~) Pergamon S0040-4039(96)00606-5 Tetrahedron Letters, Vol. 37, No. 20, pp. 3537-3540, 1996 Copyright © 1996Elsevier ScienceLtd Printedin GreatBritain.All rightsreserved 0040-4039/96 $15.00 + 0.00 A New Entry to Nucleoside Phosphorofluoridate and Nucleoside Phosphorofluoridothioate Diesters Martin Bollmark, Rula Zain, and Jacek Stawifiski* Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, S-106 91 Stockholm, Sweden. Abstract: Oxidation of H-phosphonate or H-phosphonothioate diesters with iodine in the presence of triethylamine trishydrofluoride furnished a rapid and quantitative formation of the corresponding phosphorofluoridate or phosphorofluoridothioate diesters. Copyright© 1996 Elsevier ScienceLtd Recent years have witnessed a tremendous revival of fluoroorganic chemistry t not least due to finding of molecules with useful biological activity. This includes the chemistry of fluorophosphates. Nucleoside phosphorofluoridates have been synthesised for the first time by Wittmann2 some thirty years ago, but it is only recently that the synthetic3q6 and biological17,18potential of this class of compounds has begun to be explored. The attractive features of nucleoside phosphorofluoridate diesters, which bear a high resemblance to natural intemucleotidic linkage, are that they may provide new means for a covalent attachment of molecular probes to proteins or that the fluoride may serve as a reporter group for probing conformational properties of nucleic acid fragments. In addition, these compounds themselves can be considered as potential therapeutics, e.g., for the antisense/antigene modulation of gene expression. Replacement of a phosphorus-bound chlorine by fluoride using variety of experimental procedures is by far the most common way for the preparation of fluorophosphoric acids or simple alkyl fluorophosphate diesters 19. However, the reported methods suffer from several disadvantages when it comes to the preparation of natural products derivatives containing P-F bond. The major obstacles are poor availability of the corresponding phosphorochloridates and the elevated temperature usually required to effect the replacement. To overcome these limitations, new synthetic routes via P(V) derivatives (with, e.g., azolides3,9, thiomethyl 11.20, or selenomethy115 as a leaving group) and via tervalent P(III) compounds (e.g., using dinucleoside silyl phosphites 4,s,7, dinucleoside phosphorofluoridites9AO, 12, or phosphitylating agents bearing fluorine 14) have been pursued. Efficiency of these approaches has been demonstrated in the synthesis of ribo- and deoxyribonucleoside cyclic 3',5'-phosphorofluoridatesll, 16, dinucleoside phosphorofluoridates 9,15 and phosphorofluoridothioatesl2. 3537