Nucleoside derivatives, Mitsunobu reaction

Phosphorus dithioacids [RR P(S)SH] are effective sulfur nucleophiles for the synthesis of 3 -S-or 5 -5 -nucleosides [107]. Furthermore, Mitsunobu reactions have also been used to convert primary sugar alcohols into corresponding thiosugar derivatives in one-pot manner [108]. 

Cyclic phosphonate analogues of PMEA (36) have been obtained after stereoselective cyclisation of an acyclic phosphonyl intermediate to the phos-phonyltetrahydrofuran nucleoside derivative. A series of cyclopropylphos-phonate analogues (37) has been synthesised stereoselectively via intramolecular epoxide opening reaction of y,5-epoxyalkanephosphonates with subsequent Mitsunobu coupling reaction to purine bases. Acyclic phosphonate derivatives of thymine (38-43) have been prepared and evaluated as multisubstrate analogue inhibitors of Escherichia coli thymidine phosphor-... 

The iso-4 -thiopurine and pyrimidine L-nucleosides 211 were synthesized from 1,4-thio-L-arabinitol (151) via 3-fluoro derivative 209, which was transformed into 210 by a Mitsunobu reaction. Coupling of 210 with purine and pyrimidine bases by the Mitsunobu reaction, followed by deprotection, gave the desired 211. 

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. ... 

A special subclass of amine formation reaction is the coupling of alcohols with purines to form nucleoside derivatives. The application of the Mitsunobu reaction in this context is sufficiently expansive to warrant a mini-review in its own right, but due to space constraints only a limited number of recent examples are shown below (195 - 198). "" The reader is referred to the references for additional information. Additional examples using iV -benzoylthymine, adenine, deazapurine, 6-azauracil, and 3-benzoyluracir have been reported in the literature as well. The preparation of racemic isonucleosides via the Mitsunobu reaction is also known. 

Mitsunobu reactions between appropriate ribose derivatives and M-hydroxyheterocycles gave novel C-O-N nucleoside analogues of type (9) in moderate yield. 2 The triester (9, R=R =Bz) is also available by interaction of the ribofuranosyl chloride with 1-hydroxyuracil and triethylamine under... 

The reaction of an epoxide containing molecule with a nucleophile is typically an excellent manner in which to open the epoxide ring. A recent synthesis of carbocyclic nucleoside analogues provides an excellent example of reaction conditions that epoxides can sometimes withstand <07T5050>. Treatment of epoxide 18 with chloropurine under Mitsunobu conditions provides a good yield of epoxy purine derivative 19. This derivative was then converted to adenine derivative 20 by ester hydrolysis and subsequent chloride displacement with cyclopropylamine. 

It was found recently that 2, 3 -0,0-protected adenosine and similar derivatives could be efficiently phosphorylated under Mitsunobu conditions when the reaction was carried out in anhydrous pyridine. Less nucleophilic phosphonates also reacted, but gave lower yields [114]. The use of nucleosides non-protected at the 2 and 3 positions led to the formation of by-products, and 5 -phospho-rylated adenosine or derivatives could not be isolated satisfactorily. 

Lewis acid-catalysed reaction of diisopropyl (hydroxymethyl)phosphonate [( Pr0)2p(O)CH2OH] with di-O-acetyl-D-xylal, followed by reaction with metha-nolic ammonia, affords 14 as the major isomer a brief description of the diastereoselectivity of this reaction is also given. Compoimd 14 on reaction with 2-amino-6-chloropurine under Mitsunobu conditions affords access to dihydro-pyranyl nucleoside phosphonate analogues, which on reduction of the double bond lead to the corresponding tetrahydropyranyl derivatives. EH-O-acetyl-L-arabinal was also used as a starting material. ... 

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