Purines lithiation

Purines lithiated at C-2 or C-6 can be generated by way of halogen exchange with alkylUthiums, but it is important to maintain a very low temperature in order to avoid subsequent equihbration to the more stable... 

Other 1,3-diazaheterocycles related to the benzimidazole system that can be lithiated include purine nucleosides 53-55 and the related cordy-cepin analogs 56, which undergo lithiation with LDA at the 8-position when the ribose or deoxyribose hydroxy groups, are suitably protected (87CPB72 89JHCI89). Some aspects of the nucleoside metalation work have been recently reviewed (89MII). 

The iodination of cross-linked polystyrene has been achieved using iodine under strongly acidic reaction conditions [55] or in the presence of thallium(III) acetate [61], but this reaction does not proceed as smoothly as the bromination. More electron-rich arenes, such as thiophenes [45,62-64], furans [46], purines [65], indoles [66], or phenols [67,68] are readily halogenated, even in the presence of oxidant-labile linkers (Figure 6.2). Polystyrene-bound thiophenes have also been iodinated by lithiation with LDA followed by treatment with iodine [64],... 

The electrophilic chlorination of cordycepin and other purine nucleosides is carried out via lithium diisopropylamide lithiation, e.g. formation of 7. ... 

A simple entry to the C8 substituted purine nucleosides appears to be via lithiation combined with subsequent reaction with a carbon electrophile, e.g. formation of 10 and 11. 

Pyrrolopyridines can be lithiated at the 2-position, in direct analogy to pyrrole itself. The reaction is sufficiently mild that it has been applied to the functionalization of purine nucleosides, as illustrated by the examples in Scheme 22. ... 

Most commonly, palladium-catalysed substitutions on pnrines are carried ont on the halo-purine, bnt some metallated pnrines are useful. 2-Stannyl-6-chloropurines can be prepared via direct (C-H) lithiation, without protection of C-8 (27.7.1). 6-Pnrinyl zinc componnds can be prepared by reaction of the iodide with activated zinc metal." ... 

Preparative lithiation of purines requires the protection of the 7/9-position lithiation then takes place at C-8. ° 9-Blocked purines can be deprotonated at C-8 with strong bases, such as LDA, even in the presence of A-hydrogen in the other ring. Good yields of 8-halo-purines can be obtained by reaction with a variety of halogen donors 8-lithiation of 0-silyl-protected 9-ribofuranosyl-purines can be achieved using about three mole equivalents of lithium diisopropylamide. ... 

After selective lithiation at C-8 in a 6-chloro-purine riboside, quenching with a stannyl or silyl chloride leads to the isolation of the 2-substituted compound, via rearrangement of a 2-anion formed by a second lithiation of the initial 8-substituted product, as illustrated below. "... 

The reactions of the 2-, 6-, and 8-halopurines are very important in purine synthesis. Halo-purines can be prepared from oxy-, amino- or thiopurines and the 8-isomers are also available by direct halogenation or via lithiated intermediates. Chloropurines have been the most commonly used, but bromo- and iodopurines react similarly, though without any great operational advantage fluorides, are more reactive. 

Preparative lithiation of purines requires the protection of the 7/9-position lithiation... 

While aminations of pyrimidines typically exploit SnAt substitutions, direct lithiation of pyrmidine derivatives 45 with LDA or sec-BuLi, and in situ quenching with the nitroso electrophile MNP led to the formation of the new C-N bond in the products 46 <01JOC3513>. These hydroxyl amines were subsequently oxidized to aminoxyl radical spin labels. Analogous chemistry on purine nucleosides was also reported. 

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. 

Conformationally-locked C-nucleosides such as 147 have been reported from Imanishi s laboratory. These were prepared by formation of the C-T-O bond in Mitsunobu reactions, the necessary diols being formed by stereoselective addition of Grignard derivatives of the heterocycles to an aldehyde. Use of lithiated heterocycles gave substantially more of the other epimers of the diols, thus permitting access to the a-anomers after Mitsunobu reaction. The oxazole 147 and the compound without the phenyl group were incorporated into oUgonuc-leotides, and the triplex-forming ability of the these towards a purine sequence of duplex DNA was studied. ... 

The aza-C-nucleosides 149 pC = H, NH2) are potent inhibitors of purine nucleoside phosphorylase. These compounds, termed immucillins , have been prepared from the acetonitrile derivative 148, which could itself be made by addition of lithiated acetonitrile to the cyclic imine. Various 5 -deoxy-, 5 -deoxy-5 -fluoro-, and 2 -deoxy-analogues were also prepared. ... 

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