Synthesis of C-Arylnucleoside Analogues

Len, Christophe; Enderlin, Gérald

doi:10.3390/molecules20034967

“…The introduction of aromatic or heteroaromatic functionalities on the nucleosides (that help enhance the fluorescent properties) via metal-catalyzed cross-coupling reactions [5,6] (especially palladium-catalyzed Suzuki-Miyaura coupling) has been extensively explored [7,8]. Contributions by the research groups of Len [9][10][11][12], Shaughnessy [13][14][15][16], Lakshman [17][18][19][20][21][22] and many others [18][19][20][21][22] are acknowledged for their advances in the area of nucleoside modification. We have also been active in the development of several catalytic systems (palladium-based) allowing efficient cross-coupling [23][24][25][26][27][28][29][30].…”

Section: Introductionmentioning

confidence: 99%

Rapid plugged flow synthesis of nucleoside analogues via Suzuki-Miyaura coupling and heck Alkenylation of 5-Iodo-2’-deoxyuridine (or cytidine)

Gaware

¹

,

Kori

²

,

Serrano

³

et al. 2023

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Nucleosides modification via conventional cross-coupling has been performed using different catalytic systems and found to take place via long reaction times. However, since the pandemic, nucleoside-based antivirals and vaccines have received widespread attention and the requirement for rapid modification and synthesis of these moieties has become a major objective for researchers. To address this challenge, we describe the development of a rapid flow-based cross-coupling synthesis protocol for a variety of C5-pyrimidine substituted nucleosides. The protocol allows for facile access to multiple nucleoside analogues in very good yields in a few minutes compared to conventional batch chemistry. To highlight the utility of our approach, the synthesis of an anti-HSV drug, BVDU was also achieved in an efficient manner using our new protocol.

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Modular Access to C2’‐Aryl/Alkenyl Nucleosides with Electrochemical Stereoselective Cross‐Coupling

Wang,

Shen,

Yan

et al. 2024

Angewandte Chemie

0

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Chemically modified oligonucleotides have garnered significant attention in medicinal chemistry, chemical biology, and synthetic biology due to their enhanced stability in vivo compared to naturally occurring oligonucleotides. However, current methods for synthesizing modified nucleosides, particularly at the C2′‐position, are limited in terms of efficiency, modularity, and selectivity. Herein, we report a new approach for the synthesis of highly functionalized C2′‐a‐aryl/alkenyl nucleosides via an electrochemical nickel‐catalyzed cross‐coupling of 2'‐bromo nucleosides with a variety of (hetero)aryl and alkenyl iodides. This method affords a diverse array of C2′‐ a‐aryl/ alkenyl nucleosides with excellent stereoselectivities, broad substrate scope, and good functional group compatibility. We further synthesized oligonucleotides incorporating C2′‐aryl‐modified thymidine moieties and demonstrated that their annealed double‐stranded DNAs exhibit decreased melting temperatures (Tm). Additionally, oligonucleotides with C2′‐aryl modifications at the 3′ end showed enhanced resistance to 3′‐exonuclease degradation and C2′‐aryl modifications did not impede the cellular uptake process, highlighting the potential of these modified oligonucleotides for therapeutic applications.

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Modular Access to C2’‐Aryl/Alkenyl Nucleosides with Electrochemical Stereoselective Cross‐Coupling

Wang,

Shen,

Yan

et al. 2024

Angew Chem Int Ed

0

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Chemically modified oligonucleotides have garnered significant attention in medicinal chemistry, chemical biology, and synthetic biology due to their enhanced stability in vivo compared to naturally occurring oligonucleotides. However, current methods for synthesizing modified nucleosides, particularly at the C2′‐position, are limited in terms of efficiency, modularity, and selectivity. Herein, we report a new approach for the synthesis of highly functionalized C2′‐a‐aryl/alkenyl nucleosides via an electrochemical nickel‐catalyzed cross‐coupling of 2'‐bromo nucleosides with a variety of (hetero)aryl and alkenyl iodides. This method affords a diverse array of C2′‐ a‐aryl/ alkenyl nucleosides with excellent stereoselectivities, broad substrate scope, and good functional group compatibility. We further synthesized oligonucleotides incorporating C2′‐aryl‐modified thymidine moieties and demonstrated that their annealed double‐stranded DNAs exhibit decreased melting temperatures (Tm). Additionally, oligonucleotides with C2′‐aryl modifications at the 3′ end showed enhanced resistance to 3′‐exonuclease degradation and C2′‐aryl modifications did not impede the cellular uptake process, highlighting the potential of these modified oligonucleotides for therapeutic applications.

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Synthesis of C-Arylnucleoside Analogues

Cited by 7 publications

References 55 publications

Rapid plugged flow synthesis of nucleoside analogues via Suzuki-Miyaura coupling and heck Alkenylation of 5-Iodo-2’-deoxyuridine (or cytidine)

Rapid plugged flow synthesis of nucleoside analogues via Suzuki-Miyaura coupling and heck Alkenylation of 5-Iodo-2’-deoxyuridine (or cytidine)

Modular Access to C2’‐Aryl/Alkenyl Nucleosides with Electrochemical Stereoselective Cross‐Coupling

Modular Access to C2’‐Aryl/Alkenyl Nucleosides with Electrochemical Stereoselective Cross‐Coupling

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