Synthesis Of Fondaparinux Sodium Building Block B And Preparation Of Precursor For Nitrogen Radical Reactions To Construct The Skeleton Of Indole Alkaloids

This thesis consists of two parts:(1)scalable synthesis of Fondaparinux Sodium Building Block B;(2)preparation of precursor for nitrogen radical cascade reactions to construct the skeleton of indole alkaloids.(1)Fondaparinux Sodium is widely used as a new anticoagulant drug for major cardiovascular and orthopedic surgeries such as hip fractures,knee surgery or hip replacement,preventing the occurrence of venous thrombosis.It's difficult to synthesize this pentasaccharide because of its complex structure and long synthetic steps,thus the industrial,large-scale production of Fondaparinux is very challenging.Therefore,it is imperative to develop highly efficient strategies for producing the homogeneous pentasaccharide for clinical applications.Indeed,the L-iduronic acid building block B has been a bottleneck in the total synthetic route.Herein,the scalable synthesis of building block B was investigated by two different strategies.The initial synthesis was inefficient(11 steps and 4% overall yield)and required expensive reagents and rigorous reaction conditions,and methyl ester was installed at the early stage in the synthesis.In the optimized strategy,the methyl ester was introduced at the late stage,and the synthetic route was more straightforward and gave better overall yield(10 steps and 15% overall yield).Moreover,the one-pot protocols(8 to 10,13 to 37)and crystallization procedures(10,12,13,26)considerably simplified the overall synthetic procedures and minimized wasteful purification steps.Furthermore,mild reaction conditions and inexpensive reagents were used throughout the process.Notably,each transformation could be readily achieved on a 10-g scale,some even up to 100-g scale.These results significantly improved the scalability of Fondaparinux Sodium Building Block B.(2)The generation of nitrogen radical and the application in the synthesis of complex compounds containing nitrogen were briefly summarized in the second part.In the synthetic researches of indole alkaloids,a nitrogen radical cascade reaction was designed by us to construct the crucial cores.Herein,the preparation of precursor for the nitrogen radical cascade reactions was explored.First,the important intermediate dimethyl aldehyde 116 was prepared from 2-nitrobenzaldehyde by Wittig reaction,reduction,oxidation and asymmetric Miachel addition reaction.Subsequently,condensation reactions of different amines with compound 116 were investigated and four condensation products were successfully prepared.With 4-methoxy benzylamine condensation product 126 as the substrate,Krapcho decarboxylation was successfully achieved,and the lactam reduction was tried in various conditions.These preliminary studies established the important foundation for using nitrogen radical cascade reaction to construct indole alkaloid cores.