Synthesis of 6-substituted uridines. synthesis of (R or S)-6-(3-amino-2-carboxypropyl)uridine

Abstract

Addition of 5-bromo-2′,3′- O-isopropylidene-5′- O-trityluridine ( 2) in pyridine to an excess of 2-lithio-1,3-dithiane ( 3) in oxolane at 78° gave (6 R)-5,6-dihydro-(1,3-dithian-2-yl)-2′,3′- O-isopropylidene -5′- O-trityluridine ( 4), (5 S,6 S)-5-bromo-5,6-dihydro-(1,3-dithian-2-yl)-2′,3′- O-isopropylidene-5′- O-trityluridine ( 5), and its (5 R) isomer 6 in yields of 37, 35, and 10%, respectively. The structure of 4 was proved by Raney nickel desulphurization to (6 S)-5,6-dihydro-2′,3′- O-isopropylidene-6-methyl-5′- O-trityluridine ( 7) and by acid hydrolysis to give D-ribose and (6 R)-5,6-dihydro-6-(1,3-dithian-2-yl)uracil ( 9). Treatment of 4 with methyl iodide in aqueous acetone gave a 30&%; yield of ( R, S)-5,6-dihydro-6-formyl-2′,3′- O-isopropylidene-5′- O-trityl-uridine ( 10), characterized as its semicarbazone 11. Both 5 and 6 gave 4 upon brief treatment with Raney nickel. Both 5 and 6 also gave 6-formyl-2′,3′- O-isopropylidene-5′- O-trityluridine ( 12) in ∼41%; yield when treated with methyl iodide in aqueous acetone containin- 10%; dimethyl sulfoxide. A by-product, identified as the N-methyl derivative ( 13) of 12 was also formed in yields which varied with the amount of dimethyl sulfoxide used. Reduction of 12 with sodium borohydride, followed by deprotection, afforded 6-(hydroxymethyl)uridine ( 17), characterized by hydrolysis to the known 6-(hydroxymethyl)uracil ( 18). Knoevenagel condensation of a mixture of the aldehydes 12 and 13 with ethyl cyanoacetate yielded 38%; of E- (or Z-)6-[(2-cyano-2-ethoxycarbonyl)ethylidene]-2′,3′- O-isopropylidene-5′- O-trityluridine ( 19) and 10%; of its N-methyl derivative 20. Hydrogenation of 19 over platinum oxide in acetic anhydride followed by deprotection gave R (or S)-6-(3-amino-2-carboxypropyl)uridine ( 23).