Synthesis of Conformationally Constrained 2'-N,4'-C-Ethylene-Bridged Adenosine (aza-ENA-A)
2007 (English)In: Heterocycles, ISSN 0385-5414, Vol. 73, no 1, 303-324 p.Article in journal (Refereed) Published
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 beta anomer in glycosylation reaction was achieved using Vorbruggen 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-toluoyloxyetliyl)-D- ribofur anose (10) as a glycosyl donor and persilylated N-6-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 H-1-C-13 NMR correlation (HMBC), TOCSY, COSY and nOe experiments.
Place, publisher, year, edition, pages
2007. Vol. 73, no 1, 303-324 p.
antisense, conformationally constrained nucleoside, stereoselactivity, piperidino skeleton, conformational analysis
IdentifiersURN: urn:nbn:se:uu:diva-97298DOI: 10.1002/chin.200819206ISI: 000253154500026OAI: oai:DiVA.org:uu-97298DiVA: diva2:172170