Phosphonate derivatives of 2-deoxyribose have been synthesized for the first time, by Lewis acid-mediated reaction of glycosyl donors with diisopropylhydroxymetylphosphonate for compounds 2 or with triisopropyl phosphite for compounds 3. Although, the selectivity of the reaction was moderate, in both cases the α-glycosides were predominantly obtained.Glycosyl phosphates are important metabolic intermediates in the biosynthesis of nucleic acids and glycosides. Among them, 2-deoxy-α− D-ribose-1-phosphate (1) is a natural substrate of thymidine phosphorylase (EC 2.4.2.4), an enzyme involved in the metabolism of pyrimidine nucleosides and whose increased levels have been associated with the development of solid tumours and metastasis. 1 The synthesis of stable analogues of glycosyl phosphates (i.e. phosphonate derivatives) is of great interest since they may act either as inhibitors or regulators in the metabolic processes where the natural phosphates are involved.Recently, we have started a programme directed to the synthesis of stable analogues of 2-deoxy-α-D-ribose-1-phosphate (1) as potential inhibitors of thymidine phosphorylase (EC 2.4.2.4). Here we describe the synthesis of the phosphonate derivatives 2 and 3 as analogues of the natural substrate 1, in which the phosphate group has been replaced by the isosteric phosphonomethoxy moiety. 2,3 To the best of our knowledge, this is the first time that glycosyl phosphonate derivatives of 2-deoxyribose are reported.
Figure 1In the synthesis of 2 and 3, special attention was paid to the preparation of the α-anomers (2α, 3α), that show the same stereochemistry as the natural substrate 1. Here we also report our attempts to selectively obtain these 2-deoxy-α-glycosides, together with the unexpected results encountered.Compounds 2α and 2β were initially synthesized starting from methyl 3,5-bis-O-benzoyl-erythro-pentofuranoside (4) 4 (Scheme 1). To favour the α-anomers, 5 4 (1 eq.) was reacted with diisopropyl hydroxymethylphosphonate 6 (3 eq.) in the presence of trimethylsilyltriflate (1.7 eq., CH 3 CN, 0 °C, 4h) to afford a mixture of 5α (51%) 7a and 5β (25%) 7b in a 2:1 ratio, that were separated by flash column chromatography, using CH 2 Cl 2 : acetone (20:1) as eluent. The stereochemistry of the anomeric center was assigned as α for the major isomer 5α and β for the minor 5β based on 1 H-NMR NOESY experiments. 8 Treatment of 1 eq. of 5α or 5β with bromotrimethylsilane (10 eq.) in dry acetonitrile, in the presence of 2,6-lutidine 9 (15 eq.), (deprotection of the phosphonate esters), followed by reaction with saturated methanolic ammonia (deprotection of the benzoyl esters), afforded compounds 2α 10a and 2β 10b that were isolated as their disodium salts, by treatment with Dowex 50W-X-4 (Na + form), (43 and 48% yields, from 5α and 5β, respectively).The synthesis of glycosyl phosphonates 3α and 3β was accomplished by Lewis acid-promoted reaction of glycosyl donors with phosphites 11 (Scheme 2). Initial attempts to react the methyl derivative 4 with P(OiPr) 3 in the pres...
