Ribofuranose synthesis

Preparation of 2-fluorofuranoses is also important in relation to the synthesis of biologically active 2 -fluoro derivatives of nucleosides (see Section 111,4). Su and coworkers prepared the 2-triflates 236 and 239 through acid-catalyzed methanolysis of 3,5-di-O-benzyl-1,2-(9-isopropylidene-a-D-ribofuranose [to give 235 (major) and 238] and subsequent triflylation. On treatment with fluoride ion, the anomer 236 afforded exclusively the furan derivative 237, whereas the a anomer 239 gave the 2-fluoro compound 240... 

Any discussion of the prebiotic phosphorylation of nucleosides must take into account the probably neutral or alkaline conditions in a prebiotic environment. Some model phosphorylating systems have been studied, for example, the synthesis of /S-o-ribofuranose 1-phosphate from ribose and inorganic phosphate in the presence of cyanogen. Sodium trimetaphosphate will phosphorylate cw-glycols in good yield under alkaline... 

Ir(CO)2(aniline-dithiocarbamate) shows a moderate activity against Ehrlich ascites at 50 mg kg 1,704 The synthesis of air-unstable [Ir2(//-L)(cod)2], where H2L = RiSSH2(l,2-0-isopropylidene-2,5-dithio-a-D-ribofuranose, XySSH2(l,2-0-isopropylidene-3,5-dithio-a-Z)-xylofuranose), is described.705... 

These acid-catalyzed C-glycosylations were successfully extended to the D-ribofuranose series by Sorm and coworkers,148 who utilized the reaction in the first reported synthesis of showdomycin. Thus, treatment of 2,3,5-tri-0-benzoyl-/3-D-ribofuranosyl bromide (81) with 1,2,5-trimethoxybenzene in the presence of zinc oxide gave 2,4,6-trimethoxy-l-(2,3,5-tri-0-benzoyl-/3-D-ribofuranosyl)benzene (196). Ozonolysis of the corresponding acetate derivative, followed by esterification, gave the highly functionalized C-/3-I>ribofuranosyl derivative (197), which was used as a key intermediate in the synthesis of showdomycin (see Section III,l,b). 

The synthesis of L-ribofuranose derivatives from 16a has been carried out by Walker and Hogenkamp (35). The procedure involves oxidation of the hydroxymethyl group of 16a with dimethyl sulfoxide N,N dicyclohexylcarbodiimide and acid hydrolysis of the protecting group to give L-riburonic acid, which was converted into methyl (methyl a,/ -ribofurano-sid)uronates (26). Reduction of 26 with sodium bis(2-methoxyethoxy)alu-minum hydride gave the chromatographically separable anomers of methyl L-ribofuranoside (27). 

Carbohydrates.—The acid (87), an intermediate in the synthesis of oxaprostaglandin derivatives from D-ribofuranose sugars,84 is obtained from the aldehyde (88) and the sodium salt of (79). The condensation of 2,5-anhydro-D-allose derivatives with (89) gave the expected products (90).85 Similarly, 1,4-furanoses (91) afford (92).86 These unsaturated halides are useful intermediates for further modifications. 

X = O, R, R = H) with tetra-(9-acetyl-)S-D-ribofuranose affords 2-(2,3,5-tri-0-acetyl-j6-D-ribofuranosyl)-l,2,4-oxadiazolidine-3,5-dione <81JMC1172). Quisqualic acid is biomimetically synthesized (8-10%) by alkylation of (226) (X = O, R , R = H) with 0-acetylserine in the presence of pyridoxal-5 -phosphate and metal ions <74CPB473,86CPB1473). A synthesis of the neurodepressant quisqualamine has been described (Scheme 102) <828781). 

The use of 2,3,5-tri-O-benzyl-D-ribofuranose 48 or xylofuranose 49 instead of arabinofuranose 45 as starting material, allowed the straightforward synthesis of two diastereomeric methylimidazolium-based ionic liquids, 50 and 51, respectively, although only as chloride salts (Scheme 13). 

Two ciT-dihydroxylation reactions of alkenes formed steps in the synthesis of the antiviral drug (-)-oseltamvir ( tamiflu ) were carried out with RuO /aq. Na(IO )/ EtOAc-CH3CN/4°C [169]. Terminal alkene groups in nucleosides were oxidised to alcohols by RuClj/aq. Na(lO )/EtOAc-CH3CN/0°C thus 3,5-di-0-benzyl-l,2-di-O-isopropylidene-3-C-vinyl-a-D-ribofuranose (1) gave the diol (2) which, on cleavage with Na(lO ) and reduction with NaBH yielded 3,5-di-0-benzyl-l,2-di-O-isopropylidene-3-C-hydroxy-methyl-a-D-ribofuranose (3) (Fig. 3.4) [170]. 

J. Ning and F. Kong, Synthesis and coupling reactions of l,2-anhydro-3,5-di-0-benzyl-a-L-ribofuranose and l,2-anhydro-5-0-benzyl-3-0-methyl-a-L-ribofuranose, J. Carbohydr. Chem., 16 (1997) 311-325. 

Vorbruggen s strategy, involving a Friedel-Crafts catalyzed silyl Hilbert-Johnson procedure, offered an alternative approach to the synthesis of 5-azacytidines.23 Utilizing these conditions, a related analog, 1-O-acetyl-2,3,5-tri-O-benzoyl-p-D-ribofuranose (14) was reacted with 2,4-bis(trimethylsilyloxy)-6-azauracil (15) and SnCl4 in 1,2-dichloroethane on a 10-kg scale. After hydrolysis of the reactive intermediate, 93% of recrystallized 6-azauridine-2,3, 5 -tri-(9-benzoate(16) was obtained. 

Neufellner, E. et al. A Novel Access to Derivatives of 3-Azido-3-deoxy-4a-carba-a-DL-ribofuranose, Potential Intermediates for the Synthesis of Carbachryscandin and Carbapuromycin. 2.4 1998 [158]... 

Shoberu, K.A. et al. Synthesis of Pseudo-Ribofuranoses by Stereocontrolled Reactions on 4-Hydroxycyclopent-2-enylmethanol Derivatives. 2.1 1992 [179]... 

As confirmation of the structure of D-ribofuranose tetraacetate, may be mentioned its use in the synthesis of the naturally occurring D-ribo-furanoside xanthosine.100... 

Debenzylation of the benzyl esters of phosphoric acid has been employed in the synthesis of phosphorylated alcohols. Examples are shown in eqs. 13.2348 and 13.24.49 Tener and Khorana synthesized a-D-ribofuranose 1,5-diphosphate (36) by hydrogenolysis of the benzyl phenyl phosphate 35, first, in the presence of 5% Pd-C, and then in the presence of Adams platinum to remove, respectively, the benzyl and the phenyl groups (eq. 13.25).50... 

More recently, the use of the chloroformate-aqueous alkali method has been revived by G. R. Barker and his associates in order to prepare a suitably protected D-ribose carbonate for a synthesis of a-D-ribofuranosyl phosphate. (An analogous synthesis of the latter compoimd, involving a phosgene-pyridine reaction, appeared almost simultaneously. ) Condensation of D-ribose with methyl chloroformate in the presence of aqueous sodium hydroxide led to the formation of a mixture of the anomers of l,5-di-0-(methoxycarbonyl)-D-ribofuranose 2,3-carbonate (LII), which was resolved by fractional recrystallization. The treatment of either of the derived D-ribofuranosyl chlorides with methanol and silver carbonate... 

Persilylated intermediates such as 170 are also obtained during nucleoside synthesis. Thus, reaction of 3,5-bis-(trimethylsilyloxy)-l,2,4-triazine (168) with l-0-acetyl-2,3,5-tri-0-benzoyl-/8-D-ribofuranose (169) in the presence of 0.76 equivalents of SnCU in 1,2-dichloroethane leads to 170 as intermediate, which reacts with a 10-fold excess of pyrrolidine to give 0-benzoylated 6-azacytidine (171) in 57% yield (75LA988). Inosine (172a), guanosine (172b), or xanthosine (172c) have hitherto been trans-... 

For synthesis of nucleosides, methyl 4-acetamido-2,3-di-0-benzoyl-4-deoxy-a-D-ribopyranoside (198c), obtained from 198a, was trans-formed by acetolysis into 4-acetamido-l,5-di-0-acetyl-2,3-di-0-benzoyl-4-deoxy-D-ribofuranose (199b). Either with preliminary treatment with hydrogen chloride in acetyl chloride, or directly, in the presence of titanium tetrachloride, 199b gave with chloromercuri-(6-... 

The synthesis of corresponding pyrimidine nucleosides was not possible by the mercuric chloride method. The syntheses succeeded, however, on application of the Hilbert—Johnson procedure. Tetra-O-acetyl-4-thio-D-ribofuranose was transformed with ethereal hydrogen chloride into the glycosyl chloride derivative 254, and this was directly heated for five days with 2,4-diethoxy-5-methylpyrimidine. The anomeric forms of 4-ethoxy-5-methyl-l-(2,3,5-tri-0-acetyl-4-thio-D-ribofuranosyl)-2(lH)-pyrimidinone obtained could be separated... 

A typical example is the synthesis of 2-chloro-2 -deoxyadenosine (13) by fusion of 2,6-dichloropurine with 2-deoxy-l-0-methyl-3,5-di-C -(4-toluoyl)- -D-ribofuranose. ... 

This silyl method has become one of the most used among the various methods for the synthesis of nucleosides. The introduction of the trimethylsilyl groups greatly enhances the solubility of the purine. Condensation of 0 ,9-bis(trimethylsilyl)hypoxanthine and 1-O-acetyl-2,3,5-tri-0-benzoyl-j8-D-ribofuranose, with tin(IV) chloride as catalyst, gives 2, 3, 5 -tri-0-ben-zoylinosine (16) in 71 /o yield after removal of the silyl groups by water treatment. ... 

Mukaiyama and co-workers revealed that Li salts play a significant role in controlling the novel stereochemical preference that is involved in the glycosidation with ribofur-anose derivatives (Sch. 52). In particular, LiC104 [101-105] and LiNTf2 [105] were found to be effective additives in the stereocontrolled synthesis of a-o-ribofuranosides from 2,3,5-tri-O-benzyl-D-ribofuranose and several alcohols, whereas p anomers were formed in the absence of the lithium salts. Sch. 52 shows several examples that emphasize general characteristics with or without the addition of lithium salts. In the most recently advanced system (Sch. 53), a hypothetical mechanism of this reverse stereocontrol to yield 110 with the influence of lithium salt is also discussed. In the presence of 10 mol % TrC104, both pure a anomer 110 (a /3 = >99 <1) and P anomer 111 a-.p = <1 >99) isomerized to afford a P anomer-rich mixture (a p = 6 94). 

Mukaiyama, T, Koki, M, Suda, S, An efficient method for the stereoselective synthesis of 1,2-cis- and l,2-traui -ribofuranosides from 1-hydroxy ribofuranose by the use of diphenyltin sulfide and trifluoromethanesulfonic anhydride, Chem. Lett., 981-984, 1991. 

Schmidt, R R, Reichrath, M, Facile, highly selective synthesis of a- and 3-disaccharides from 1-0-metalated D-ribofuranoses, Angew. Chem. Int. Ed. Engl, 18, 466-467, 1979. 

A few 4a-carba-furanoses were synthesized using the same methodology. However, after saturation of the alcohol 40 the syntheses diverged when protection of the hydroxyl, cleavage of the acetonide and oxidative cleavage of the diol afforded the aldehyde 44 (Scheme 8.15). This compound underwent an aldolisation reaction whose stereoselectivity could be controlled by the reaction temperature. Specifically, at — 90°C the bicyclic product 46 was obtained in a yield of 71%. Alternately, bicyclic derivative 45 was the principle product obtained when the reaction was run at room temperature (78%). Reduction of the lactone and desilylation afforded 4a-carba-(3-D-xylofuranose from isomer 45, whereas 4a-carba-(3-D-ribofuranose was formed from 46. Isomerisation of compound 40 led to the synthesis of two other isomeric carba-sugars 4a-carba-(3-L-lyxofuranose and 4a-carba-(3-L-arabinofuranose [36]. 

BeUon, L, Barascut, J-L, Imbach, J-L, Efficient synthesis of 4-thio-D-ribofuranose and some 4 -thioribonucleosides, Nucleos. Nucleot, 11, 1467-1479, 1992. 

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