The Synthesis of C8-Aryl Purines, Nucleosides and Phosphoramidites

Abstract

C8-Aryl purines, their nucleosides, and phosphoramidites has been synthetic targets for more than 60 years. Interest in these compounds stems from their utility as fluorescent markers, they have therapeutic uses, are biomarkers, biomolecular probes, supramolecular building blocks, and for conformational studies. Until recently, the selective arylation of the C8-position of purines has been a challenging task. Several approaches have been explored including building them up from a pyrimidine or selective C8-modification of an unsubstituted purine. Neither of these approaches has proven to have broad scope. The discovery that C8-aryl purine nucleosides can be made via the Suzuki cross-coupling reaction has allowed a diverse array of analogues to be prepared and, in turn, the corresponding phosphoramidites. The latter is particularly significant as C8-aryl purine adducts are a major mutation observed from aromatic carcinogens and ready access to C8-aryl phosphoramidites will facilitate the synthesis and study of C8-aryl purine biomarkers and modified oligonucleotides.

A modified guanosine phosphoramidite for click functionalization of RNA on the sugar edge

“…Hence, dye labeling directly onto the Watson-Crick face of a given nucleobase is expected to be detrimental to duplex formation. On the other hand, popular labeling strategies on the Hoogsteen edge focus mainly on the N7 or C8 of purines [2][3][4] or the C5 position of pyrimidines 5,6 and although labeling directly onto the sugar edge is a promising approach, such attachment points are so far restricted to the 2 0 -position of the ribose. 7,8 Such derivatization is, however, known to heavily affect the sugar pucker and thus also stability and hybridization properties of the RNA duplex.…”

Orthoesters: Multiple Role Players in Organic Synthesis

“…Notably, when TEOF was replaced with N , N ‐dimethylformamide dimethyl acetal DMF‐DMA the 5‐aza‐adenine yield considerably dropped. Due to the importance of 8‐aryl substituted purines in offering a promising direction to the therapeutic agents synthesis of 8‐aryl substituted 5‐aza‐adenines was attempted using triazoles, TEOF and cyanamide as shown in Scheme .…”

Microwave-assisted synthesis of C-8 aryl and heteroaryl inosines and determination of their inhibitory activities against Plasmodium falciparum purine nucleoside phosphorylase

“…It has been described that 8-substituted purine nucleosides are more sensitive to acidic conditions than their non-substituted analogues [1,21] and indeed we have experienced serious difficulties to remove the isopropylidene group by acid treatment without affecting the glycosidic bond. In this scenario, we considered relevant to determine the hydrolytic stability of the synthesised 8substituted inosines at different pH values.…”

“…C-8 Arylpurine nucleosides are interesting chemical entities due to their potential as therapeutic agents and as tools for biomolecular applications, as recently reviewed [1]. These compounds are mostly synthesized by Suzuki or Stille cross-coupling processes starting from the corresponding 8bromonucleosides.…”

“…The elemental compositions of the compounds fell within ± 0.4% of the calculated values. Electrospray mass spectra were measured on a quadrupole mass spectrometer equipped with an electrospray source (Hewlett-Packard, LC/MS HP 1100) 1. H and 13 C NMR spectra were recorded on a Varian INNOVA 300 operating at 299 MHz ( 1 H) and 75 MHz ( 13 C), respectively, and Varian INNOVA-400 operating at 399 MHZ ( 1 H) and 99 MHz ( 13 C), respectively.…”