Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Jan 24;27(3):795-801.
doi: 10.1021/acs.orglett.4c04439. Epub 2025 Jan 13.

Photoredox-Catalyzed Site-Selective Intermolecular C(sp3)-H Alkylation of Tetrahydrofurfuryl Alcohol Derivatives

Reiji Abe  1 , Kazunori Nagao  1 , Tomohiro Seki  2 , Dai Hata  2 , Yusuke Sasaki  2 , Hirohisa Ohmiya  1
Affiliations

Photoredox-Catalyzed Site-Selective Intermolecular C(sp3)-H Alkylation of Tetrahydrofurfuryl Alcohol Derivatives

Reiji Abe et al. Org Lett. .

Abstract

4'-Selective alkylation of nucleosides has been recognized as one of the ideal and straightforward approaches to chemically modified nucleosides, but such a transformation has been scarce and less explored. In this Letter, we combine a visible-light-mediated photoredox catalysis and hydrogen atom transfer (HAT) auxiliary to achieve β-C(sp3)-H alkylation of alcohol on tetrahydrofurfuryl alcohol scaffolds and exploit it for 4'-selective alkylation of nucleosides. The reaction involves an intramolecular 1,5-HAT process and stereocontrolled Giese addition of the resultant radicals.

PubMed Disclaimer

Conflict of interest statement

The authors declare no competing financial interest.

Figures

Scheme 1
Scheme 1. Synthetic Approaches to 4′-Carbon-Substituted Nucleosides
Figure 1
Figure 1
Substrate scope. Reaction was carried out with 1 (0.1 mmol), 2 (0.15 mmol), Ir[dF(CF3)ppy]2(dtbbpy)PF6 (0.002 mmol), and PMP (0.2 mmol) in MeCN (10 mL) and water (1 mL) under blue LED irradiation for 2 h. Isolated yield based on 1. aIsolated as desilylated product. Isolated yield in 2 steps including 4′-alkylation and desilylation.
Figure 2
Figure 2
Mechanistic studies.
Figure 3
Figure 3
Computational studies.
See this image and copyright information in PMC

References

    1. Yoshida Y.; Honma M.; Kimura Y.; Abe H. Structure, Synthesis and Inhibition Mechanism of Nucleoside Analogues as HIV-1 Reverse Transcriptase Inhibitors (NRTIs). ChemMedChem. 2021, 16, 743–766. 10.1002/cmdc.202000695. - DOI - PubMed
    1. Wan W. B.; Seth P. P. The Medicinal Chemistry of Therapeutic Oligonucleotides. J. Med. Chem. 2016, 59, 9645–9667. 10.1021/acs.jmedchem.6b00551. - DOI - PubMed
    1. Nawrat C. C.; Whittaker A. M.; Huffman M. A.; McLaughlin M.; Cohen R. D.; Andreani T.; Ding B.; Li H.; Weisel M.; Tschaen D. M. Nine-Step Stereoselective Synthesis of Islatravir from Deoxyribose. Org. Lett. 2020, 22, 2167–2172. 10.1021/acs.orglett.0c00239. - DOI - PubMed
    2. McLaughlin M.; Kong J.; Belyk K. M.; Chen B.; Gibson A. W.; Keen S. P.; Lieberman D. R.; Milczek E. M.; Moore J. C.; Murray D.; Peng F.; Qi J.; Reamer R. A.; Song Z. J.; Tan L.; Wang L.; Williams M. J. Enantioselective Synthesis of 4′-Ethynyl-2-Fluoro-2′-Deoxyadenosine (EFdA) via Enzymatic Desymmetrization. Org. Lett. 2017, 19, 926–929. 10.1021/acs.orglett.7b00091. - DOI - PubMed
    1. Obika S. Development of Bridged Nucleic Acid Analogues for Antigene Technology. Chem. Pharma. Bull. 2004, 52, 1399–1404. 10.1248/cpb.52.1399. - DOI - PubMed
    2. Kaur H.; Babu B. R.; Maiti S. Perspectives on Chemistry and Therapeutic Applications of Locked Nucleic Acid (LNA). Chem. Rev. 2007, 107, 4672–4697. 10.1021/cr050266u. - DOI - PubMed
    1. Capaldo L.; Ravelli D.; Fagnoni M. Direct Photocatalyzed Hydrogen Atom Transfer (HAT) for Aliphatic C–H Bonds Elaboration. Chem. Rev. 2022, 122, 1875–1924. 10.1021/acs.chemrev.1c00263. - DOI - PMC - PubMed