Tetrazole C-nucleosides

Cyclization of O-benzylated 2-pyridyl acyclo C-nucleoside using diethyl azodicarboxylate and triphenylphosphine to pyridyl C-nucleosides has been reported [95JAP(K)95/118268]. 

Recently, C-nucleoside synthesis by glycosyl free radical coupling with protonated nitrogen heterocycles started to gain impetus. Thus, photoirradiation of the l-(2,5-anhydro-D-allonoyloxy)pyridine-2-thione derivative 798 gave the D-ribofuranosyl free radical 799 that couples with substituted pyridines to give a mixture of the two anomers of 2-pyridyl C-nucleosides 

Only 2-carbamoyl-6-()8-D-ribofuranosyl)pyridine (88CPB634) and its 4-carbamoyl congener (91MI25) revealed weak to moderate antitumor activity the many other differently substituted 2-pyridyl C-nucleosides were inactive as antitumor and antiviral agents (86MI8 92HCA1613 93-JHC1245). 

Similar to their 2-pyridyl analogs, 3-pyridyl C-nucleosides (804) were prepared by acid-catalyzed cyclization of 3-(2-methylsulfonyloxypentitol- 

Palladium-mediated C—C bond formation between the glycal derivative 813 and 3-iodopyridines (e.g., 814) generated solely the /1-linked 3-pyridyl 

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These compounds were mainly synthesized by the reaction of tetrazole C-nucleosides (Section XXII,A) such as 730 with acid anhydrides or acid chlorides the intermediate V-acyltetrazoles 731 were converted to 7213 through the elimination of nitrogen [78KGS893 81ACH(106)61 84-ACH(115)319 94MI11] (Scheme 196). 

Similar to the preparation of the parent tetrazole C-nucleosides, the carbocyclic analog 784 was prepared from the carbocyclic nitrile derivative 782 and lithium azide (93M112) (Scheme 216). 

Harusawa et synthesised CS-linked Cq- and C2-ribonucleoside phosphoramidites via tetrazole C-nucleosides for probing RNA catalysis. The nitrogen in the tetrazole was protected by methyl-substituted piva-loylojgmiethyl (43) and pivaloylojgmiethyl (44) groups which can easily be removed under basic conditions. 

An intramolecular cyclization of a tetrazole-containing nucleoside 64 has been observed by Chu and co-workers <1997JOC7267> (cf. other properties of this compound in Table 3). These authors reported that the 3-OH group on the arabinofuranose ring participates in an addition reaction at position 7 of the tetrazolo[l,5-c]pyrimidine ring to form 65 which is a dihydro derivative of the parent heterocycle. The final structure elucidation has been carried out with the help of the tricyclic tandem mass spectrometry (MS/MS) fragment 66. 

An interesting synthesis of these C-nucleosides utilized the easily accessible 5-(j3-D-ribofuranosyl)tetrazoles 235 as masked C-glycosyl-diazometh-ane. Reacting 235 with 2-chloro-3-nitropyridine gave a mixture of 1,2,4-triazolo[4,3-fl]pyridin-3-yl (236) and l,2,4-triazolo[l,5-a]pyridin-2-yl (237) C-nucleosides. The latter (237) resulted from thermally induced Dimroth-like rearrangement of the former (236) (86MI9) (Scheme 70). Compounds 236 and 237 possess considerable cytotoxic effect (86MI9). 

The tetrazole acydo C-nucleoside 749 (Section XXII,C) afforded the 1,3,4-oxadiazole acyclo analogs 752 upon treatment with acid anhydrides or acid chlorides (76MI12 91MI14 92MI1 94AQ130) (Scheme 202). 

Cycloaddition of hydrazoic acid to aldononitriles (618) (71MI2 75MI5 79MI13 90MI3) or thermolysis of the 1,1-diazido acyclic sugar derivatives 789 [95JCS(P1)1747] yielded the tetrazole acyclo C-nucleosides 749 (Scheme 218). 

The number of five-membered heterocycles with four hetero atoms is limited to those with nitrogen atoms. Thus, the tetrazole acyclonucleo-sides were formed from sugars N,N -diphenylformazanes by the action of AT-bromosuccinimide or lead tetraacetate [133,134]. The synthesis of the tetra-O-benzoyl-D-lyxononitrile and its conversion to (o-lyxo-tetritol-l-yl)-tetrazole derivatives upon reaction with sodium azide was reported [133, 134]. A pseudo C-nucleoside including a tetrazole ring was achieved by conversion of 3- 0-benzyl- 1,2-O-isopropylidene-D-ribo-pentodialdehydo-1,4-furanose to the respective nitrile and then reaction with sodiiun azide [86]. 

Various 3-ribofuranosyl-indoles, -pyrroles and -pyrazoles have been made by reaction of V-blocked heterocycles with 2,3,5-tri-C -benzyl-3-D-ribofuranosyl fluoride.Lithiation of 2,6-dichloroimida2o[l,2-a]pyridine occurs predominantly at C-5, and reaction with a ribono-y-lactone derivative and anomeric deoxygenation gives the 5-ribofuranosyl system 151 with good P-selectivity. The alternative 3-glycosylation pattern 152 could be obtained by palladium-catalysed coupling of 2,6-dichloro-3-iodoimidazo[l,2-a]pyridine with 2,3-dihydrofuran, followed by hydroxylation. Various pyrazolo[4,3-c]pyridine C-nucleosides such as 153 have been made using an effective tetrazole-to-pyrazole transformation carried out on a C-ribofuranosyltetrazole. A paper on the conformational properties of some purine-like C-nucleosides is mentioned in Chapter 21. 

Addition reactions to unsaturated C-glycosides have continued to be utilized to synthesize C-nucleosides. Thus 2,3,5-tri-0-benzoyl-/3-D-ribofuranosyl cyanide with sodium azide-ammonium chloride in DMF gave the tetrazole (72) in 72% yield. Treatment of (72) with acetic anhydride gave the 1,3,4-oxadiazole nucleoside (73). The benzothiazole (74) was obtained from the ribosyl cyanide by reaction with 2-aminothiophenol. Analogous compounds were derived from jS-D-ribo-, 8-D-xylo-, and j3-D-galactopyranosyl cyanides. A similar reaction has been used by a different group to synthesize a-D-arabinosyl tetrazole (75). Reaction of 3,4-di-0-benzoyl-2,5-anhydro-D-... 

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