A versatile approach to novel homo-C-nucleosides based on aldehydes and acetylenic ketones derived from ribo- and 2-deoxy-ribofuranose C-glycosides

Abstract

A series of ribofuranosyl-and 2-deoxyribofuranosyl homo-and spacered-C-nucleosides have been synthesized by reaction of fully protected 3-(1-deoxy-β-D-ribofuranosyl-1-yl)propanal (1), 3-(1,2-dideoxy-β-D-ribofuranos-1-yl)propanal (14), 1-(1-desoxy-β-D-ribofuranos-1-yl)pent-4-yn-3-on (19), 1-(1-desoxy-β-D-ribofuranos-1-yl)-5-phenyl-pent-4-yn-3-on (20), 1-(1,2-didesoxy-β-D-ribofuranos-1-yl)pent-4-yn-3-on (29), and 1-(1,2-didesoxy-β-D-ribofuranos-1-yl)-5-phenylpent-4-yn-3-on (30) with different nucleophiles. The preparation of 1 and 14 proceeds by Knoevenagel reaction with malononitrile, cyanoacetamide and 2-cyano-N-(4-methoxyphenyl)acetamide and subsequent cyclization with sulphur to thiophenes 5, 7, 8, 16 and then by cyclization with triethyl orthoformate to give thienopyrimidine 6 and thienopyrimidinone 9, 10, and 17. Treatment of acetylenic ketones 19, 20, 29, and 30 with acetamidinium chloride, benzamidinium chloride, and S-methylisothiouronium sulphate provided the corresponding pyrimidines 21-26, 31, 32. Finally, the use of 4H-1,2,4-triazol-3-amine and 2-aminobenzimidazole as 1,3-N,N'-dinucleophiles afforded the triazolopyrimidines 35, 39 and the pyrimidobenzimidazoles 36, 37, and 40, respectively. Deprotection of a selected number of Cnucleosides was achieved by one or two steps procedure without serious problems. That makes these C-nucleosides promising candidates for the synthesis of monomers suitable for solid phase nucleic acid oligomerization.

Approaches to the synthesis of heterocyclic C-nucleosides

“…No yields of compounds 274a,b are given. 103 Reaction of compound 267 with alkynyl organometallic compounds followed by the Dess-Martin oxidation gave intermediates 277a,b (Scheme 89). Compounds 277a,b were involved in the reactions with various diamines to afford C-nucleosides 278-281 with the pyrimidine, triazolopyrimidine, and benzimidazopyrimidine scaff olds as the aglycons.…”

“…Compounds 277a,b were involved in the reactions with various diamines to afford C-nucleosides 278-281 with the pyrimidine, triazolopyrimidine, and benzimidazopyrimidine scaff olds as the aglycons. 103 Schneller and coworkers 104 developed an effi cient synthesis of a series of carbocyclic formycin derivatives structurally related to 3-deazaaristeromycin. This approach is characterized by high yields on each step (Scheme 90).…”

A Parallel Approach to 7-(Hetero)arylpyrazolo[1,5-a]pyrimidin-5-ones

“…8 Presumably, this reaction proceeds through aza-Michael addition of the pyrazole ring nitrogen to the ynoate, followed by cyclization of the exocyclic amine onto the ester to provide the 7-phenyl regioisomer. 9 In contrast, cyclocondensation of aminopyrazole with ethyl benzoylacetate is known to provide the 5-phenyl regioisomer (Scheme 2). 10 Noting that ynoates would likely be required to achieve the desired regioselectivity (rather than β-ketoesters, vinylogous carbamates, 11 or other 1,3-dielectrophiles), we aimed to devise a high throughput sequence for the conversion of aryl halides to β-aryl ynoates.…”

“…Our synthetic approach was inspired by Reimlinger’s regioselective cyclocondensation of aminopyrazole with ethyl phenylpropiolate to afford the 7-phenyl pyrazolo­[1.5- a ]­pyrimidone . Presumably, this reaction proceeds through aza-Michael addition of the pyrazole ring nitrogen to the ynoate, followed by cyclization of the exocyclic amine onto the ester to provide the 7-phenyl regioisomer . In contrast, cyclocondensation of aminopyrazole with ethyl benzoylacetate is known to provide the 5-phenyl regioisomer (Scheme ).…”