Synthesis of Acyclic Nitroazole Nucleosides and Their Incorporation into Oligonucleotides, and Their Duplex and Triplex Formation

Abstract

Abstract Acyclic nucleosides of 4‐nitro‐1 H ‐imidazole and 4‐nitropyrazole have been synthesized by nucleophilic addition of the appropriate 4‐nitroazole to (−)‐( S )‐(hydroxymethyl)oxirane in the presence of a catalytic amount of potassium carbonate. (+)‐( R )‐3‐(4‐nitro‐1 H ‐imidazol‐1‐yl)propane‐1,2‐diol and (+)‐( R )‐3‐(2‐methyl‐4‐nitro‐1 H ‐imidazol‐1‐yl)propane‐1,2‐diol were also obtained in an independent reaction starting from appropriate 1,4‐dinitro‐1 H ‐imidazole and (+)‐( R )‐3‐aminopropane‐1,2‐diol. (+)‐( R )‐3‐(4‐Nitropyrazol‐1‐yl)propane‐1,2‐diol was also obtained by direct noncatalyzed addition of 4‐nitropyrazole to (−)‐( S )‐(hydroxymethyl)oxirane, whereas the ( S )‐enantiomer was obtained by reaction of 4‐nitropyrazole with (+)‐( S )‐1,2‐ O ‐isopropylideneglycerol under Mitsunobu reaction conditions, followed by a cleavage of the isopropylidene group with 80% AcOH. Racemization during any of these syntheses has not been observed. 3‐(4‐Nitroazol‐1‐yl)propane‐1,2‐diols were incorporated into a 26‐mer oligonucleotide. UV Thermal melting studies of duplexes of the oligonucleotides with 4‐nitropyrazole or 4‐nitro‐1 H ‐imidazole paired with four natural bases showed moderately decreased stabilities of the duplexes. A narrow range of melting temperatures, typically being within 2° for each acyclic nucleoside, fulfill one of the requirements of using acyclic 4‐nitroazoles as general bases. Single incorporation of 4‐nitroazoles into a 14‐mer triplex forming oligonucleotide resulted in considerably decreased triplex stabilities.