General and Modular Synthesis of Isomeric 5-Substituted Pyridin-2-yl and 6-Substituted Pyridin-3-yl C-Ribonucleosides Bearing Diverse Alkyl, Aryl, Hetaryl, Amino, Carbamoyl, and Hydroxy Groups

Abstract

A general modular and practical methodology for preparation of diverse 5-substituted pyridin-2-yl and 6-substituted pyridin-3-yl C-ribonucleosides was developed. Regioselective lithiation of 2,5-dibromopyridine proceeded at position 5 or 2 depending on the solvent, and the resulting bromopyridyl lithium species underwent additions to TBS-protected ribonolactone and follow-up transformations to corresponding acetylated hemiketal intermediates 7 and 10 that were diastereoselectively reduced to give either 5-bromopyridin-2-yl or 6-bromopyridin-3-yl silyl-protected C-ribonucleosides 8 or 11 in 68% and 77% overall yields as pure β-anomers. These bromopyridyl C-nucleoside intermediates were then subjected to a series of palladium-catalyzed cross-coupling reactions, aminations, aminocarbonylations, and hydroxylations to give a series of protected 1β-(5-alkyl-, 5-aryl-, 5-amino-, 5-carbamoyl-, and 5-hydroxypyridin-2-yl)-C-ribonucleosides 13a-i and β-(6-alkyl-, 6-aryl-, 6-amino-, 6-carbamoyl-, and 6-hydroxypyridin-3-yl)-C-ribonucleosides 15a-i. Deprotection of silylated nucleosides by Et(3)N·3HF, TBAF, or TFA gave a series of free C-nucleosides 14a-i and 16a-i.

Expanding the Scope of Replicable Unnatural DNA: Stepwise Optimization of a Predominantly Hydrophobic Base Pair

“…Free nucleosides 3 – 5 were converted to the corresponding triphosphates 6 – 8 under Ludwig conditions, 20 and purified by anion exchange chromatography followed by HPLC. The purity of each triphosphate was confirmed by 31 P NMR, HPLC, and MALDI-TOF MS (Supporting Information). …”

Me3(OMe)tBuXPhos: A Surrogate Ligand for Me4tBuXPhos in Palladium-Catalyzed C–N and C–O Bond-Forming Reactions

“…Me 4 t BuXPhos ( L1 , Figure ) is a useful ligand in Au-catalyzed carbocyclization and Pd-catalyzed arylation reactions of nitrogen/oxygen nucleophiles, including amides, benzimidazoles, phenols, and water . We recently demonstrated that the combination of Pd and L1 was the most effective catalyst system for the highly N 2 -selective arylation of 1,2,3-triazoles and completely N 1 -selective arylation of unsymmetric imidazoles …”

“…We recently demonstrated that the combination of Pd and L1 was the most effective catalyst system for the highly N 2 -selective arylation of 1,2,3-triazoles and completely N 1 -selective arylation of unsymmetric imidazoles , However, the high cost and limited availability of the 1,2,3,4-tetramethylbenzene could potentially prevent the utilization of Pd/ L1 systems, as well as the future development of methods using L1 as a supporting ligand for various metals. To circumvent this problem, the development of an inexpensive and robust alternative to L1 is highly desirable.…”

Metal‐Dependent Nucleobase Recognition by Picolinamide

“…The desired picolinamide C ‐nucleoside 7 was obtained in 63 % yield. Synthesis of the respective ribonucleoside by the same method has been described previously . Finally, C ‐nucleoside 7 was desilylated, 5′‐ O ‐dimethoxytritylated and 3′‐ O ‐phosphitylatetd by conventional methods to afford the phosphoramidite product 1 .…”