A Highly Efficient One-Flask Method for the Preparation of the Individual Diastereoisomers of Ribonucleoside 3',5'-Cyclic N-Substituted Phosphoramidates via the Direct Appel Reaction. X-ray Structure of trans-5-Isopropyl-2'-deoxyuridine 3',5'-Cyclic N-Benzylphosphoramidate

Article abstract of DOI:10.1021/jo00208a023

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 Ph3P/CCl4 pretreatment followed by addition of the requisite amine gives the corresponding phosphoramidate as a mixture of diastereomers in 31-85percent isolated yields.Separation of the individual diastereomers is accomplished by chromatography on SiO2.Most notably the reactions proceed readily with 3',5'-cyclic ribonucleoside monophosphates without protection of the 2'-OH or potentially reactive functionality on the nitrogen base.In most instances both diastereomers are formed in useful amounts.Amino groups used included C6H5CH2NH, C6H5NH, and (CH2)5N.Nucleosides employed were adenosine, deoxyadenosine, uridine, 5-isopropyl-2'-deoxyuridine, and 5-iodo-2'-deoxyuridine.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 PhCH2NH and nitrogen base as well as the equatorial position of the PhCH2NH 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 cyclic nucleotide derivatives.