Stereoselective Synthesis of 4'-Benzophenone-Substituted Nucleoside Analogs: Photoactive Models for Ribonucleotide Reductases.

ABSTRACT

Ribonucleotide reductases (RNRs) catalyze the 2'-reduction of ribonucleotides, thus providing 2'-deoxyribonucleotides, the monomers for DNA biosynthesis. The current mechanistic hypothesis for the catalysis effected by this class of enzymes involves a sequence of radical reactions. A reversible 3'-hydrogen abstraction, effected by a radical at the enzyme's active site, is believed to initiate the catalytic cycle. For the study of this substrate-enzyme interaction, a series of 4'-benzophenone-substituted model compounds was designed and synthesized. In these models, the benzophenone carbonyl group is oriented such that irradiation is expected to result in an enzyme-like, reversible 3'-hydrogen abstraction. The key step of our synthetic approach is the highly diastereoselective (dr > 955) Grignard-addition of carbonyl-protected o-benzophenone magnesium bromide to 2,3-O-isopropylidene-beta-L-erythrofuranose. The configuration of the newly established chiral center was unambiguously proven by X-ray crystallography. The erythritol derivative thus obtained was dehydrated to a base-free, 4'-benzophenone-substituted 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-mesylates. 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.