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. 2008 Jul 4;73(13):4874-81.
doi: 10.1021/jo800444y. Epub 2008 Jun 4.

Synthesis of 5-fluoroalkylated pyrimidine nucleosides via Negishi cross-coupling

Ann-Marie Chacko  1 , Wenchao Qu, Hank F Kung
Affiliations

Synthesis of 5-fluoroalkylated pyrimidine nucleosides via Negishi cross-coupling

Ann-Marie Chacko et al. J Org Chem. .

Abstract

5-Fluoroalkylated pyrimidine nucleosides (1) have potential as therapeutic agents and molecular imaging agents targeting HSV1-tk suicide gene therapy. Thus, straightforward preparation of 5-fluoroalkylated nucleoside derivatives has been developed. Reported herein are the first examples of Pd-catalyzed Negishi cross-coupling of 3-N-benzoyl-3',5'-di-O-benzoyl-5-iodo-2'-deoxyuridine (2a) and 3-N-benzoyl-3',5'-di-O-benzoyl-5-iodo-2'-deoxy-2'-fluoroarabinouridine (2b) with unactivated Csp(3) fluoroalkylzinc bromides. This paper demonstrates the first synthesis of six 5-fluoroalkyl-2'-deoxypyrimidine nucleoside derivatives with three to five methylene chain lengths (5). Furthermore, this methodology has been extended to create a series of 13 5-alkyl-substituted nucleosides, including the target nucleosides 5 and 5-silyloxypropyl and 5-cyanobutyl derivatives.

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Figures

FIGURE 1
FIGURE 1
Structure of 5-[18F]Fluoroalkyl Nucleosides as Molecular Imaging Agents for HSV1-tk Gene Therapy
SCHEME 1
SCHEME 1
Synthesis of 5-(3-Fluoropropyl) Pyrimidine Nucleoside 5a via Sonogashira Coupling Approach
SCHEME 2
SCHEME 2
Synthesis of 5-Fluoroalkylated Pyrimidine Nucleosides 5a–f Using Saturated Fluoroalkylzincates
SCHEME 3
SCHEME 3
Synthesis of 5-[18F]Fluoroalkylated Pyrimidine Nucleosides [18F]1a–f
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References

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    1. CAUTION: 18F is a radioactive material (radioactive half-life (t1/2) = 110 min, β+ emission = 511 keV) and should only be used by trained research personnel with the appropriate safety precautions.

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