Electrophilic Cyclization of α-Alkynyl Carbonyl Compounds

Abstract

Pyrimidine nucleoside derivatives have been shown to exhibit high antiviral activity and selectivity. The class of 5-alkynyl-2'-deoxyuridines has been studied because substitution at the 5-position of the uracil base allows for the study of various alkynes and their antiviral properties. In this work, 5-alkynyl-2'-deoxyuridines were reacted with N-iodosuccinimide or N-bromosuccinimide in acetone to synthesize bicyclic iodo- and bromofuropyrimidine nucleosides [R = cyclohexanol (c-C6H10OH) and p-pentylphenyl (p-CH3(CH2)4C6H4)]. Electrophilic cyclization with use of NIS reagent was successful in only the 5-alkynyl-2'-deoxyuridine containing the p-pentylphenyl R-group and 3-(2'-deoxy-β-D-ribofuranosyl)-5-iodo-6-(p-pentylphenyl)-2,3-dihydrofuro-[2,3-d]pyrimidin-2-one was synthesized in yields of up to 64%. Cyclization of the alkynyluridine with R= c-C6H10OH using NIS did not proceed to give the desired bicyclic furopyrimidine nucleoside and the end result was unidentified products. The electrophilic cyclization reaction of the 5-alkynyl-2'-deoxyuridine containing the p-pentylphenyl R-group with the use of NBS was successful, however, cleavage of the N-glycosidic bond was observed. Successive reactions using slightly different methods gave the furopyrimidine base product of R = p-pentylphenyl in yields up to 63%. Bromocyclization of the alkynyl derivative with R= c-C6H10OH did not proceed, possibly due to the sterically hindered structure of the R-group.