Olefin Cross‐Metathesis for the Synthesis of Alkenyl Acyclonucleoside Phosphonates

Maxime Bessières1, Coralie De Schutter1, Vincent Roy1, Luigi A. Agofoglio1

1 University of Orléans, CNRS, ICOA UMR 7311, Orléans
Publication Name:  Current Protocols in Nucleic Acid Chemistry
Unit Number:  Unit 14.11
DOI:  10.1002/0471142700.nc1411s59
Online Posting Date:  December, 2014
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Abstract

The detailed synthetic protocol for the straightforward, efficient synthesis of various alkenyl acyclonucleosides, including challenging trisubstituted alkenyl acyclonucleoside phosphonates, is described. The key step of those syntheses is an olefin cross‐metathesis reaction between two olefins selected based on their reactivity using well‐defined ruthenium alkylidene catalysts. © 2014 by John Wiley & Sons, Inc.

Keywords: olefin cross‐metathesis; nucleosides; ruthenium catalyst; prodrug; chemical; synthesis

     
 
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Table of Contents

  • Introduction
  • Basic Protocol 1: Preparation of 2′‐Butenyl Phosphonate Derivatives of 5‐Substituted Uracils by Olefin Cross Metathesis
  • Basic Protocol 2: Preparation of 2′‐Hydroxymethylbutenyl Phosphonate From 2‐Methylene Propanediol by Cross Metathesis
  • Basic Protocol 3: Preparation of bis(POM) Prodrugs of Alkenyl Nucleoside Phosphonates by Olefin Cross‐Metathesis
  • Commentary
  • Literature Cited
  • Figures
     
 
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Materials

Basic Protocol 1: Preparation of 2′‐Butenyl Phosphonate Derivatives of 5‐Substituted Uracils by Olefin Cross Metathesis

  Materials
  • Nitrogen gas (>99.99% pure)
  • Dry acetonitrile, freshly distilled from CaH 2 (store under nitrogen)
  • Dry pyridine, freshly distilled from CaH 2 (Aldrich) (store over 4Å molecular sieves)
  • Uracil (1a), >99% pure (Aldrich)
  • Thymine (1b), 99% pure (Apollo Scientific)
  • Benzoyl chloride, ACS reagent, 99% (Aldrich)
  • Ethyl acetate (EtOAc), HPLC grade
  • Petroleum ether (PE), analytical grade
  • Methanol (MeOH), HPLC grade
  • Toluene, analytical grade
  • Acetone, analytical grade
  • Dimethylformamide (DMF) (dried and store over 4Å molecular sieves)
  • Potassium carbonate (K 2CO 3), > 99% pure (Aldrich)
  • Dichloromethane (CH 2Cl 2), freshly distilled from CaH 2 (store under nitrogen)
  • Crotyl bromide, technical grade (Aldrich)
  • 5% (w/v) ammonium chloride (NH 4Cl)
  • Magnesium sulfate (MgSO 4), anhydrous
  • Silica gel: 40 to 63 μm Geduran Kieselgel 60
  • Dimethyl allylphosphonate, technical grade (Alfa Aesar)
  • [RuCl 2(PCy 3)(IMes)(=CHPh)], ruthenium alkylidene catalyst ([Ru]=) [obtained by a generous gift of Nolan SP; the saturated Grubbs analog [RuCl2(PCy3)(H2IMes)(=CHPh)] can be used as surrogate (Steam)]
  • Ammonia solution, 7 N in methanol (Alfa Aesar)
  • Deuterated chloroform (CDCl 3), 99% pure (eurisol, CDCl 3 is used for NMR characterization)
  • 250‐mL round‐bottom flasks
  • Rotatory evaporator equipped with a vacuum pump
  • TLC plate: silica‐coated aluminum plate with fluorescent indicator (Merck silica gel 60 F 254)
  • 254‐nm UV lamp
  • Fritted glass (P4 porosity)
  • Vacuum oil pump
  • Additional reagents and equipment for thin‐layer chromatography (TLC; appendix 3D)

Basic Protocol 2: Preparation of 2′‐Hydroxymethylbutenyl Phosphonate From 2‐Methylene Propanediol by Cross Metathesis

  Additional Materials (also see protocol 1)
  • 2‐methylene‐1,3‐propanediol (6), >97% pure (Aldrich)
  • Vinyl acetate, >99% pure (Aldrich)
  • Lipase acrylic resin from Candida antarctica, recombinant, expressed in Aspergillus niger, (CAL‐B, Sigma, L4777)
  • Hoveyda‐Grubbs Catalyst 2nd Generation, >97% pure (Aldrich)
  • Activated carbon (Merck), optional
  • Phosphate buffer (0.1 M, pH 7)
  • bis‐Boc‐adenine (Porcheddu et al., )
  • Triphenylphosphine (PPh 3), >99% pure (Aldrich)
  • Diisopropyl azodicarboxylate (DIAD), >94% pure (Alfa aesar)
  • Hydrochloric acid (HCl): 1 M in methanol
  • Ethanol (EtOH), analytical grade
  • Compact Multifunctional Digital Ultrasonic Cleaner, Elmasonic P30H
  • Ice bath

Basic Protocol 3: Preparation of bis(POM) Prodrugs of Alkenyl Nucleoside Phosphonates by Olefin Cross‐Metathesis

  Additional Materials (also see Basic Protocols protocol 11 and protocol 22)
  • bis(POM)‐allylphosphonate
  • Cytosine (S.14), (Apollo Scientific)
  • Dimethylaminopyridine (DMAP), >99% pure (Acros Organics)
  • Di‐tert‐butyldicarbonate (Boc 2O), >97% pure (Aldrich)
  • 10% (w/v) sodium bicarbonate (NaHCO 3)
  • Cesium carbonate (Cs 2CO 3), >99% pure (Aldrich)
  • Ceric ammonium nitrate (CAN), >99% pure (Alfa Aesar)
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Figures

Videos

Literature Cited

Literature Cited
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