydride in an optically pure form to accomplish the asymmetric total synthesis of (+)-biotin is also described in this part.