The growing demand for 4′-modified nucleoside analogs in medicinal and biological chemistry is contrasted by the challenging synthetic access to these molecules and the lack of efficient diversification strategies. Herein, we report the development of a biocatalytic diversification approach based on nucleoside phosphorylases, which allows the straightforward installation of a variety of pyrimidine and purine nucleobases on a 4′-alkylated sugar scaffold. Following the identification of a suitable biocatalyst as well as its characterization with kinetic experiments and docking studies, we systematically explored the equilibrium thermodynamics of this reaction system to enable rational yield prediction in transglycosylation reactions via principles of thermodynamic control. Collectively, this work provides analytical methods and thermodynamic frameworks that outline a general roadmap for the characterization of nucleoside phosphorolysis and transglycosylation systems.
The Simmons−Smith−Furukawa reaction was used to generate 4′/5′-spirocyclopropanated uridine analogs from electron-rich exocyclic enol esters. During synthesis, the native hydroxylation pattern of the nucleoside is preserved and offers the possibility for a late stage 5′-phosphorylation at the spirocyclopropanol moiety. All synthesized spirocyclopropanated uridine derivatives, including the corresponding 5′-monophosphate (cpUMP), were evaluated with respect to their antiviral activity in an HRSV assay showing moderate, but promising activity.
Adjusting the protecting group strategy, from an alkyl ether to
a bidentate ketal at the carbohydrate backbone of uridine, facilitates
a switchable diastereoselective α- or β-C4′/C5′-spirocyclopropanation.
Using these spirocyclopropanated nucleosides as key intermediates,
we synthesized a variety of C4′-methylated d-ribose
and l-lyxose-configured uridine derivatives by a base-mediated
ring-opening of the spirocyclopropanol moiety. Investigations of antiviral
activity against the human respiratory syncytial virus were carried
out for selected derivatives, showing moderate activity.
The growing demand for 4'-modified nucleoside analogs in medicinal and biological chemistry is contrasted by the challenging synthetic access to these molecules and the lack of efficient diversification strategies. Herein, we report the development of a biocatalytic diversification approach based on nucleoside phosphorylases, which allows the straightforward installation of a variety of pyrimidine and purine nucleobases on a 4'-alkylated sugar scaffold. Following the identification of a suitable biocatalyst as well as its characterization with kinetic experiments and docking studies, we systematically explored the equilibrium thermodynamics of this reaction system to enable rational yield prediction in transglycosylation reactions via principles of thermodynamic control.<br>
C5/C6-Spirocyclopropanation of exocyclic enol esters followed by alkali ring-opening of the three-membered ring was used for the diastereoselective preparation of 5-C-methylated d-mannose, d-galactose, l-gulose, and l-altrose. Extensive NMR studies demonstrated an increase of furanose form by 5-C-methylation in almost all cases.
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