Studies On Catalytic Asymmetric Synthesis Of Thiamphenicol Antibiotics And Related Reactions

Thiamphenicol (1) and florfenicol (2) were a class of broad spectrum antibiotics with two stereocentres andβ-amino alcohol structures. Over the past 30 years, there has been continuous interest in developing novel and practical asymmetric approaches towards 1 and 2 for the installization of their two adjacent stereocentres by utilizing asymmetric catalysis as key chiral technology. In this thesis, two novel and efficient synthetic routes for target molecule 1 and 2 have been developed.In chapter 1, the significant advancement of 1 and 2 by utilizing different strategies over the past 60 years is described. The synthetic strategy developed by Schering-Plough company in USA starting from commercially available 4-(methylsulfonyl)-benzaldehyde, via (-)-threo-2-amino-1-4-(methylsulfonyl)phenyl-1,3-propanediol (14), as an advanced intermediate, remains a reliable approach towards 1 and 2 in industry.In chapter 2, an efficient approach for the enantioselective synthesis of 1 and 2 was completed via 14 from commercially available 4-chlorobenzaldehyde in 42% and 37% overall yield respectively, in which a vanadium-catalyzed asymmetric epoxidation was used as key reaction. The asymmetric epoxidation was carried out in the presence of 70% tert-butyl hydroperoxide (TBHP), overriding the use of anhydrous TBHP in Sharpless epoxidation. A highly regio-and stereoselective ring-opening of chiral 2,3-epoxy alcohol was furnished by neighboring group effect. Besides, The utilization of n-perfluorobutanesulfonyl fluoride/Et3N·3HF provided foundation for the fluorination of 2. This route is characterized by cheap and readily available reagents, mild conditions, convenient workup, good yield and stereoselectivity, making it practical for large-scale preparation.In chapter 3, an alternative approach towards 1 and 2 was accomplished by utilized the Sharpless epoxidation of (E)-[4-(methylsulfanyl)phenyl]propenol as key reation in 23% and 13% overall yield respectively. The key features of the approach include a one-step oxidation of allyl and thioether group to form the key chiral epoxide 8 under the Sharpless epoxidation conditions, a BF3·Et2O-mediated regio-and stereoselective ring-opening reaction of protected 2,3-epoxy alcohol with benzyl alcohol, and a high efficient conversion of the azide 28 into the key intermediate aminoalcohol 14 via debenzylation and reduction of azido moiety in one-pot operation.The absolute configuration of 10 was unambiguously confirmed by means of X-ray diffraction and the configuration of 26 was assigned on the basis of 2D NOESY experiment.