Modular, Step-Efficient Palladium-Catalyzed Cross-Coupling Strategy To Access C6-Heteroaryl 2-Aminopurine Ribonucleosides

Abstract

Two Pd-catalyzed methods to access 6-heteroaryl 2-aminopurine ribonucleosides from 6-chloroguanosine are described. First, Pd-132-catalyzed Suzuki-Miyaura cross-coupling using a series of boron substrates and 6-chloroguanosine forms 6-heteroaryl-2-aminopurines in a single step. The versatility of 6-chloroguanosine is further demonstrated using a modified Sonogashira coupling employing potassium iodide as an additive. Finally, the utility of the 6-alkynyl-2-aminopurine ribonucleoside as a dipolarophile in [3 + 2] cycloadditions is presented, affording triazoles and isoxazoles when reacted with azide and isonitrile 1,3-dipoles, respectively.

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.…”

Highly Fluorescent 2‐Aminopurine Derivatives: Synthesis, Photo‐physical Characterization, and Preliminary Cytotoxicity Evaluation

“…Triphosphate derivatives of these analogues have been enzymatically incorporated into RNA at desired positions and studied as unnatural base pairs to be used in a wide range of applications. Advances in the preparation of this kind of C6‐heteroaryl 2‐aminopurines had been achieved, but the required cross‐coupling reaction still depend on the expensive commercial purines and Pd‐catalysts [18] …”

“…Advances in the preparation of this kind of C6-heteroaryl 2aminopurines had been achieved, but the required crosscoupling reaction still depend on the expensive commercial purines and Pd-catalysts. [18] Nitrile-containing pharmaceuticals have been increasing due to the biocompatibility and robustness to metabolic degradation of the nitrile functionality. [19] In fact, it is important to note that release of cyanide from aromatic carbons was not observed.…”

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

“…With this logic in mind, we focused our attention on the functionalization of the purine nucleobase. One of the transformations used most often for this purpose is nucleophilic aromatic substitution, which can be effective for installation of heteroatom substituents but is not broadly useful for the formation of C–C bonds. , Advances in sp 2 –sp 2 cross-coupling have facilitated the installation of aryl/heteroaryl groups, , but the installation of alkyl functionality remains challenging. Common strategies rely on the use of reactive nucleophiles that may limit functional group compatibility and reaction scope , or require multiple-step sequences to convert alkene functionality installed via sp 2 –sp 2 cross-coupling into an alkyl group (Figure B).…”