C‐C Bond Formation: Synthesis of C5 Substituted Pyrimidine and C8 Substituted Purine Nucleosides Using Water Soluble Pd‐imidate Complex

Vijay Gayakhe1, Ajaykumar V. Ardhapure1, Anant R. Kapdi1, Yogesh S. Sanghvi2, Jose Luis Serrano3, Carola Schulzke4

1 Institute of Chemical Technology, Mumbai, 2 Rasayan, Encinitas, California, 3 Departamento de Ingeniería Minera, Geológica, y Cartográfica, Área de Química Inorgánica, Regional Campus of International Excellence “Campus Mare Nostrum,” Universidad Politécnica de Cartagena, Cartagena, 4 Ernst‐Moritz‐Arndt‐Universität Greifswald, Institut für Biochemie, Greifswald
Publication Name:  Current Protocols in Nucleic Acid Chemistry
Unit Number:  Unit 1.37
DOI:  10.1002/cpnc.1
Online Posting Date:  June, 2016
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Abstract

The synthesis of a highly efficient, water soluble [Pd(Sacc)2(TPA)2] complex for C‐C bond formation is described. Additionally, application of the [Pd(Sacc)2(TPA)2] complex for Suzuki‐Miyaura arylation of all four nucleosides (5‐iodo‐2′‐deoxyuridine [5‐IdU], 5‐iodo‐2′‐deoxycytidine [5‐IdC], 8‐bromo‐2′‐deoxyadenosine, and 8‐bromo‐2′‐deoxyguanosine) with various aryl/heteroaryl boronic acids in plain water under milder conditions is demonstrated. © 2016 by John Wiley & Sons, Inc.

Keywords: Suzuki‐Miyaura cross‐coupling; base‐modified nucleosides; nucleotides; palladium catalyst

     
 
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Table of Contents

  • Introduction
  • Basic Protocol 1: Synthesis of Water Soluble [Pd(Sacc)2(TPA)2]
  • Basic Protocol 2: Suzuki‐Miyaura Cross‐Coupling of 2′‐Deoxypyrimidine and 2′‐Deoxypurine Nucleosides
  • Basic Protocol 3: Synthesis of the Phosphoramidite Reagent
  • Commentary
  • Literature Cited
  • Figures
     
 
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Materials

Basic Protocol 1: Synthesis of Water Soluble [Pd(Sacc)2(TPA)2]

  Materials
  • Palladium(II) acetate (e.g., Sigma Aldrich)
  • Dimethyl sulfide, >99% pure (Me 2S; e.g., ACROS Organics)
  • Saccharin, ≥98% pure (e.g., Sigma Aldrich)
  • Methanol
  • Diethyl ether, anhydrous
  • Dichloromethane (DCM), anhydrous
  • 1,3,5‐Triaza‐7‐phosphaadamantane (TPA; Phillips et al., )
  • 50‐mL single‐neck round‐bottom flask
  • Magnetic stir plate with stir bar
  • Vacuum pump
  • Dropping funnel
  • 25‐mL Schlenk tube
  • Additional reagents and equipment for mass spectrometry (unit 7.2; Castleberry et al., ), infrared spectroscopy, and 1H and 31P NMR spectroscopy (unit 7.2; James, )

Basic Protocol 2: Suzuki‐Miyaura Cross‐Coupling of 2′‐Deoxypyrimidine and 2′‐Deoxypurine Nucleosides

  Materials
  • Nitrogen gas, ultra‐high purity
  • [Pd(Sacc) 2(PTA) 2] (see protocol 1)
  • Halonucleoside:
  • 5‐Iodo‐2′‐deoxyuridine (5‐IdU), ≥99% purity
  • 5‐Iodo‐2′‐deoxycytidine (5‐IdC), ≥99% purity
  • 8‐Bromo‐2′‐deoxyadenosine (8‐BrdA), ≥99% purity
  • 8‐Bromo‐2′‐deoxyguanosine (8‐BrdG), ≥99% purity
  • Triethylamine
  • Boronic acids (available from Combi‐Blocks):
  • Phenyl boronic acid
  • 4‐Methyl phenyl boronic acid
  • 4‐Methoxy phenyl boronic acid
  • 4‐Thiomethyl phenyl boronic acid
  • 4‐Formyl phenyl boronic acid
  • Napthalene‐2‐boronic acid
  • Benzofuran‐2‐boronic acid
  • Furan‐2‐boronic acid
  • Thiophene‐3‐boronic acid
  • 3,4‐Dimethoxy phenyl boronic acid
  • 3,5‐Dimethyl phenyl boronic acid
  • 3,4‐Methylenedioxy phenyl boronic acid
  • Ethyl acetate
  • Silica gel
  • Dichloromethane (DCM)
  • Methanol
  • 25‐mL Schlenk tube equipped with a glass stopper
  • Magnetic stir plate with stir bar
  • Vacuum pump
  • 1‐mL and 5‐mL syringe
  • 20‐G stainless steel needles
  • 80°C oil bath
  • Thread seal tape (e.g., Teflon tape)
  • Rotary evaporator equipped with a water aspirator
  • Additional reagents and equipment for performing thin‐layer chromatography ( appendix 3D; Meyers and Meyers, ), column chromatography ( appendix 3E; Meyers, ), mass spectrometry (unit 10.2; Castleberry et al., ), and 1H and 13C NMR spectroscopy (unit 7.2; James, )

Basic Protocol 3: Synthesis of the Phosphoramidite Reagent

  Materials
  • 5‐Phenyl‐2′‐deoxyuridine (see protocol 2)
  • Pyridine, anhydrous
  • Toluene, anhydrous
  • Nitrogen gas, ultra‐high purity
  • 4‐Dimethylaminopyridine (DMAP)
  • 4,4′‐Dimethoxytrityl chloride (DMTr‐Cl)
  • Dichloromethane (DCM)
  • 5% (w/v) NaHCO 3
  • Brine
  • Na 2SO 4
  • Hexane, anhydrous
  • Acetonitrile
  • Bis(N,N‐disopropylamine)‐2‐cyanoethoxyphosphoramidite (Phos reagent)
  • 1,1′‐Carbonyldiimidazole
  • Ethyl acetate
  • 50‐mL single‐neck round‐bottom flask
  • Vacuum pump
  • Magnetic stir plate with stir bar
  • Rotary evaporator
  • Stainless steel spatula
  • C18 column
  • –20°C freezer
  • Additional reagents and equipment for thin‐layer chromatography ( appendix 3D; Meyers and Meyers, ), HPLC (unit 10.5; Sinha and Jung, ), and 1H and 13C NMR spectroscopy (unit 7.2; James, )
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Figures

Videos

Literature Cited

Literature Cited
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