STEREOSELECTIVITY SYNTHESIS OF 4'-BENZOPHENONE-SUBSTITUTED NUCLEOSIDEANALOGS - PHOTOACTIVE MODELS FOR RIBONUCLEOTIDE REDUCTASES

Ribonucleotide reductases (RNRs) catalyze the 2'-reduction of ribonucl eotides, thus providing 2'-deoxyribonucleotides, the monomers for DNA biosynthesis. The current mechanistic hypothesis for the catalysis eff ected by this class of enzymes involves a sequence of radical reaction s. A reversible 3'-hydrogen abstraction, effected by a radical at the enzyme's active site, is believed to initiate the catalytic cycle. Far the study of this substrate-enzyme interaction, a series of 4'-benzop henone-substituted model compounds was designed and synthesized. In th ese models, the benzophenone carbonyl group is oriented such that irra diation is expected to result in an enzyme-like, reversible 3'-hydroge n abstraction. The key step of our synthetic approach is the highly di astereoselective (dr > 95:5) Grignard-addition of carbonyl-protected o -benzophenone magnesium bromide to 2,3-O-isopropylidene-beta-L-erythro furanose. The configuration of the newly established chiral center was unambiguously proven by X-ray crystallography. The erythritol derivat ive thus obtained was dehydrated to a base-free, 4'-benzophenone-subst ituted nucleoside analog. This first model system was further modified by transforming the free 2',3'-hydroxyl groups into the mono-and bis- methyl ethers, into the cyclic carbonate, and into the mono- and bis-m esylates. Alternatively, the primary hydroxyl group of the erythritol intermediate was selectively oxidized to the aldehyde. In the furanose thus obtained, the stage is set for the additional introduction of a nucleobase at the 1'-position.