Synthesis of Fluoroneplanocin A

Lak Shin Jeong1, Dilip K. Tosh1, Won Jun Choi1, Shantana Pal1

1 Laboratory of Medicinal Chemistry, College of Pharmacy, Ewha Womans University, Seoul, Korea
Publication Name:  Current Protocols in Nucleic Acid Chemistry
Unit Number:  Unit 14.6
DOI:  10.1002/0471142700.nc1406s34
Online Posting Date:  September, 2008
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Abstract

Fluoroneplanocin A, designed as a potent mechanism‐based irreversible inhibitor of S‐adenosylhomocysteine hydrolase (SAH), is synthesized from D‐ribose via a key D‐cyclopentenone intermediate. This intermediate is synthesized using a stereoselective Grignard reaction, a ring‐closing metathesis (RCM) reaction, and oxidative rearrangement as key steps. Curr. Protoc. Nucleic Acid Chem. 34:14.6.1‐14.6.18. © 2008 by John Wiley & Sons, Inc.

Keywords: fluoroneplanocin A; S‐adenosylhomocysteine hydrolase; ring‐closing metathesis; electrophilic vinyl fluorination; oxidative rearrangement

     
 
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Table of Contents

  • Introduction
  • Basic Protocol 1: Preparation of D‐Cyclopentenone Intermediate
  • Basic Protocol 2: Synthesis of Fluoroneplanocin A
  • Commentary
  • Literature Cited
  • Figures
     
 
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Materials

Basic Protocol 1: Preparation of D‐Cyclopentenone Intermediate

  Materials
  • D‐Ribose
  • Acetone (dry)
  • Sulfuric acid (H 2SO 4), concentrated
  • Nitrogen gas
  • Hexane
  • Ethyl acetate
  • Sodium bicarbonate (NaHCO 3)
  • Silica gel 60 (230 to 400 mesh, Merck)
  • Sea sand
  • Methylene chloride (CH 2Cl 2), anhydrous
  • Dimethylaminopyridine (DMAP)
  • Triethylamine (TEA)
  • tert‐Butylchlorodiphenylsilane (TBDPS‐Cl)
  • Magnesium sulfate (MgSO 4), anhydrous
  • Saturated sodium chloride solution (brine)
  • Methyl triphenylphosphonium bromide
  • Tetrahydrofuran (THF), anhydrous
  • Potassium tert‐butoxide
  • Saturated ammonium chloride (NH 4Cl) solution
  • Oxalyl chloride
  • Dry ice
  • Dimethyl sulfoxide (DMSO)
  • Vinyl magnesium bromide
  • Tetrabutylammonium fluoride (TBAF)
  • Toluene
  • Dibutyltinoxide (Bu 2SnO)
  • Tetrabutylammonium iodide (TBAI)
  • Benzyl bromide (BnBr)
  • Grubbs 2nd generation catalyst: benzylidene[1,3‐bis(2,4,6‐trimethylphenyl)‐2‐imidazolidinylidene]dichloro(tricyclohexylphosphine)ruthenium (Aldrich)
  • N,N‐Dimethylformamide (DMF), anhydrous
  • Pyridinium dichromate (PDC)
  • 4‐Å molecular sieves
  • Diethyl ether
  • pH paper
  • Funnel equipped with 25‐ to 50‐µm glass filter
  • Rotary evaporator
  • 5 × 50–cm and 10 × 50–cm chromatography columns
  • 500‐mL, and 2000‐mL separatory funnels
  • Cannula
  • 500‐, 1000‐, and 2000‐mL round‐bottom flasks
  • 50‐mL two‐neck round‐bottom flask
  • Dean‐Stark apparatus (e.g., Sigma‐Aldrich)
  • Silicon oil bath
  • Additional reagents and equipment for performing column chromatography ( appendix 3E) and TLC ( appendix 3D)

Basic Protocol 2: Synthesis of Fluoroneplanocin A

  Materials
  • (4R,5R)‐(+)‐3‐(Benzyloxymethyl)‐4,5‐O‐isopropylidene‐2‐cyclopentenone (S.9; see protocol 1)
  • Carbon tetrachloride (CCl 4)
  • Iodine (I 2)
  • Nitrogen gas
  • Pyridine
  • Hexane
  • Ethyl acetate
  • Methylene chloride (CH 2Cl 2), anhydrous
  • Saturated sodium thiosulfate solution
  • Magnesium sulfate (MgSO 4), anhydrous
  • Silica gel 60 (230 to 400 mesh, Merck)
  • Sea sand
  • Methanol
  • Cerium (III) chloride heptahydrate (CeCl 3·7H 2O)
  • Sodium borohydride (NaBH 4)
  • Saturated sodium chloride solution (brine)
  • Imidazole
  • N,N‐Dimethylformamide (DMF)
  • tert‐Butylchlorodiphenylsilane (TBDPS‐Cl)
  • Diethyl ether
  • Tetrahydrofuran (THF), anhydrous
  • N‐Fluorobenzenesulfonimide (NFSI)
  • n‐Butyllithium
  • Saturated ammonium chloride (NH 4Cl) solution
  • Tetrabutylammonium fluoride (TBAF)
  • Triethylamine (TEA)
  • Methanesulfonyl chloride
  • Adenine
  • Potassium carbonate (K 2CO 3)
  • 18‐Crown‐6 ether
  • Boron tribromide (BBr 3)
  • Acetic anhydride
  • Saturated methanolic ammonia solution (prepare fresh before use)
  • 30‐mL, 50‐mL, 100‐mL separatory funnels
  • Funnel equipped with 25‐ to 50‐µm glass filter
  • Rotary evaporator
  • 2 × 30–cm, 3 × 50–cm, and 4 × 50–cm chromatography columns
  • pH paper
  • 15‐, 25‐, and 50‐mL round‐bottom flasks
  • Septum and sealing tape
  • Silicon oil bath
  • Additional reagents and equipment for performing column chromatography ( appendix 3E) and TLC ( appendix 3D)
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Figures

Videos

Literature Cited

Literature Cited
   Borchardt, R.T. and Wolfe, M.S. 1991. S‐Adenosyl‐L‐homocysteine hydrolase as a target for antiviral chemotherapy. J. Med. Chem. 34:1521‐1530.
   Choi, W.J., Moon, H.R., Kim, H.O., Yoo, B.N., Lee, J.A., Shin, D.H., and Jeong, L.S. 2004. Preparative and stereoselctive synthesis of the versatile intermediate for carbocyclic nucleosides: Effects of the bulky protecting groups to enforce facial selectivity. J. Org. Chem. 69:2634‐2636.
   Jeong, L.S. and Lee, J.A. 2004. Recent advances in the synthesis of the carbocyclic nucleosides as potential antiviral agents. Antiviral Chem. Chemother. 15:235‐250.
   Jeong, L.S., Moon, H.R., Park, J.G., Shin, D.H., Choi, W.J., Lee, K.M., Kim, H.O., Kim, H.‐D., Chun, M.W., and Kim, J.H. 2003a. Synthesis and biological evaluation of halo‐neplanocin A as novel mechanism‐based inhibitors of S‐adenosylhomocysteine hydrolase. Nucleosides Nucleotides Nucleic Acids. 22:589‐592.
   Jeong, L.S., Yoo, S.J., Lee, K.M., Koo, M.J., Choi, W.J., Kim, H.O., Moon, H.R., Lee, M.Y., Park, J.G., Lee, S.K., and Chun, M.W. 2003b. Design, synthesis and biological evaluation of fluoro‐neplanocin A as the novel mechanism‐based inhibitor of S‐adenosylhomocysteine hydrolase. J. Med. Chem. 46:201‐203.
   Moon, H.R., Choi, W.J., Kim, H.O., and Jeong, L.S. 2004. Preparative synthesis of the key intermediate, (4R,5R)‐3‐benzyloxymethyl‐4,5‐isopropylidenedioxyxyclopent‐2‐enone for carbocyclic nucleosides. Chem. Lett. 33:506‐507.
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