Conversion of 2-deoxy-d-ribose into 2-amino-5-(2-deoxy-β-d-ribofuranosyl)pyridine, 2′-deoxypseudouridine, and other C-(2′-deoxyribonucleosides)

Abstract

The synthesis of 2-amino-5-(2-deoxy-beta-D-ribofuranosyl)pyridine 2a, 2-amino-5-(2-deoxy-alpha-D-ribofuranosyl)-pyridine 23, 2-amino-5-(2-deoxy-beta-D-ribofuranosyl)-3-methylpyridine 2b, 2-amino-5-(2-deoxy-alpha-D-ribofuranosyl)-3-methylpyridine 29 and 5-(2-deoxy-beta-D-ribofuranosyl)-2,4-dioxopyrimidine [2'-deoxypseudouridine] 30a is described. These C-nucleosides are prepared either from 2-deoxy-3,5-O-(1,1,3,3-tetraisopropyldisiloxan-1,3-diyl)-D-ribofuranose 15 or from 2-deoxy-3,5-O-(1,1,3,3-tetraisopropyldisiloxan-1,3-diyl)-D-ribono-1,4-lactone 16, which are themselves prepared from 2-deoxy-D-ribose 13. The sugar derivatives are first allowed to react with the appropriate 5-lithio-pyridine or 5-lithio-pyrimidine derivatives, which are prepared from 5-bromo-2-(dibenzylamino)pyridine 12a, 5-bromo-2-[bis(4-methoxybenzyl)amino]pyridine 12b, 5-bromo-2-dibenzylamino-3-methylpyridine 25 and 5-bromo-2,4-bis(4-methoxybenzyloxy)pyrimidine 33. The products from the reactions between the lithio-derivatives and the lactol 15 are cyclized under Mitsunobu conditions; the products from the reactions between the lithio-derivatives and the lactone 16 are first reduced with L-Selectride before cyclization, also under Mitsunobu conditions. In all cases, the beta-anomers of the protected C-nucleosides are the predominant products. Finally, the separation of the alpha- and beta-anomers and the removal of all of the protecting groups are described.

Discovery of a Novel, Isothiazolonaphthoquinone-Based Small Molecule Activator of FOXO Nuclear-Cytoplasmic Shuttling

“…Then, the 1,3-dipolar cycloaddition between the nitrile sulfide generated in situ by termal decarboxylation of 3a and 3b [32] and the naphthoquinone gave isothiazolonaphthoquinones 1a and 4 . The intermediate 4 was then treated with cerium ammonium nitrate (CAN) in acetonitrile–water [33] at room temperature and compound 1b was obtained in high yield. Following the same synthetic strategy isothiazolonaphthoquinones 1c was obtained starting from 1,3,4-oxathiazol-2-ones 3c.…”

Synthetic Methodologies for C-Nucleosides

“…In the context of our work on the synthesis of 2-amino-5-(2¢-deoxy-D-b-ribofuranosyl)pyridine, 29 Later, Togo et al 30 reported the effect of different metal ions on the stereochemistry of the coupling products, the diols. In most cases, the coupling reaction of arylcadmium, arylzinc derivatives and Grignard reagents with the ribofuranose derivatives 13, 31 and 39 displayed higher stereoselectivity than the corresponding reactions with aryl lithium reagents.…”

“…In the same way, reduction of compound 169 with NaBH 4, followed by cyclization under Mitsunobu conditions, gave the C-nucleosides 171 in good yield with the b-anomers as the major products (Scheme 39). 75 In the course of our study of the synthesis of C-nucleosides, 29 mer (b/a ratio 7:1) in 51% overall yield. In contrast to the coupling reaction between bicyclic lactol and lithiopyridine derivatives (Scheme 9), this approach possibly gives rise to stereocontrolled synthesis of C-nucleosides through the use of appropriate reducing agents.…”

“…When di(4-methoxybenzyl) pyrimidine derivative 178 was lithiated and then treated with ribonolactone 114, the open-chain product 179 was obtained (Scheme 42). 29 Reduction of 179 with L-selectride, followed by cyclization under Mitsunobu conditions, gave almost exclusively the b-nucleoside 180 in 43% overall yield. Starting from ribonolactone 114, pseudouridine 1 was prepared in a manner 93 similar to that described above.…”

Advances in the Synthesis of 5- and 6-Substituted Uracil Derivatives

“…To prepare uracils, there are three main synthetic strategies: a) building the uracil nucleus from acyclic precursors with appropriate substituents; b) modification of the structure of functionalized uracils or uracil itself by reaction with different reagents, as illustrated by the recent synthesis of 5-trifluoromethyluracil 3 and uridines with oxiranyl and tetrahydrofuranyl substituents; 4 c) functionalization of masked uracil moieties with reactions incompatible with the nucleus, for example the synthesis of 6-aryl and 6-acyluracils 5 and 2 -deoxypseudouridine. 6 Combinations of these approaches are often found in the synthesis of target compounds with potential biological activities.…”