Studies On The Synthesis Of Nucleoside Polyphosphates And ?-aminophosphonates

Nucleoside polyphosphates are important naturally occurring compounds.The CDP-choline is the rate-limiting step in phosphatidylcholine(PC)biosynthetic pathway.Dinucleoside polyphosphates are present in human and other mammalian species and known as intra-and extra-cellular regulators of many important biological processes.In addition,as structural mimics of natural amino acids,aminophosphonic acids and their esters have been extensively investigated as transition-state analog inhibitors of a huge variety of enzymes with physiological and pathologcial importance,such as metallo-proteases,aspartic proteases,phosphatases,ligases,and glycotranferases.The thesis focuses on development of the nucleoside phosphoropiperidates via the P(V)-N activation strategy provided a reliable synthetic method for nucleoside diphosphate choline.The method synthesis of nucleoside phosphoroperidates via was ptomoted for synthesis of nucleodise ?-diphosphoroperidates/?-triphosphoroperidates.The P(V)-N activation strategy presents a novel and highly effivient approach for the synthesis of nicleoside polyphosphates and dinucleoside polyphosphates.At the same time,a highly efficient one-pot method for the synthesis of a variety of a-aminophosphonates via the one-pot three-component reaction of aldehyde,amine,and phosphite has been developed by using a little of HfCl4 as the catalyst.The reaction conditions were system optimization,and the reaction mechanism was deep research.The detailed research contents are described as follow.1)Efficient synthesis of cytidine diphosphate choline(CDP-choline)and its analogs:the nucleoside phosphoropiperidate was used as active intermediate,adding phosphorylcholine,activating reagent(4,5-bis-cyanide-imidazole,DCI)for synthesis of nucleoside diphosphate choline.The system optimization of reaction conditions(reactants,activating reagent,reaction temperature,reaction solvent)build an efficient method for synthesis of those compounds.On the basis of the P(V)-N activation strategy,we report in this part an efficient approach for the preparation of CDP-choline and related nucleotide analogs from nuvleoside phosphoropiperidates in high yields.2)Synthesis of(di-)nucleoside polyphosphates from nucleoside phosphoroperidates via the activation of P(V)-N activation strategy:the method synthesis of nucleoside phosphoroperidates via was successful used in synthesis of nucleodise ?-diphosphoroperidates/y-triphosphoroperidates.In the part,a general and facile approach was built for the synthesis of nucleoside tetra-,pentaphosphates(Np4s/Np5S),and the synthesis of dinucleoside penta-,hexa-,heptaphosphates(NpsN's/Np6N's/Np7N's)via the 4,5-dicyanoimidazole(DCI)-promoted coupling of nucleoside ?-diphosphoroperidates with nucleoside propa-,tetra-,pentaphosphates.As a result,we developed efficient P(V)-N activation methods for synthesis of both nucleoside polyphosphates and dinucleoside polyphosphates,and this new accessible features easily accessible starting materials,mild reaction conditions,and moderate to good isolated yields.3)Highly efficient synthesis of ?-aminophosphonates catalyzed by hafnium(?)chloride:the original method for synthesis of ?-phosphoramidate is base on a pot ternary reaction.New Lewis acid(HfCl4)was used as catalyst.The conditions of reactivation reagents,reaction solvent,reaction concentration and reaction temperature were reached,and got the target products of a high rate.As a result,this is a successful method for synthesis of a-phosphoramidate,include aryl aldehyde/aryl amine,alkyl aldehyde/aryl amine,aryl aldehyde/alkyl amine,alkyl aldehyde/alkyl amine,and double alkyl amines.In this part,the method was found for synthesis of ?-phosphoramidate,and different types of compounds were successful synthesis.As this time,a new method was built for synthesis of ?-phosphoramidate.