A highly efficient one-flask method for the preparation of the individual diastereoisomers of ribonucleoside 3',5'-cycle N-substituted phosphoramidates via the direct Appel reaction. X-ray structure of trans-5-isopropyl-2'-deoxyuridine 3'5'-cyclic N-benzylphosphoramidate

A superior method for the preparation of 3',5'-cyclic N-substituted phosphoramidates of purine and pyrimidine ribo- and deoxyribonucleosides is reported. An Appel-type reaction of various 3',5'-cyclic nucleoside monophosphates using a Ph sub(3)P/CCl sub(4) pretreatment followed by addition of the requisite amine gives the corresponding phosphoramidate as a mixture of diastereomers in 31-85% isolated yields. Separation of the individual diastereomers is accomplished by chromatography in SiO sub(2). An X-ray crystallographic study of one diastereomer of the N-benzylphosphoramidate based on the 3',5'-cyclic diester of adenosine established the trans relationship of the PhCH sub(2)NH and nitrogen base as well as the equatorial position of the PhCH sub(2)NH on the chair form of the 1,3,2-dioxaphosphorinane ring. The structural parameters observed for the five- and six-membered rings are consistent with those of other neutral nucleotide derivatives.