Stereocontrolled synthesis of oligonucleoside phosphorothioates and PO/PS-chimeric oligonucleotides by using oxazaphospholidine derivatives.
Solid-phase synthesis of oligonucleotides having a fully-modified stereoregular phosphorothioate backbone or a stereoregular phosphate/phosphorothioate chimeric backbone was achieved by using diastereopure nucleoside 3'-bicyclic oxazaphospholidine derivatives and beta-cyanoethyl phosphoramidites as monomer units and N-(cyanomethyl)pyrrolidinium trifluoromethanesulfonate (CMPT) as an acidic activator. The trans-isomers of the oxazaphospholidines were obtained exclusively by the reaction of the 3'-OH of appropriately protected nucleosides and the corresponding 2-chloro-1,3,2-oxazaphospholidine derivative. The trans-isomers were configurationally stable and did not epimerize almost at all even in the presence of CMPT. As a result, the formation of phosphorothioate internucleotide linkages using the oxazaphospholidine derivatives and CMPT proceeded without any loss of diastereopurity. In addition to the synthesis of stereoregular phosphorothioate linkages, the synthesis of phosphate internucleotide linkages through the same method was studied. As a result of the study, stereoregular phosphate/phosphorothioate chimeric oligonucleotides as well as stereoregular oligonucleoside phosphorothioates were efficiently synthesized by using the same method.
Oka
Natsuhisa
N
Department of Medical Genome Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Chiba 277-8562, Japan.
Yamamoto
Mika
M
Sato
Terutoshi
T
Wada
Takeshi
T
D009841:Oligonucleotides / Q000138:chemical synthesis* / Q000737:chemistry; D010080:Oxazoles / Q000737:chemistry*; D013237:Stereoisomerism; D013873:Thionucleotides / Q000138:chemical synthesis* / Q000737:chemistry
D009841:Oligonucleotides; D010080:Oxazoles; D013873:Thionucleotides