Diversely C8-functionalized adenine nucleosides via their underexplored carboxaldehydes

The potentially versatile N-unprotected 8-formyl derivatives of adenosine and 2 '-deoxyadenosine are highly underexploited for C8 modifications of these nucleosides. Only in situ formation of 8-formyladenosine is known and a single application of an N-benzoyl derivative has been reported. On the other hand, 8-formyl-2 '-deoxyadenosine and its applications remain unknown. Herein, we report straightforward, scalable syntheses of both N-unprotected 8-formyladenine nucleoside derivatives, and demonstrate broad diversification at the C8 position by hydroxymethylation, azidation, CuAAC ligation, reductive amination, as well as olefination and fluoroolefination with modified Julia and a Horner-Wadsworth-Emmons reagents.

Automated summary

The underexploited potential of N-unprotected 8-formyl derivatives of adenosine and 2'-deoxyadenosine for C8 modifications of these nucleosides is discussed in this study. The researchers report the straightforward and scalable synthesis of N-unprotected 8-formyladenine nucleoside derivatives, and demonstrate their versatility for C8 diversification through various reactions.