PAPER 1668 Nucleoside H-Phosphonates XX. Efficient Method for the Preparation of Nucleoside H-Phosphonoselenoate Monoesters Nucleoside H-Phosphonates Martin Kullberg, a Jacek Stawinski* a,b a Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, 106 91 Stockholm, Sweden b Institute of Bioorganic Chemistry, Polish Academy of Sciences, Noskowskiego 12/14, 61-704 Poznan, Poland E-mail: js@organ.su.se Received 20 January 2005 SYNTHESIS 2005, No. 10, pp 1668–1674xx.xx.2005 Advanced online publication: 07.04.2005 DOI: 10.1055/s-2005-865300; Art ID: P01005SS © Georg Thieme Verlag Stuttgart · New York Abstract: The preparation of an H-phosphonoselenoyl group trans- ferring reagent, 9-fluorenemethyl H-phosphonoselenoate, and its application to the synthesis of separate diastereomers of nucleoside 3¢-H-phosphonoselenoate monoesters, are described. Key words: nucleotides, phosphorylation, selenium, protecting groups, elimination Introduction A close resemblance of selenium to biologically impor- tant element sulfur, constitutes a strong rationale for in- corporation of selenium into potential medicinal agents. The toxic nature of most selenium compounds may pose a serious obstacle in drug development but does not per se rule out this type of modification for drug use. 1 Kindled by hopes of finding novel, useful properties, selenium has been incorporated into various biologically important compounds, e.g. carbohydrates, 2 lipids, 3,4 nucleosides, 5 oligonucleotides. 6,7 Selenophosphates are usually prepared via selenization of suitable P(III) precursors, e.g. phosphite triesters, 6,8 H- phosphonate 3,7 and H-phosphonothioate 7 diesters, al- though derivatives accessible by these routes are usually limited to the corresponding selenophosphate di- and tri- esters, and selenothiophosphate diesters. Recently, we started to explore a new type of synthetic intermediates, H-phosphonoselenoate monoesters 9,10 that can provide access to new selenophosphate derivatives with double modifications at the phosphorus centre. In this paper we report on the synthesis and application of a dedicated H-phosphonoselenoyl group-transferring re- agent, namely, 9-fluorenemethyl H-phosphonoselenoate, that permits an easy preparation of nucleoside H- phosphonoselenoate monoesters either as diastereomeric mixtures or as separate P-diastereomers. This latter possi- bility can be potentially exploited in a stereospecific syn- thesis of P-chiral selenophosphate derivatives. Results and Discussion Since nucleoside H-phosphonoselenoate monoesters are chiral at the phosphorus centre, access to the separate R P and S P diastereomers is required to exploit in full their synthetic potential. Unfortunately, the presence of a neg- ative charge in an H-phosphonoselenoate moiety usually overshadows possible chromatographic differences be- tween isomeric compounds and effectively prevents sepa- ration of their P-diastereomers on silica gel. 9 To overcome this problem, we designed a dedicated H-phosphonosele- noyl group transferring reagent, 9-fluorenemethyl H- phosphonoselenoate 4 (Scheme 1), which upon reaction with a hydroxylic component (e.g. a nucleoside) can pro- duce uncharged H-phosphonoselenoate diesters of type 6 (Scheme 2). These are much more easy to separate into di- astereomers and after the removal of the fluorenemethyl group, R P and S P diastereomers of H-phosphonoselenoate monoesters 7 can be obtained. The fluorenemethyl group in H-phosphonoselenoate diesters 6 acts as a lipophilic handle that facilitates separation of these compounds by a silica gel column chromatography, and since it is remov- able via a b-elimination mechanism, its deprotection does not affect stereochemical integrity of the phosphorus cen- ter. The added value of this approach is that, if separate diastereomers of H-phosphonoselenoates 7 are not re- quired the synthesis can be simplified by subjecting H- phosphonoselenoate diesters 6 to deprotection directly af- ter condensation to afford diastereomeric mixture of the corresponding H-phosphonoselenoate monoesters. Synthesis of H-Phosphonoselenoyl Group Transfer- ring Reagent 4 9-Fluorenemethyl H-phosphonoselenoate 4 10 was pre- pared using standard phosphinate approach previously de- veloped for the synthesis of H-phosphonothioate monoesters. 11 Thus treatment of 9-fluorenemethanol (1) with triethylammonium phosphinate (2) ( 31 P NMR: d = 2.85, 1 J P,H = 517 Hz, t) in pyridine in the presence of pivaloyl chloride, followed by selenization of the pro- duced phosphinate intermediate 3 ( 31 P NMR: d = 14.22, 1 J P,H = 572 Hz, 3 J P,H = 9.8 Hz, tt) with elemental selenium for two hours, produced 9-fluorenemethyl H-phospho- noselenoate 4 as the major product (>90%, 31 P NMR: d = 50.41, 1 J P,H = 570 Hz, 3 J P,H = 9.1 Hz, dt; 1 J P,Se = 685.2 Hz) (Scheme 1). Since reagent 4 in the form of triethylam-