Synthesis and restricted furanose conformations of three novel bicyclic thymine nucleosides: a xylo-LNA nucleoside, a 3′-O,5′-C-methylene-linked nucleoside, and a 2′-O,5′-C-methylene-linked nucleoside

Abstract

The xylo-LNA nucleoside 1-(2-O,4-C-methylene-β-D-xylofuranosyl)thymine (9) and the 2′-O,5′-C-methylene linked nucleoside 1-(2,6-anhydro-β-D-altrofuranosyl)thymine (28) were obtained in overall yields of 13% (8 steps) and 31% (7 steps) starting from furanose derivatives 1 and 21, respectively. In the synthesis of 3′-O,5′-C-methylene-linked nucleoside derivatives, cyclization by intramolecular attack from the 6-hydroxy group on the 3-keto functionality to give C-3-hemiketal furanose 11 and its subsequent transformation into nucleoside 15 proved very efficient. It was, however, impossible to isolate the debenzylated 2′-hydroxy, 2′-O-methyl and 2′-O-tert-butyldimethylsilyl derivatives 16, 18 and 20, respectively, in analytically pure form. Solution-phase conformational analysis showed the bicyclic nucleosides 8, 9, 14, 15, 17 and 19 to exist predominantly in an N-type furanose conformation and bicyclic nucleotides 27 and 28 to adopt an S-type conformation.