Synthesis and Rearrangement of 3 0 -a-Diethylphosphono-3 0 -b-O-methanesulfonyluridines Tracy J. Baker ² and David F. Wiemer * Department of Chemistry, University of Iowa, Iowa City, IA 52242-1294, USA Received 4 February 2000; revised 5 March 2000; accepted 6 March 2000 Abstract ÐPreparation of a uridine derivative bearing both diethylphosphono and methanesulfonate substituents at the 3 0 -position has been accomplished by reaction of the corresponding a-hydroxy phosphonate with methanesul®nyl chloride and subsequent oxidation. While this methanesulfonate did not undergo elimination under standard reaction conditions, treatment with TBAF results in a novel rearrangement leading to the corresponding 2 0 -phosphate. q 2000 Elsevier Science Ltd. All rights reserved. In recent years, a number of nucleoside analogues have been found to display signi®cant anti-viral activity and several have become medically useful. 1 Even though these drugs have shown signi®cant clinical value, ®rst when used alone and now as used in combination therapies, their use can be haunted by undesired side effects and complex dosing schemes that risk non-compliance. 2 To aid the search for new biologically active compounds with reduced toxi- city and simpler dosing schemes, we have reported methods for preparation of several types of modi®ed nucleosides, including geminal hydroxy phosphonates (such as the uridine derivative 1) 3 and their deoxygenated (2) 4 and epox- ide (3) 5 derivatives (Scheme 1). In this report, we describe ®rst the synthesis of a nucleoside bearing both diethylphos- phono and methanesulfonate substituents at the 3 0 -position, a highly functionalized compound that might serve as an intermediate for preparation of other modi®ed nucleosides, as well as a new phosphonate±phosphate rearrangement found in this system. Efforts to prepare the desired methanesulfonate 6 (Scheme 2) through direct reaction of the a-hydroxy phosphonate 4 with methanesulfonyl chloride in the presence of triethyl- amine or 4-dimethylaminopyridine (DMAP), or after treat- ment with potassium hydride and 18-crown-6, went unrewarded. This was not entirely surprising, given that our earlier efforts to conduct a Barton deoxygenation on this substrate had suggested that this hydroxyl group is sterically hindered. 4 Fortunately a method for preparation of the methanesulfonate of tertiary a-hydroxy phosphonates through reaction with methanesul®nyl chloride and subse- quent oxidation has been reported by Creary et al. 6 based on their adaptation of an earlier tosylation procedure developed by Coates and Chen. 7 Following Creary's procedure, Tetrahedron 56 (2000) 3127±3131 Pergamon TETRAHEDRON 0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved. PII: S0040-4020(00)00198-8 Keywords: nucleosides; nucleotides; phosphonic acids and derivatives; phosphoric acids and derivatives; rearrangements. * Corresponding author. Tel.: 1319-335-1365; fax: 1319-335-1270; e-mail: david-wiemer@uiowa.edu ² E-mail: tbaker@chem.ucsd.edu Scheme 1.