Studies On The Synthesis Of Several 2?-Modified Nucleoside Derivatives

Most 2?-modified nucleoside derivatives exhibit significant biological properties,including anti-cancer,anti-virus,anti-tumor activities and gene therapy.Thus,they are essential ingredients of the second generation antisense drugs.With the deepening of the research on 2?-modified nucleoside derivatives,a large number of 2?-modified nucleoside derivatives have been designed and synthesized.These works can be mainly classified as following:halogen,alkyl,alkoxy,alkynes,aromatic,azide,and amino modification.In this paper,for the purpose of enriching the diversity of 2?-modified nucleoside derivatives,seven terminal target products have been synthesized.Firstly,according to kanagawamicin,a synthetic route for carboxylic acid derivatives of kanagawamycin was designed.Using 1,3,5-tribenzoyl-?-D-ribofuranose as the raw material,2?-azidoglycoside was synthesized.Then it was reacted with N²-pivaloyl-4-chloro-5-cyano-6-bromo-7H-pyrrole[2,3-d]pyrimidine through a Vorbrüggen glycosylation reaction to obtain 2?-azidonucleoside.The 2?-azidonucleoside undergoes a seven-step reaction such as the hydrolysis of the 4-position chlorine at the base,the palladium-carbon hydrogenation to reduce the 2?-azido group and the6-position bromine,deprotection,and cyano hydrolysis to obtain the target product?-/?-Kanagawamycin carboxylic acid derivatives.Secondly,based on the reported novel nucleoside 2?-O-methyl-?-L-arabinuridine,a simple and fast synthetic route was designed.Using 1,3,5-tri-O-benzoyl-?-L-ribofuranose as the raw material,the ribose was converted into arabinose.Then,the arabinose is subjected to five-step reactions such as methylation,Vorbrüggen glycosylation reaction,and deprotection to obtain the target products2?-O-methyl-?-L-arabinuridine and 2?-O-methyl-?-L-arabinuridine.These two compounds are the first reported in fully synthetic studies.However,the NMR data of the synthesized compounds were inconsistent with the reported in the literature.According to the NMR data and optical rotation of the reported compound,it was inferred that the nucleoside might be ribonucleoside.Therefore,2?-O-methyl-?-L-uridine was designed and synthesized.According to NMR,X-ray diffraction analysis and optical rotation,it was determined that the compound of Guo Zhiyong's group isolated from Penicillium sp.?NO.64?was 2?-O-methyl-?-L-uridine.Finally,the synthetic routes of nerabine and fludarabine were optimized.Using2-O-?2-iodobenzoyl?-1,3,5-tri-O-benzoyl-?-D-ribose as the raw material.Six-step reactions including Sonogashira reaction,Vorbrüggen glycosylation reaction,removed ortho-alkynyl benzoate group in the presence of Ph₃PAu TFA,produce arabinoglycosides,strong base hydrolysis or deprotection.The target products of nerabine and fludarabine were 24.9%and 35.5%,respectively.This route is faster,easier and more efficient than traditional methods.