A General and Efficient Synthesis of Pyridin-2-yl C-Ribonucleosides Bearing Diverse Alkyl, Aryl, Amino, and Carbamoyl Groups in Position 6

Abstract

An efficient and practical methodology of preparation of 6-substituted pyridin-2-yl C-ribonucleosides was developed. A one-pot two-step addition of 2-lithio-6-bromopyridine to TBS-protected ribonolactone followed by acetylation gave 1beta-(6-bromopyridin-2-yl)-1-O-acetyl-2,3,5-tri-O-(tert-butyldimethylsilyl)-D-ribofuranose in high yield. Its reduction with Et(3)SiH and BF(3) x Et(2)O afforded the desired TBS-protected 6-bromopyridine C-ribonucleoside as pure beta-anomer in good overall yield of 63%. This intermediate was then subjected to a series of palladium catalyzed cross-coupling reactions, aminations and aminocarbonylations to give a series of protected 1beta-(6-alkyl-, 6-aryl-, 6-amino-, and 6-carbamoylpyridin-2-yl)-C-ribonucleosides. Deprotection of silylated nucleosides by Et(3)N x 3HF gave a series of title free C-ribonucleosides (12 examples).

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

“…Surprisingly, the solid-state conformation of the sugar part in compounds 14a , 14f , and 16c was found to be C2′-endo (S-type) typical for 2′-deoxyribonucleosides, whereas only amide 14h adopted expected C3′-endo configuration (N-type). No intramolecular H-bonds from 5′-OH to pyridine nitrogen were observed (in contrast to previously reported 6-substituted pyridin-2-yl C -ribonucleosides). Therefore, we have determined solution conformation of selected nucleosides by 1 H NMR in DMSO- d 6 and CDCl 3 .…”

“…Then we turned our attention to reduction of 5 under standard conditions using Et 3 SiH/BF 3 ·Et 2 O, but all attempts to perform this reduction failed and only unreacted starting material was isolated. Therefore, in analogy to previous works of others , and us, we tried to convert the hemiketal 5 to its O -acetate 6 which should be more reactive toward the reduction. Thus, the hemiketal alkoxide, generated by addition of monolithiated pyridine 2 to lactone 4 was directly in situ acylated on treatment with Ac 2 O to give the hemiketal-acetate 6 in low yield of 18% accompanied by hemiketal 5 (51%).…”

“…In this way, we have prepared 3- and 4-substituted benzene, 6-substituted pyridin-2-yl and pyridin-3-yl, 5-substituted thiophen-2-yl, 5-substituted furan-2-yl, and 2,4-disubstituted pyrimidin-5-yl C -2′-deoxyribonucleosides some of which were used for chemical biology studies on DNA polymerases and primases . In the ribonucleoside series, we reported only the synthesis of benzene ,, and 6-substituted pyridin-2-yl derivatives so far (Chart ).…”

pH-Dependent Switching of Base Pairs Using Artificial Nucleobases with Carboxyl Groups

“…For the incorporation of benzoic acid residue on a deoxyribose backbone (X 1 ), , bis-TBDMS-protected ribofuranoid glycal 1 , was coupled with methyl 3-iodobenzoate ( 2 ) by a Pd 0 -mediated C–C coupling reaction − to afford adduct 3 with an isolated yield of 48%, as shown in Scheme . Although previous studies recommend the use of a mono-3′-TBDMS-protected ribofuranoid glycal for more efficient cross-coupling reaction, , bis-protected-TBDMS glycal 1 was used in this study because its preparation from thymidine is much more efficient than the preparation of the mono-3′-TBDMS-protected glycal .…”

Clarifying the Use of Benzylidene Protecting Group for D-(+)-Ribono-1,4-Lactone, an Essential Building Block in the Synthesis of C-Nucleosides

“…Unfortunately, it is limited to the synthesis of pyrimidine analogues, as in the Lactone 2 is a natural compound present in the leaves of Listea japonica and, therefore, is commercially available from renewable sources. Because of its high functionalization with contiguous chiral centers, it has been widely used as a versatile chiral building block for the construction of a variety of natural products [13,14] as well as compounds relevant to medicinal chemistry and/or chemical biology, including nucleotides and C-ribonucleosides as antiviral agents [15,16].…”