Expanding the genetic alphabet: Pyrazine nucleosides that support a donor-donor-acceptor hydrogen-bonding pattern

The 6-aminopyrazin-2(1H)-one, when incorporated as a pyrimidine-base analog into an oligonucleotide chain, presents a H-bond donor- donor- acceptor pattern to a complementary DNA or RNA strand. When paired with the corresponding acceptor-acceptor-donor purine in oligonucleotides, the heterocycle selectively contributes to the stability of the duplex, presumably by forming a base pair of Watson-Crick geometry joined by a nonstandard H-bonding pattern, expanding the genetic alphabet. Reported here is a short, high yielding, beta-D-selective synthesis of a 6-aminopyrazin-2(l H) -one nucleoside via the glycine riboside derivative 28. The key steps include a Wittig-Horner reaction of an appropriately protected ribose derivative (Scheme 10, 19 --> 21) followed by a Michael-like ring closure (Scheme 12, 30 --> la and 32 --> 1b). Thus, a variety of pyrazine nucleosides (Scheme 73) including the target 6-aminopyrazin-2(1H)-one riboside la, and its 5-methyl derivative 1b, 6-amino-5-methylpyrazin-2(1H)-one riboside, are obtained.