Bicyclic nucleosides

The 2-oxabicyclo[3.1.0]hexane nucleoside 166 was obtained via a Simmons-Smith type cyclopropanation reaction of intermediate 164, followed by glycosidation with several natural heterocyclic bases 05JOC6891 05NNNA383 . A restricted version of puromycin built on a bicyclo[3.1.0]hexane template was synthesized by Choi via Mitsunobu coupling of a 3-azido-substituted carbocyclic moiety with 6-chloropurine to give compound 167 02OL589 . 

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Reaction of 5 -0-tosyl derivative 343 <1995ARS281> with an excess of ethylenediamine in refluxing acetonitrile afforded the hyper-modified tricyclic nucleoside 344 (28%) together with bicyclic nucleoside 345 (20%) and 4, 5 -dihydro nucleoside 346 (35%) (Scheme 73) <2003JOC6695>. 

In studies on new bicyclic nucleosides the derivative 57 containing a ribose moiety has been synthesized <1996TL901>. The X-ray analysis showed that the CO bond attached to the triazine ring is only slightly longer (1.23 A) than a standard carbonyl bond. 

An overview of various synthetic approaches to bicyclic nucleosides such as the octosyl acids and the ezomycins is presented. Details of the total synthesis of octosyl acids A and C are disclosed. 

Until recently, these unusual classes of bicyclic nucleosides had eluded the grasp of synthetic chemists. It is clear that the main challenge in the synthesis of these unusual nucleosides resides in the method of bicyclic ring formation. If one also considers the type of functionality that adorns these molecules, then the whole exercise becomes one of judicious choice of reactions and protective... 

The 5 -phosphoramidite of the novel bicyclic nucleoside (14), restricted to an S-type conformation, has been synthesised in eight steps via double inversion of configuration at the C4 position of protected l-(3 -deoxy-p-D-psicofuranosyl)uracyl and introduction of an azide moiety. The secondary amino group at C4 permitted the subsequent incorporation of (14) into oligonucleotides via a 5 -3 directed variation of the standard phosphoramidite approach for synthesis of oligonucleotides. Thermal denaturation studies showed rather large decreases in duplex stabilities toward complementary DNA and RNA. ... 

Nucleosides with a bicyclic sugar ring are often called conformationaly restricted or looked. The two major conformations of natural nucleosides are C-3 -endo and C-2 -endo. The formation of a second ring induces a restriction of the pseudorotational cycle of the ribofuranose puekering. The application of bicyclic nucleosides goes from the synthesis of modified oligonueleotides to enzyme inhibitors. 

A series of novel, chiral (and racemic) 1,4-dioxepanofuranose nucleosides have been described. These are an interesting new class of bicyclic nucleoside derivatives <05CAR1081>. 

Bicyclic nucleosides and conformational restriction of oligonucleotides 00JCS(P1)3539. 

Bicyclic nucleoside derivatives formed biosyntheti-cally by linkage of oxaloacetate to adenosine. The three components (G. A to C) are produced by Streptomyces griseoaurantiacus. They are competitive inhibitors of eyclic AMP phosphodiesterase (Kj=0.16 mM). G. A stimulates glycogen mobilisation in the liver, in the mouse this leads to a higher blood glucose level. 

Structures of a range of base and/or sugar-modified nucleoside analogues have been described. The 6-azacytosine 71, pyrazolo[3,4-/>]quinoline P-ribo-furanoside 72 5 -0-benzoyl-3 -deoxy-2 -keto-a-uridine, 3 -deoxy-3 -5-(2-nitrophenyldisulfanyl)thymidine, ° anhydronucleoside 73, 5-adamantyl-2 -deoxy-4 -thio-a-uridine, the bicyclic nucleoside analogue 74, and bicyclic analogues 75 (both epimers) and 76. ... 

An account from Wengel s laboratory covers the synthesis of bicyclic nucleosides and their use in conformational restriction of resultant oligonucleotides. Structural types such as 3 -C, 5 -C-linked bicyclic nucleosides, as in bicyclo-DNA, and 2 -0,4 -C-linked systems, as in Locked Nucleic Acid (LNA) are reviewed to the end of 1999. ... 

Interest continues in conformationally-locked bicyclic nucleosides and their oligomers. A report from Wengel s laboratory describes details of the synthesis of the a-L-LNA (locked nucleic acid) nucleoside 129, in which a key step is the treatment of ditosylate 128 with NaOH in aqueous ethanol to establish the bicycle, a reaction thought to involve a 2,2 -anhydronucleoside as an intermediate. Also reported is the similar conversion of 130 into the a-L-xy/o-LNA nucleoside 131." The effect on RNA binding of the incorporation of these two compounds, and the previously-prepared P-D-xyfo-isomer and LNA nucleoside itself, into oligonucleotides has been studied the behaviour of the other four stereoisomers of LNA, enantiomeric with those synthesized, was also studied... 

Various synthetic approaches to bicyclic nucleosides, including octosyl acids and the ezomycins, have been reviewed. 

A series of phosphonylated bicyclic nucleosides (locked in a South conformation, no o>ygen atom in the rings) was synthesised by Nencka and co-workers. The synthesis begun with norbornane derivative 34 (Scheme 10), which, in a multistep process was converted into the bicyclic nucleoside 35 bearing 6-chloropurine or 2-amino-6-chloropurine. The chlorine atom was then replaced with several other substituents. Finally, a methylphosphonate group was attached at the hydroxyl group... 

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