Synthesis of C6-Substituted Purine Nucleoside Analogues via Late-Stage Photoredox/Nickel Dual Catalytic Cross-Coupling

Abstract

Nucleoside analogues have been and continue to be extremely important compounds in drug discovery. Despite the significant effort dedicated to their synthesis, medicinal chemistry campaigns around these structures are often hampered by synthetic challenges. We describe a strategy for the functionalization of purine nucleosides via photoredox and nickel-catalyzed sp2–sp3 cross-coupling. The conditions described herein allow for coupling of unprotected nucleosides with readily available alkyl bromides, providing opportunities for their application to parallel medicinal chemistry.

O6-[(2″,3″-O-Isopropylidene-5″-O-tbutyldimethylsilyl)pentyl]-5′-O-tbutyldiphenylsilyl-2′,3′-O-isopropylideneinosine

“…Purine bases and nucleosides carrying O-, N-and C-substituents at the C6 position represent an important class of compounds endowed with important biological activities. These compounds are generally prepared by nucleophilic aromatic (S N Ar) substitutions, [34] metal-mediated cross-coupling reactions [35,36] and by Grignard's reagents addition [26] to 6-halopurine ribosides. In our search of new cADPR analogues, we have obtained the O6-alkylated inosine 9 as a side product during the S N 2 reaction between the nucleoside 10 and the tosylate 11.…”

Radical Brook Rearrangements: Concept and Recent Developments

“…Based on this concept, this electron-rich N-substituted supersilane regent 9.6 was also employed in the synthesis of a diverse array of trifluoromethyl, pentafluoroethyl, and heptafluoropropyl adducts through the perfluoroalkylation of organobromides obtained from the reaction of Ruppert-Prakash-type reagents (TMSCF 3 , TMSC 2 F 5 , and TMSC 3 F 7 ) with aryl or alkyl bromides. [74] The concept of combining a radical Brook rearrangement with metallaphotoredox chemistry has already been applied in the synthesis of nucleoside analogues by scientists at Merck [75] and in DNA-encoded chemistry by chemists at Pfizer. [76]…”

Industrial potential of the enzymatic synthesis of nucleoside analogs: Existing challenges and perspectives

“…by crosscoupling. 60,61 Such approaches could also benefit from other upcoming disciplines such as artificial intelligence and big data management as this facilitates rational reaction optimization in both biocatalysis and synthetic chemistry. 62 Thus, we believe that the field of nucleoside biocatalysis currently stands at a turning point where the rapid progress in adjacent fields will act as a catalyst for innovation.…”