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The C-glycosyl alkynecarboxylic acid orthoamides 22 and 23 are proposed as versatile precursors for the synthesis of new types of C-nucleoside analogs. The new synthetic strategy includes alkynylation of protected aldoses 13 or ketoses by Grignard ethynylation or Barbier propargylation, O-protection of the resulting alkynols 14-16, and nucleophilic addition of the metalated protected terminal alkynes 20 and 21 to peralkylguanidinium salt 2 to afford the corresponding alkynecarboxylic acid orthoamides 22 and 23, which in reactions with mono or bis-nucleophiles could serve as building blocks for the construction of a wide variety of C-nucleoside-like binary conjugates. All the steps are demonstrated on 2,4,3,5-bis(4-methoxybenzylidene)-protected L-xylose 11 as a model compound. The synthesis of a representative series of C-glycosidic conjugates of highly substituted “push-pull” 1,3-butadienes 32-35, pyrimidines 24-31, and 2-pyridones 36-39 is included. The stereochemistry of all described compounds is established by 2D-NMR techniques. A general character of the proposed synthetic strategy, when applied to different appropriately protected sugar derivatives, is suggested, and a biomedical applicability of the described type of conjugates is expected.

3-O-Benzyl-6-deoxy-1,2-O-isopropylidene-6-(dimethylaminomethylene)-α-D-xylo-hept-5-ulofuranurononitrile (1) was reacted with amidinium salts, S-methylisothiouronium sulfate, and guanidinium chloride, respectively, in the presence of bases to furnish the 4-(3-O-benzyl-1,2-O-isopropylidene- α-D-xylo-tetrofuranos-4-yl)pyrimidine-5-carbonitriles 2 and the 4-(1,2-O-isopropylidene- α-D-glycero-tetr-3-enofuranos-4-yl)pyrimidine-5-carbonitriles 3, respectively. Treatment of 1 with ethyl 5-aminopyrazole-4-carboxylates yielded the ethyl 7-(3-O-benzyl-1,2-O-isopropylidene- α-D-xylo-tetrofuranos-4-yl)-6-cyanopyrazolo[1,5-a]pyrimidine-3-carboxylates 4 and the ethyl 7-amino-6-(3-O-benzyl-1,2-O-isopropylidene-α-D-xylo-pentofuranuronoyl)pyrazolo[1,5-a]pyrimidine- 3-carboxylates 5, respectively. Reaction of 1 with 2-benzimidazolylacetonitrile in the presence of sodium methanolate afforded 1-amino-2-(3-O-benzyl-1,2-O-isopropylidene-α-D-xylo-pentofuranuronoyl) benzo[4,5]imidazo[1,2-a]pyridine-4-carbonitrile (6) and 1-amino-2-(3-deoxy-1,2-O-isopropylidene- α-D-glycero-pent-3-enofuranuronoyl)benzo[4,5]imidazo[1,2-a]pyridine-4-carbonitrile (7).

1-(Methyl 2-O-benzyl-4,6-O-benzylidene-3-deoxy-α-D-altropyranosid-3-yl)but-3-yn-2-one (3a) reacted with 3-amino-1H-1,2,4-triazole and 5-aminopyrazole-4-carboxylic acid derivatives in the presence of base to furnish the triazolo[1,5-a]pyrimidine (5) and the pyrazolo[1,5- a]pyrimidines (8a - d), respectively. Treatment of 1-(methyl 2-O-benzyl-4,6-O-benzylidene-3- deoxy-α-D-altropyranosid-3-yl)-4-phenyl-but-3-yn-2-one (3b) with cyanacetamide, 2-cyano-N- (4-methoxyphenyl)acetamide und N-aryl-3-oxo-butyramides afforded the substituted nicotinonitriles (11a - d). Furthermore, reaction of 3b with 2-benzimidazolyl-acetonitrile yielded the benz[4,5]imidazo[1,2-a]pyridine-4-carbonitrile (13). Deprotection of 8d in two steps afforded the 2-amino-N-benzyl-5-(methyl 3-deoxy-α-D-altropyranosid-3-yl-methyl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide (10). Compounds 5 and 11d were treated with AcOH/H2O to furnish the 5-(methyl 2-O-benzyl-3-deoxy-α-D-altropyranosid-3-yl-methyl)[1,2,4]triazolo[1,5-a]pyrimidine (6) and the 3-acetyl-1,2-dihydro-1-(4-methoxyphenyl)-6-(methyl 2-O-benzyl-3-deoxy-α-D-altropyranosid-3-ylmethyl)- 4-phenylpyridin-2-one (12), respectively.

Cyclization of 2-hydrazino-5,6-dimethyl-3H-thieno[2,3-d]pyrimidin-4-one (1) with acetic acid gave 3,6,7-trimethyl-l,2,4-triazolo[3,4-a]thieno[2,3-d] pyrimidin-5-one (5) whose Dimroth rearrangement gave 2,6,7-trimethyl-l,2,4-triazolo[3,4-a]thieno[2,3-d]pyrimidin-5-one (11). Alternatively, 5 was obtained from the dehydrogenative cyclization of acetaldehyde 5,6- dimethyl-4-3H-oxo-thieno[2,3-d]pyrimidin-2-yl hydrazone (7). Reaction of 1 and 2 with a number of sugars gave the respective hydrazones 19 and 20. Those of the D-glucose exist in the cyclic pyranosyl structure in addition to minor amounts of the acyclic structure. Dehydrogenative cyclization of the sugar hydrazones gave the respective fused tricyclic compounds 25 and 26

The novel imido esters of 2-deoxy-α- and -β-D-ribose 8 and 9 have been synthesized and successfully transformed to the protected 1,2,4-triazine-C -nucleosides 11 and 12 using an inverse type Diels-Alder reaction with the 1,2,4,5-tetrazine 10. The electron deficient diazadiene system of both C -nucleosides 11 and 12 proved to be highly reactive in a consecutive [4 + 2] cycloaddition with inverse electron demand towards several electron rich dienophiles yielding after successful deprotection the novel pyridine-, pyrindine- and isoquinoline-C-nucleosides 15, 18 and 21 of 2 -deoxy-α-D-ribose and 23, 25 and 27 of 2-deoxy-β-D-ribose.

1,3-Dipolar cycloaddition of dipolarophiles (1) and (2) with endocyclic heterocyclic azomethine ylides (4), (14) and (24), prepared in situ, leads to the protected β-and α-C-nucleo-sides (7), (8), (17), (18), (27) and (28), respectively. These, on subsequent hydrolysis, provide the corresponding C-nucleosides. The structures of all the synthesized com pounds are con­ firmed through analytical and spectral data. The assignment of configuration at C -1′ position of the C-nucleosides could be done by a comparative study of the properties of the corre­sponding α and β anomers with a reasonable degree of certainity.

1-Acyclo C-nucleosides of 7-methyl-10H-1,2,4-triazolo[3’,4’:3,4][1,2,4]triazino[5,6-b]indoles (9) have been prepared by cyclodehydrogenation of the sugar derivatives of 3-hydrazino-8-methyl-5H-1,2,4-triazino[5,6-b]indole (1). The respective linear isomer as 4 has been prepared by a dehydrative cyclization of the amides of 1. Acetylation of the sugar hydrazones and their cyclized products gave the per-N,O-acetyl derivatives. The molecular connectivity of the products was established by 1H, 13C, and 2D H ,H Cosy spectra.

The determination of the energetics of the temperature-dependent two-state N reversible arrow S pseudorotational equilibrium through (3)J(HH) analysis in 36 nucleos(t)ides and 3 abasic sugars has a ...