Synthesis of 5-Phenyl-2(1H)-pyrimidinone Nucleosides

Abstract

Reaction of 2-phenyltrimethinium salt 1 with thiourea and subsequent reaction with chloroacetic acid afforded 5-phenyl-2(1H)-pyrimidinone (3). Its silyl derivative 4 was condensed with 1-O-acetyl-2,3,5-tri-O-benzoyl-D-ribofuranose under catalysis with tin tetrachloride or trimethylsilyl trifluoromethanesulfonate to give protected nucleoside 5 together with 5',O6-cyclo-5-phenyl-1,3-bis- (β-D-ribofuranosyl)-6-hydroxy-5,6-dihydro-2(1H,3H)-pyrimidinone (7). The greatest amounts of 7 were formed with the latter catalyst. Nucleosidation of the silyl derivative 4 with protected methyl 2-deoxy-D-ribofuranoside 8 or 2-deoxy-D-ribofuranosyl chloride 9 afforded 1-(2-deoxy-3,5-di-O-p-toluoyl-β-D-ribofuranosyl)-5-phenyl-2(1H)-pyrimidinone (10) and its α-anomer 11. Reaction of 10 and 11 with methanolic ammonia gave free 2'-deoxynucleosides 12 and 13. Compound 13 was converted into 5'-O-tert-butyldiphenylsilyl-3'-O-mesyl derivative 14 which on heating with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and subsequent cleavage with tetrabutylammonium fluoride afforded 2',3'-dideoxy-2',3'-didehydronucleoside 15. Reaction of the silyl derivative 4 with 1,2-di-O-acetyl-3,5-di-O-benzoylxylofuranose (18), catalyzed with tin tetrachloride, furnished 1-(2-O-acetyl-3,5-di-O-benzoyl-β-D-xylofuranosyl)-2(1H)-pyrimidinone (19) which was deprotected to give the β-D-xylofuranosyl derivative 22. As a side product, the nucleosidation afforded the β-D-xylopyranosyl derivative 23. Deacetylation of compound 19 gave 1-(3,5-di-O-benzoyl-β-D-xylofuranosyl)-5-phenyl-2(1H)-pyrimidinone (24) which on reaction with thionyl chloride afforded 2'-chloro-2'-deoxynucleoside 25 and 2',O6-cyclonucleoside 26. Heating of compound 25 with DBU in dimethylformamide furnished the lyxo-epoxide 27 which on reaction with methanolic ammonia was converted into free 1-(2,3-anhydro-β-D-lyxofuranosyl)-5-phenyl-2(1H)-pyrimidinone (28). Reaction of 1,2-di-O-acetyl-5-O-benzoyl-3-O-methanesulfonyl-D-xylofuranose (30) with silyl derivative 4 gave the nucleoside 31 which by treatment with DBU was converted into an equilibrium mixture of 5'-benzoylated arabinofuranoside 33a and its 2',6-anhydro derivative 33b.