Oligonucleosides with a nucleobase-including backbone - Part 1 - Concept, force-field calculations, and synthesis of uridine-derived monomers and dimers

A new type of oligonucleosides has been devised to investigate the potentia l of oligonucleosides with a nucleobase-including backbone to form homo- an d/or heteroduplexes (cf: Fig. 2). It is characterised by ethynyl-linkages b etween C(5') and C(6) of uridine, and between C(5') and C(8) of adenosine. Force-field calculations and Maruzen model studies suggest that such oligon ucleosides form autonomous pairing systems and hybridize with RNA. We descr ibe the syntheses of uridine-derived monomers, suitable for the constructio n of oligomers, and of a dimer. Treatment of uridine-5'-carbaldehyde (2) wi th triethylsilyl acetylide gave the diastereoisomeric propargylic alcohols 6 and 7 (1:2, 80%;Scheme 1). Their configuration at C(5') was determined on the basis of NOE experiments and X-ray crystal-structure analysis. Iodinat ion at C(6) of the (R)-configured alcohol 7 by treatment with lithium diiso propylamide (LDA) and N-iodosuccinimide (NIS) gave the iodide 17 (62%),whic h was silylated at O- C(5') to yield 18 (89%;Scheme 2). C-Desilylation of 7 with NaOH in MeOH/H2O led to the alkyne 10 (98%); O-silylation of 10 at O- C(5') gave 16 (84%). Cross-coupling of 18 and 16 yielded 63% of the dimer 19, which was C-desilylated to 20 in 63% yield. Cross-coupling of 10 and th e 6-iodouridine 13 (70%), followed by treatment of the resulting dimer 14 w ith HF and HCl in MeCN/H2O, gave the deprotected dimer 15 (73%).