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Review
. 2015 May 22;20(5):9419-54.
doi: 10.3390/molecules20059419.

Palladium-catalyzed modification of unprotected nucleosides, nucleotides, and oligonucleotides

Kevin H Shaughnessy  1
Affiliations
Review

Palladium-catalyzed modification of unprotected nucleosides, nucleotides, and oligonucleotides

Kevin H Shaughnessy. Molecules. .

Abstract

Synthetic modification of nucleoside structures provides access to molecules of interest as pharmaceuticals, biochemical probes, and models to study diseases. Covalent modification of the purine and pyrimidine bases is an important strategy for the synthesis of these adducts. Palladium-catalyzed cross-coupling is a powerful method to attach groups to the base heterocycles through the formation of new carbon-carbon and carbon-heteroatom bonds. In this review, approaches to palladium-catalyzed modification of unprotected nucleosides, nucleotides, and oligonucleotides are reviewed. Polar reaction media, such as water or polar aprotic solvents, allow reactions to be performed directly on the hydrophilic nucleosides and nucleotides without the need to use protecting groups. Homogeneous aqueous-phase coupling reactions catalyzed by palladium complexes of water-soluble ligands provide a general approach to the synthesis of modified nucleosides, nucleotides, and oligonucleotides.

Keywords: aqueous-phase catalysis; cross-coupling; nucleosides; nucleotides; oligonucleotides; palladium.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Typical functionalization sites in naturally occurring nucleosides and commonly used unnatural analogs. Most common functionalization sites are bolded.
Scheme 1
Scheme 1
Synthetic approaches to palladium-catalyzed nucleoside modification.
Scheme 2
Scheme 2
Pd-mediated coupling of 5-HgCldU and styrenes.
Scheme 3
Scheme 3
Oxidative coupling of dU and methyl acrylate.
Scheme 4
Scheme 4
Hiyama coupling of 5-IdU.
Scheme 5
Scheme 5
Ligand-free Suzuki coupling of 6-IdU.
Scheme 6
Scheme 6
Heck coupling of 5-IdU with a ligand-free palladium catalyst.
Scheme 7
Scheme 7
Oxidative coupling of 4-iodotoluene and adenosine.
Scheme 8
Scheme 8
Coupling of 5-IdU and thiophene.
Scheme 9
Scheme 9
Suzuki coupling of 5-IdU and 1-pyrenylboronic acid catalyzed by Pd(PPh3)4.
Scheme 10
Scheme 10
Synthesis of anthraquinone-labeled uridine.
Scheme 11
Scheme 11
Synthesis of a spin-labeled uridine derivative via a Suzuki coupling.
Scheme 12
Scheme 12
Suzuki coupling of 8-BrdA as first step in AICAR synthesis.
Scheme 13
Scheme 13
Synthesis of 5-(10-methylphenothiazin-3-yl)dU.
Scheme 14
Scheme 14
Synthesis of BODIPY-functionalized uridine.
Scheme 15
Scheme 15
Stille coupling of 2-thienylstannane and 5-IdU.
Scheme 16
Scheme 16
Sonogashira coupling catalyzed by Pd(PPh3)4/CuI.
Scheme 17
Scheme 17
Sonogashira coupling of protected and unprotected 5-IdU.
Scheme 18
Scheme 18
Rearrangement of 1-phenyl-2-propyn-1-ol during Sonogashira coupling.
Scheme 19
Scheme 19
Sonogashira coupling of 8-BrdA with 2-ethynyl-para-carborane.
Scheme 20
Scheme 20
Synthesis of doubly pyrene-substituted oligonucleotides.
Scheme 21
Scheme 21
Heck coupling of 2-IA mediated by Pd(OAc)2/P(o-tolyl)3.
Scheme 22
Scheme 22
Heck coupling of 5-IdU catalyzed by Pd(PTA)2(saccharinate)2.
Figure 2
Figure 2
Hydrophilic ligands commonly applied in nucleoside cross-coupling reactions.
Scheme 23
Scheme 23
Pd(OAc)2/TPPTS-catalyzed Suzuki coupling of 8-BrdG.
Scheme 24
Scheme 24
Pd(PTA)2(phthalimidate)2-catalyzed Suzuki coupling of 5-IdU.
Scheme 25
Scheme 25
Suzuki coupling of 5-IdU catalyzed by Pd-APD complexes.
Scheme 26
Scheme 26
Pd/TPPTS-catalyzed coupling of 8-bromoadenosines with phenylalanine.
Scheme 27
Scheme 27
Attachment of a ruthenium(II) terpyridine complex to 7-I-7-deaza-dA.
Scheme 28
Scheme 28
Suzuki coupling/condensation sequence to prepare pyrimidopyrimidoindole nucleosides.
Scheme 29
Scheme 29
Suzuki coupling of BVDU catalyzed by Pd(OAc)2/TPPTS.
Scheme 30
Scheme 30
Double arylation sequence to prepare 8-biaryl-dA derivatives.
Scheme 31
Scheme 31
Suzuki coupling of 2′-deoxy-2′-(5-bromo-2-thiophenyl)ribose.
Scheme 32
Scheme 32
Synthesis of a photoswitchable cytidine derivative.
Scheme 33
Scheme 33
Synthesis of phenyl sulfide-substituted 7-deaza-dA derivatives.
Scheme 34
Scheme 34
Coupling of 8-BrdA with polyaromatic boronic acids.
Scheme 35
Scheme 35
Suzuki coupling of 6-chloropurine nucleoside catalyzed by Pd(OAc)2/TPPTS.
Figure 3
Figure 3
Sugar-modified purine halonucleosides.
Scheme 36
Scheme 36
SNAr/Suzuki sequence to 6-substituted-7-aryl-7-deazapurine nucleosides.
Scheme 37
Scheme 37
Sonogashira coupling approach to bipyridine-dA adduct.
Scheme 38
Scheme 38
Synthesis of bile acid-dC adducts through aqueous-phase Sonogashira coupling.
Scheme 39
Scheme 39
Pd/TXPTS-catalyzed Sonogashira coupling of 8-bromopurine nucleosides.
Scheme 40
Scheme 40
Pd/TXPTS-catalyzed Sonogashira coupling of 5-IdU.
Scheme 41
Scheme 41
Pd/TPPTS-catalyzed Suzuki coupling of 8-bromoguanosine phosphates.
Scheme 42
Scheme 42
Methylation of 8-BrATP.
Scheme 43
Scheme 43
Synthesis of benzofurane-dATP.
Scheme 44
Scheme 44
Synthesis of pH-sensitive dual fluorescent 19F-NMR probe nucleotides.
Scheme 45
Scheme 45
Synthesis of aldehyde-functionalized nucleoside triphosphates.
Scheme 46
Scheme 46
Arylation of 5-I-UDP glucoside.
Scheme 47
Scheme 47
Synthesis of 8-arylated nicotinamide adenine dinucleotides.
Scheme 48
Scheme 48
Sonogashira coupling of 5-I-dUTP and ethynylfluorescein.
Scheme 49
Scheme 49
Synthesis of ferrocenyl-modified 7-deaza-dATP.
Scheme 50
Scheme 50
Aqueous-phase Heck coupling of 7-iodo-7-deazaguanosine monophosphate.
Scheme 51
Scheme 51
Suzuki coupling of 8-BrdG-containing oligonucleotide.
Scheme 52
Scheme 52
Suzuki vinylation of 5-IdU-containing oligonucleotides.
Scheme 53
Scheme 53
Stille coupling of 5-I-UG.
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References

    1. De Clercq E. The unabated synthesis of new nucleoside analogs with antiviral potential: A tribute to Morris J. Robins. Nucleos. Nucleot. Nucl. Acids. 2009;28:586–600. doi: 10.1080/15257770903054159. - DOI - PubMed
    1. Robak T. New Purine Nucleoside Analogs for Acute Lymphoblastic Leukemia. Clin. Cancer Drugs. 2014;1:2–10. doi: 10.2174/2212697X01999131126150545. - DOI
    1. Jordheim L.P., Durantel D., Zoulim F., Dumontet C. Advances in the development of nucleoside and nucleotide analogues for cancer and viral diseases. Nat. Rev. Drug Discov. 2013;12:447–464. doi: 10.1038/nrd4010. - DOI - PubMed
    1. Sofia M.J., Chang W., Furman P.A., Mosley R.T., Ross B.S. Nucleoside, Nucleotide, and Non-Nucleoside Inhibitors of Hepatitis C Virus NS5B RNA-Dependent RNA-Polymerase. J. Med. Chem. 2012;55:2481–2531. doi: 10.1021/jm201384j. - DOI - PubMed
    1. Dai Q., Xu D., Lim K., Harvey R.G. Efficient Syntheses of C8-Aryl Adducts of Adenine and Guanine Formed by Reaction of Radical Cation Metabolites of Carcinogenic Polycyclic Aromatic Hydrocarbons with DNA. J. Org. Chem. 2007;72:4856–4863. doi: 10.1021/jo070518m. - DOI - PubMed

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