SYNTHESIS OF CONFORMATIONALLY CONSTRAINED 2'-N,4'-C-ETHYLENE-BRIDGED ADENOSINE (aza-ENA-A)

摘要

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 "are" 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 Vorbriiggen 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-ribofur anose (10) as a glycosyl donor and persilylated N-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.