Electrochemical Synthesis of Azanucleoside Derivatives Using a Lithium Perchlorate-Nitromethane System

Nucleoside analogues have played an important role in the viral decease and cancer therapy. To date, various nucleosides analogous have been investigated to improve their therapeutic effects and toxic properties. The modification of the sugar moiety has produced new active analogous. Especially, the design of furanose rings that include various heteroatoms has been one of the most useful approaches in the search for new nucleoside analogues with beneficial biological activity.

Azanucleosides, in which the furanose oxygen atom is replaced by a nitrogen atom, have attracted interest because of possibility of their further modification through the nitrogen atom and structural similarity to the franose ring system. Considerable efforts have been dedicated to develop the efficient method for the synthesis of azanucleoside derivatives. Most of the synthetic strategies have been designed in order that N-glycosyl bond has been formed through an iminium ion intermediate. This process is necessary to incorporate a leaving group into the pyrrolidinyl precursor to generate the key reactive intermediate. However, access to such precursors requires a multi-step synthetic sequence, which includes cumbersome operations and harsh reaction condition. Indeed, this process often removes the opportunity of providing diverse azanucleosides based on further modification of the nitrogen atom.

To address this challenge, we reasoned that direct and selective insertion of a nucleobase to the N-a position of prolinol moiety would avoid the redundant multi-step synthetic operation. We proposed that an electro-organic method might provide such an approach to overcome the challenge of direct introduction of a nucleobase into an unactivated pyrrolidine moiety. Previously, we have demonstrated the direct modification of pyrrolidine derivatives using LiClO₄-CH₃NO₂ electrochemical oxidation system. This reaction system can accumulate desired iminium ion intermediates, anodically derived from N-protected pyrrolidine derivatives by C-H bound activation, enabling coupling with a variety of nucleophiles in one-pot reaction. In this conference, we report the electrochemical azanucleoside synthesis by coupling an unactivated prolinol derivative with a nucleobase through anodic oxidation using LiClO₄-CH₃NO₂ solution system, and demonstrate the utility of this transformation by addition of various nucleophiles to readily available prolinol derivatives in a regioselective manner.