SYNTHESIS OF SOME NUCLEOTIDES DERIVED FROM 3'-DEOXYTHYMIDINE

Phosphorylation of 3′-deoxy-3′-iodothymidine gives the corresponding 3′-deoxy-3′-iodothymidine 5′-phosphate in high yield. Activation of the phosphate group can be achieved by formation of the phosphoromorpholidate under anhydrous conditions, and subsequent condensation with tributylammonium pyrophosphate in anhydrous dimethyl sulfoxide gives 3′-deoxy-3′-iodothymidine 5′-triphosphate in modest yield. The latter reaction is complicated by simultaneous dehydrohalogenation giving the related 2′,3′-unsaturated nucleoside 5′-triphosphate and by extensive intramolecular displacement of iodide ion by phosphate giving a 3′,5′-cyclic phosphate with the 2-deoxy-β-D-threo-pentofuranosyl configuration. The same spectrum of products is obtained using 3′-deoxy-3′-iodothymidine 5′-phosphoroimidazolate prepared from the parent nucleoside and triimidazolephosphine oxide. The various products are characterized by enzymatic and spectroscopic techniques, and reduction of either the iodotriphosphate or the unsaturated triphosphate with hydrogen and palladium gives 3′-deoxythymidine 5′-triphosphate, the enzymatic properties of which are discussed in the accompanying paper. Phosphorylation of 1-(2-deoxy-β-D-threo-pentofuranosyl)thymine with diphenyl phosphorochloridate gives the crystalline 5′-diphenyl phosphate ester that can be converted with base into the same 3′,5′-cyclic phosphate obtained as a by-product during preparation of the triphosphates above. A pair of 3′,5′-cyclic phosphate triesters diastereoisomeric about their phosphorus atoms are intermediates in this cyclization reaction. © 1969, American Chemical Society. All rights reserved.