Stereocontrolled conversion of 1-(3-hydroxyprop-1-enyl)uracil isomers into polyfunctional 3,9-propano- and 3,9(9,3)-propeno-aza-9H-xanthines

Abstract

With 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1-(3)-azido-(6) and 1-(3-trityloxy-2-methylsul-phonyloxypropyl)-3-methyluracil (12) underwent elimination to give the respective E-and Z-prop-1′-enyl isomers. Treatment of (E)-(15) and (Z)-(16) 1-(3-hydroxyprop-1-enyl)-3-methyluracil with Br₂–MeOH generated asymmetric centres at C-1′ and C-2′, providing threo-(17) and erythro-(18) 5-bromo-1-(2-bromo-3-hydroxy-1-methoxypropyl)-3-methyluracil. Conversion of compound (17) and (18) into erythro-(19) and threo-(20) 5-bromo-1-(2,3-epoxy-1-methoxypropyl)-3-methyluracil was accomplished under mild DBU-elimination conditions. The reaction of the diastereoisomeric epoxides (19) and (20) with NaN₃–DMF produced the respective erythro-(21) and threo-(22) 1-(3-azido-2-hydroxy-1-methoxypropyl)-3-methyluracil. These isomers underwent two types of intramolecular cyclisation reaction, which gave trans-(23) and cis-(24) 2-azidomethyl-3-methoxy-6-methyl-2,3-dihydro-oxazolo[3,2-c]pyrimidine-5,7-dione and cis-(25) and trans-(26) 11-hydroxy-12-methoxy-1-methyl-3,9-propano-8-aza-9H-xanthine. The elimination reaction of 12-methoxy-1-methyl-11-methylsulphonyloxy-3,9-propano-8-aza-9H-xanthine (29) by DBU led to formation of 12-methoxy-1-methyl-9,3-propeno-8-aza-9H-xanthine (30). Its 3,9-propeno isomer (33) was obtained from a DBU-elimination of 11-bromo-10-methoxy-1-methyl-3,9-propano-8-aza-9H-xanthine (32). The 9,3-propeno compound (30) was also converted into 11-bromo-10,12-dimethoxy-1-methyl-3,9-propano-8-aza-9H-xanthine (34) on treatment with Br₂–MeOH.