Studies On Asymmetric Total Synthesis Of (+)-Biotin And Related Reaction

The total synthesis studies on the natural product-(+)-biotin are described in this dessertation, which includes two chapters as follows:In Chapter 1,the siginificant progress of Roche’s Sternbach total synthesis of (+)-biotin over the past 60 years has been reviewed,including:1) the synthesis of the key chiral building block-(3aS,6aR)-lactone,2) the conversion of (3aS,6aR)-lactone into (3aS,6aR)-thiolactone,3) the Introduction of carboxybutyl chain on (3aS,6aR)-thiolactone,4) debenzylation of (+)-dibenzylbiotin.In addition,the further improvements of the Sternbach approach are still the development of a high effient synthesis of (3aS,6aR)-lactone and a short installation of carboxybutyl side chain.In Chapter 2, a new route of stereospecific total synthesis of (+)-biotin starting from the easily available Fumaric acid, was put forward. The pivotal reactions of this new approach included the quinine-mediated asymmetric alcoholysis of meso-cyclic anhydride 6 and the introduction of carboxybutyl chain onto the key intermediate (3aS, 6aR)-thiolactone 8 via an one-pot Grignard reaction. Various experimental conditions of the quinine-catalyzed enantioselective alcoholysis were investigated with an aim to determine the optimized condition. Subsquent debenzylation upon treatment of 47% HBr followed by ring-closure afforded (+)-biotin with an overall yield of 24%.In addition, compound 4-11 in this thesis were new compounds, and the structures of all compounds synthesized were identified by IR、1H NMR、13C NMR、ESI or EI.