An alpha-D-configured bicyclic nucleoside restricted in an E-type conformation: synthesis and parallel RNA recognition.

An alpha-D-arabino configured bicyclic nucleoside strongly restricted in an E-type conformation by a 2'-3'-fused oxetane ring is synthesized. Several synthetic strategies toward the target compound are described, and the successful preparation from a D-xylose derivative is based on a ruthenium-mediated cleavage of a double bond, an S(N)2-inversion at the 2-position to give an arabino-configuration, nucleobase coupling, and finally ring closure to give the oxetane ring. The E-type conformation is confirmed by molecular modeling and NMR. The nucleoside is incorporated into short alpha-DNA sequences. In a mixed pyrimidine context, these recognize complementary parallel RNA-sequences with mainly increased affinity and complementary parallel DNA-sequences with decreased affinity. The present bicyclic analogue represents the first conformationally restricted alpha-DNA-analogue to improve nucleic acid recognition in mixmers with alpha-DNA monomers.