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 potential of oligonucleosides with a nucleobase‐including backbone to form homo‐ and/or heteroduplexes (cf. Fig. 2). It is characterised by ethynyl‐linkages between 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 oligonucleosides form autonomous pairing systems and hybridize with RNA. We describe the syntheses of uridine‐derived monomers, suitable for the construction of oligomers, and of a dimer. Treatment of uridine‐5′‐carbaldehyde ( 2 ) with 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. Iodination at C(6) of the (R)‐configured alcohol 7 by treatment with lithium diisopropylamide (LDA) and N‐iodosuccinimide (NIS) gave the iodide 17 (62%), which 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 the 6‐iodouridine 13 (70%), followed by treatment of the resulting dimer 14 with HF and HCl in MeCN/H₂O, gave the deprotected dimer 15 (73%).