Photochemistry of 4 '-benzophenone-substituted nucleoside derivatives as models for ribonucleotide reductases: Competing generation of 3 '-radicals and photoenols

Ribonucleotide reductases (RNRs) catalyze the 2'-reduction of ribonucleotid es, thus providing 2'-deoxyribonucleotides, the monomers for DNA-biosynthes is. The current mechanistic hypothesis for the catalysis effected by this c lass of enzymes involves a sequence of radical reactions. A 3'-hydrogen abs traction, effected by a radical at the enzyme's active site, is believed to initiate the catalytic cycle. As models for this substrate-enzyme interact ion, the photochemically induced intramolecular hydrogen abstraction in a s eries of 4'-benzophenone-substituted nucleoside analogues was studied. Mode l compounds with hydroxy-, methoxy-, mesyloxy-groups or a cyclic carbonate in 2'- and S'-positions were investigated. Depending on the substitution pa ttern, two different types of photoproducts were observed: Those which resu lt from photoenol formation (gamma-H-abstraction) and those which result fr om abstraction of the 3'-H-atom (delta-H-abstraction). Photoenol formation was further supported by H/D-exchange experiments. Thus, the S'-H-abstracti on postulated as the initial step in RNR action was successfully modeled by photolysis of 4'-benzophenone-substituted nucleoside analogues. The regios electivity of the photochemical H-abstraction and thus of the product distr ibution as a function of the 2'- and 3'-substituents was rationalized on th e basis of a conformational analysis of the four model systems, utilizing m olecular mechanics simulations.