| This thesis aims at the total synthesis of Tripdiolide and synthesis of the key intermediate of Dorzolomide hydrochloride,a anti-glaucoma drug.This thesis consists of the following three chapters:Chapter 1.Catalytic asymmetric Diels-Alder reactionIn recent years,catalytic asymmetric Diels-Alder reaction has made great progress.Some good performance,high selectivity chiral catalyst system has been found,and new catalysts are still going to appear.Some catalysts have great applicable potential for scale production.In this chapter,the reactions were reviewed according to the types of catalysts,such as Lewis acid catalyst、Lewis base catalyst、Bronsted acid catalyst、Bronsted base catalyst and bifunctional organic catalyst.Chapter 2.Studies on the total synthesis of TripdiolideUsing Diels-Alder reaction as key step,two linear synthetic routes to Tripdiolide were designed.Firstly,two key precursors for the Diels-Alder reactions were synthesized.The first scheme started from 5-methoxy-1-tetralone and carried out through HWE reaction、reduction、oxidation and enolization.The second synthetic route started from o-cresol as starting material and proceeded through methylation,reacting with 2-methyl-2-vinyloxirane,oxidation of formed allyl alcohol,and Wittig reaction of the aldehyde with BnOCH2PPh3Cl.Then,the Diels-Alder reactions were investigated using model substrates and the synthesized precursors with y-butyrolactone and maleic acid as dienophiles in turn.The desired products with necessary skeletons were obtained.The Further exploration using these intermediates to synthesize tripdiolide has been doing.Chapter 3.Synthesis of the key intermediate of Dorzolomide hydrochlorideThis chapter mainly focused on the asymmetric synthesis of the key intermediate of Dorozolomide.From methyl(R)-3-hydroxybutyrate as starting material,through toluenesulfonylation of hydroxyl group,SN2 substitution by 2-mercapto-thiophene,acid hydrolysis,Friedel-Crafts acylation reaction,reduction and hydroxy configuration inversion,oxidation by hydrogen peroxide,the dorzolamide intermediate was synthesized.The modification made the synthesis more convenient,efficient,and lower cost.Firstly,the use of a mild organic base triethylamine instead of metal alkali made the synthetic route more economy-friendly and environmental-friendly,and using a weak acid to change its configuration avoided use of advanced and expensive reducing agent and made the synthetic route more economical. |
