The Synthesis of Nucleosides

Expressed simply, nucleosides are formed by linking an organic base (here guanine, adenine, uracil or cytosine) to a sugar (here D-ribose) with the elimination of water  

This reaction looks simple, but an enzyme-free prebiotic synthesis, in particular involving pyrimidine bases, is still very difficult. It is possible that completely new synthetic strategies will need to be devised. 

The problems in the nucleoside synthesis arise in the linkage of the 3-N atoms of the pyrimidines and the 9-N atoms of the purines with the l -C atom of ribose, not only without enzyme control, but also under conditions extant on the primordial Earth. How might such reactions occur There have naturally been many attempts 

---

This methodology has also been applied to the synthesis of nucleoside derivatives, which are used in the preparation of drugs against AIDS (Eq. 7.85).130... 

The use of thionocarbamates in the synthesis of nucleoside analogues was explored for the first time by Ranganathan, who described a five-step synthesis of 9-p-D-arabinofuranosyladenine, starting from a d-arabino-anchored OZT14 (Scheme 58). 

Sulfoxides have also been used in the synthesis of nucleoside analogs (Scheme 3.2). Chanteloup and Beau reported the synthesis of ribofuranosyl sulfoxide 13 and its use in the glycosylation of a series of silylated pyrimidine and purine bases.7 Although 16 is not an anomeric sulfoxide, its reaction with cytosine derivative 17 is conceptually related.8... 

The synthesis of nucleosides, nucleotides and nucleic acids is described and discussed in Chapter 20. 

Example 47 Dabkowski et al. have devised a strategy for the synthesis of nucleoside phosphorfiuoridites based on the replacement of a 4-nitrophe-noxy group attached to a P centre by fluoride anion [11b, 31]. 

This section examines the synthesis of nucleosides that contain seven-membered sugar analogues in place of the deoxyribose component. Nucleosides from the last group have been further incorporated into ONs via solid-phase DNA synthesis. A physical and biochemical investigation of the oligomers thus prepared continues in the next section. The study under review culminated in the assessment of the ability of the oligomers to complex with single-stranded RNA and for the heteroduplexes so formed to serve as substrates of RNAseH. 

The process is operated at a platinum electrode and a reduced efficiency due to side reactions is observed. A maximum yield of 55% is reported. The use of in situ generated NBS and bromine for the synthesis of nucleosides from silylated pyrimidines has been studied. Nokami etal. [125] suggest the use of only catalytic amounts of NBS or bromine and regeneration of the catalyst by anodic electrolysis in an undivided cell system. 

This Chapter will discuss the formation of heterocycles that contain nitrogen and that involve atoms of the original sugar, and not the combination of existing heterocycles with saccharide derivatives. Thus, for example, the synthesis of nucleosides will not be included, but the formation of anhydronucleosides, in which a new heterocyclic ring has been introduced into the molecule, will be treated. 

This article collates information on the reactivity of sugar isothiocyanates and isomeric thiocyanates, and illustrates some of the chemical properties that have contributed to the synthesis of nucleoside analogs,1719 and thio and deoxy sugars. 

Sugar Isothiocyanates as Intermediates in the Synthesis of Nucleoside Analogs... 

Glycosyl—Enzyme Complex Intermediates in Biosynthesis of Complex Saccharides. The synthesis of nucleoside diphosphate sugars involves the transfer of a nucleotidyl group from a nucleoside triphosphate to a sugar 1-phosphate with the simultaneous release of pyrophosphate according to the following general reaction (11) ... 

After it was demonstrated that silylated sugars easily form diglycosides225 when they are applied to 1-halo-sugars, further studies followed. It became apparent that these silylated heterocycles are convenient intermediates, especially for the synthesis of nucleosides when acylated 1-halo-sugar are employed224,22S. ... 

K. Chow and S. Danishefsky, Stereospecific Vorbruggen-like reactions of 1,2-anhydro sugars. An alternative route to the synthesis of nucleosides, J. Org. Chem., 55 (1990) 4211-4214. 

Pd-catalysed allylation of amines proceeds smoothly. Allylamine (132) and di- and triallylamines are produced commercially by the Pd-catalysed reaction of ammonia with allyl alcohol using DPPB as a suitable ligand [69]. Allylic alcohols are rather unreactive substrates for 7r-allylpalladium complex formation under usual conditions. The intramolecular amination of 133 afforded the azaspiro ring 134 and the reaction was applied to the synthesis of perhydrohistrionicotoxin (135) [70]. Smooth Pd-catalyzed allylation of the purine base 136 gives 137, which is utilized for the synthesis of nucleosides [71]. 

In the synthesis of nucleosides from their corresponding C-glycosyl derivatives, silver acetylides have been proved effective in introducing an acetylenic ester. The ribose... 

The acetylation of D-ribose in pyridine solution at low or ordinary temperatures leads to the formation of a crystalline tetraacetate melting at 110° and showing [ ]26D — 54.3° in chloroform.56-14 The ring structure of this substance is retained on conversion to triacetyl-D-ribosyl bromide since the latter compound may be reconverted to it by treatment with silver acetate.66 While indirect evidence early indicated94 that the bromide as well as the tetraacetate possessed a pyranose structure the question was not settled unequivocally until the bromide was used in the synthesis of nucleosides which were known to be pyranosides through quantitative periodate oxidation.95 While the configuration of the crystalline tetraacetate at carbon one will not be known with certainty until its anomer is obtained, the compound may provisionally be considered jS-D-ribopyranose tetraacetate because of its strong levorotation. 

Substitution of halogen by oxygen has been used in the synthesis of nucleosides. Photolysis of 2-iodoadenosine in water provides isoguanosine725. 2 -Deoxyisoguanosine and some base-modified analogues were prepared via photochemical replacement of chlorine or bromine by water726. 

Although there are many methods available, there are two main routes for the synthesis of nucleoside monophosphates. These involve either the reaction of the nucleoside with 2-cyanoethylphosphate in the presence of a condensing agent such as dicyclohexyl carbodiimide (DCC)2,3 or phosphorylation of the nucleoside... 

In contrast, the synthesis of nucleoside 3 -phosphates is best achieved by DCC-mediated condensation of suitably protected nucleosides with 2-cyano-ethylphosphate.3... 

The synthesis of nucleoside (l-thio)triphosphates using phosphorus(V) chemistry... 

The synthesis of nucleoside diphosphates is best achieved using the Poulter reaction,9 which involves reaction of the tris(tetra-n-butylammonium) salt of pyrophosphate with a nucleoside 5 -tosylate in acetonitrile. A general procedure for the synthesis of nucleoside tosylates of thymidine and 2 -deoxyadenosine is included (Protocol 15), whilst the syntheses of the other tosylates (including ribonucleosides) have been described using related procedures. Simple modification of the protocol, whereby the tetra-n-butylammonium salt of pyrophosphoric acid is replaced by methylene or difluomethylene bis phosphonate, allows the synthesis of hydrolytically stable dNTP analogues.10... 

Iodo-li/-pyrrole-2-carbaldehyde, used in the synthesis of nucleoside derivatives, was prepared via protection of the aldehyde group in l//-pyrrole-2-carbaldehyde with an iminium salt for the efficient w f -directed electrophilic substitution of the starting pyrrole followed by a treatment of the iminium salt with N-iodosuccinimide in acetonitrile then with sodium bicarbonate (57% two-step total yield) <2003BML4515>. 

In addition to the Hilbert-Johnson reaction, the so-called mercuri process,37 and, less frequently, the cyclization procedure of Shaw et a/.,53 64 have been used for the synthesis of nucleosides and their derivatives. l-Peracylglycosyl-4-alkoxy-2(l//)-pyrimidinones, the intermediates of the Hilbert-Johnson reaction, can be, in principle, prepared 56,56 also by the mercuri process, namely by reaction of 4-ethoxy-2(lZ/)-pyrimidinone chloromercuri salt with the corresponding halogenoses, but this method is of less importance because of the contamination of iV-l-glycosyl derivatives with the 0-2 isomers, namely, with 2-peracylglycosyloxy-4-alkoxypyrimidines. The advantageous features of the mercuri process in comparison with the Hilbert-Johnson reaction might be formulated as follows. 

---