SYNTHESIS OF 2- (AND 6-) -DITHIAN-2-YLURACIL NUCLEOSIDES AND THEIR CONVERSION INTO NUCLEOSIDE DERIVATIVES

Article abstract of DOI:10.1016/S0008-6215(00)83658-7

Addition of 2,2'-anhydro-<1-(3-O-acetyl-5-O-trityl-β-D-arabinofuranosyl)uracil> (1) to excess 2-lithio-1,3-dithiane (2) in oxolane at -78 deg C gave 2-(1,3-dithian-2-yl)-1-(5-O-trityl-β-D-arabinofuranosyl)-4(1H)pyrimidinone (3), O²,2'-anhydro-5,6-dihydro-6-(S)-(1,3-dithian-2-yl)-5'-O-trityluridine (4), and 2-(1,4-dihidroxybutyl)-1,3-dithiane (5) in yields of 15, 30, and 10percent respectively.The structure of 3 was proved by its hydrolysis in acid to give 2-(1,3-dithian-2-yl)-4-pyrimidinone (6) and arabinose, and by desulfurization with Raney nickel to yield the known 2-methyl- 1-(5-O-trityl-β-D-arabinofuranosyl)-4(1H)-pyrimidinone (7).Detritylation of 3 without glycosidic cleavage could only be effected by prior acetylation to 1-(2,3-di-O-acetyl-5-trityl-β-D-arabinofuranosyl)-2-(1,3-dithian-2-yl)-4(1H)-pyrimidinone (8) which, after treatment with acetic acid at room temperature for 65 h followed by action of sodium methoxide gave 2-(1,3-dithian-2-yl)-1-β-D-arabinofuranosyl-4(1H)-pyrimidinone (10) in 45percent yield.Detritylation of 4 in boiling acetic acid gave 5,6-dihydro-6-(S)-(1,3-dithian-2-yl)-1-β-D-arabinofuranosyluracil (12) and 3-<(S)-1-(1,3-dithian-2-yl)>propionamido-(1,2-dideoxy-β-D-arabinofurano)-<1,2-d>-2-oxazolidinone (13) in 10 and 90percent yields, respectively.When 12 was kept in water or methanol for 7 days, quantitative conversion into 13 occured.Acid hydrolysis of 12 afforded arabinose and 5,6-dihydro-6-(1,3-dithian-2-yl)uracyl (14), which was desulfurized with Raney nickel to the known 5,6-dihydro-6-methyluracil (15).Treatment of 13 with trifluoroacetic anhydride-pyridine yielded 77percent of the cyano derivative 17.Similar dehydration of 3-(R)-1-methylpropionamido-(1,2-dideoxy-β-D-arabinofurano)-<1,2-d>-2-oxalidinone (18), obtained by desulfurization of 13, gave 60percent of nitrile 19.Hydrogenation of 19 over platinum oxide in acetic anhydride gave the acetamide derivative 20 in 95percent yield.Nitrobenzoylation of 13 gave 3-<(S)-1-(1,3-dithian-2-yl)>cyanomethyl-3,5-di-O-p-nitrobenzoyl-(1,2-dideoxy-β-D-arabinofurano)-<1,2-d>-2-oxazolidinone (22), which was converted in 37percent yield by treatment with methyl iodide in dimethyl sulfoxide into the aldehyde 24, characterized as the semicarbazone 25.The purification of 5 and its characterization as 2-(1,4-di-O-p-nitrobenzoylbutyl)1,3-dithiane (27) is described.