Synthesis Of Nucleoside Drug Cidofovir And Its Analogues By Sharpless Asymmetric Dihydroxylation

As one important component of nucleosides,acyclic nucleoside is a class of special structurally and with potential biologically active molecules.Such as anti-herpes virus drug(S)-Cidofovir,(R)-Buciclovir,and D-Eritadenine as one inhibitor of S-adenosyl-L-homocysteine hydrolase.Through this list of chiral acyclic nucleosides and nucleotides exhibiting biological activities,one characteristic property is that two adjacent hydroxyl groups can always be found in the corresponding sidechains,and acyclic nucleosides and their phosphonates have emerged as a key class of antiviral nucleoside analogues.Therefore,developing an efficient method to construct chiral acyclic nucleosides and nucleotides with two adjacent hydroxyl groups connected to the side chains is highly desirable.Conventional routes to synthesize chiral acyclic nucleosides and nucleotides,which contain two adjacent hydroxyl groups in the side chains,are based on a chiral pool strategy.Most of the current synthesis is formed by splicing chiral side chains with purine or pyrimidine bases.Using(S)-Cidofovir as an example,different synthetic routes are used thechiral pool strategy,the generation of chiral key startingmaterials often requires multiple steps from a chiral pool with necessary stereochemistry.Considering that the Sharpless asymmetric dihydroxylation(SAD)reaction represents a powerful strategy for the construction of optically active vicinal diols,herein we report a catalytic asymmetric synthesis of chiral acyclic nucleosides,containing two adjacent hydroxyl groups in the side chains.Through the screening of ligand,bases,solvents,and temperatures,we have developed an efficient method for the synthesis of chiral acyclic nucleosides through Sharpless asymmetric dihydroxylation reaction of N-allylpyrimidines or N-alkenylpurines.A wide range of chiral acyclic nucleosides,bearing two adjacent hydroxyl groups in the corresponding side chains,could be afforded in moderate to good yields(57-97%yields)and excellent enantioselectivities(90-99%ee).Bz-protected-(S)-N~1-(2,3-dihydroxypropyl)-cytosine,the key intermediate for the synthesis of(S)-Cidofovir,could be obtained in two steps.Furthermore,a direct and efficient method for the production of(R)-Buciclovir has been developed.Compared to conventional methods based on a chiral pool strategy,this method only employs catalytic amount of chiral catalyst,which avoids the use of equivalent chiral source and will provide a new route to synthesize chiral acyclic nucleosides.A database of chiral acyclic nucleoside compounds was further expanded.At the end of the paper,the hydrogenation,carbon spectrum,high resolution,melting point and optical rotation of the new compounds were characterized by various means.The representative compounds absolute configuration was also determined by the single-crystal X-ray diffraction analysis.