272114-54-2Relevant academic research and scientific papers
Stereoselective Synthesis of 4′-Benzophenone-Substituted Nucleoside Analogs: Photoactive Models for Ribonucleotide Reductases
Lehmann, Thomas E.,Berkessel, Albrecht
, p. 302 - 309 (2007/10/03)
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 > 95:5) Grignard-addition of carbonyl-protected o-benzophenone magnesium bromide to 2,3-O-isopropylidene-β-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.
