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Paper | Special issue | Vol 73, No. 1, 2007, pp.303-324
Published online, 26th June, 2007
DOI: 10.3987/COM-07-S(U)5
Synthesis of Conformationally Constrained 2’-N,4’-C-Ethylene-Bridged Adenosine (aza-ENA-A)

Malgorzata Wenska, Dmytro Honcharenko, Wimal Pathmasiri, and Jyoti Chattopadhyaya*

*Department of Bioorganic Chemistry, Box 581, Biomedical Center, Uppsala University, SE-75123 Uppsala, Sweden

Abstract

The synthesis of conformationally constrained 2’-N,4’-C-ethylene-bridged adenosine (aza-ENA-A), in which the pentose-sugar is cis-fused with the piperidino skeleton at C2’ and C4’ centres of the sugar ring, is reported. The corresponding phosphoramidite building block will be used for incorporation into oligo-DNA and -RNA by solid phase synthesis to examine their nuclease stability as well as their application in blocking the translation of the target RNA using the antisense and siRNA approach. 2-Aza-6-oxabicyclo[3.2.1]octane skeleton is assembled through multi-step synthetic manipulation of appropriately protected D-arabinose based sugar precursor. The conversion of appropriate arabino precursor to ribo counterpart was achieved by direct nucleophilic displacement of “ara” positioned 2-(trifluoromethanesulfonyloxy) group in the sugar precursor 8. A high regio- and enhanced stereoselectivity with preferential formation of β anomer in glycosylation reaction was achieved using Vorbrüggen conditions in the absence of any 2-participating group. Coupling step was performed using 1-O-acetyl-3,5-di-O-benzyl-(2-deoxy-2-azido)-4-C-(p-toluoyloxyethyl)-D-ribofuranose (10) as a glycosyl donor and persilylated N6-benzoyladenine. Finally, the ring-closure giving the North-type conformationally constrained cis-fused bicyclic aza-ENA-A have been confirmed unambiguously by the long range 1H-13C NMR correlation (HMBC), TOCSY, COSY and nOe experiments.