Expanding the Genetic Alphabet: Pyrazine Nucleosides That Support a DonorDonorAcceptor 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, β‐D‐selective synthesis of a 6‐aminopyrazin‐2(1H)‐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→1a and 32→1b). Thus, a variety of pyrazine nucleosides (Scheme 13) including the target 6‐aminopyrazin‐2(1H)‐one riboside 1a, and its 5‐methyl derivative 1b, 6‐amino‐5‐methylpyrazin‐2(1H)‐one riboside, are obtained.