Stereoselective Synthesis of 4′‐Selenonucleosides via the Seleno‐Michael Reaction

Pramod K. Sahu1, Dnyandev B. Jarhad1, Gyudong Kim1, Lak Shin Jeong1

1 Laboratory of Medicinal Chemistry, College of Pharmacy, Seoul National University, South Korea, Seoul
Publication Name:  Current Protocols in Nucleic Acid Chemistry
Unit Number:  Unit 14.13
DOI:  10.1002/cpnc.27
Online Posting Date:  June, 2017
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Abstract

5′‐Homo‐4′‐selenonucleosides, a class of next‐generation nucleosides, are synthesized from D‐ribose via a 4‐selenosugar intermediate. The key step in synthesizing this intermediate is a seleno‐Michael reaction. 5′‐Homo‐4′‐selenouridine and ‐adenosine are prepared using Pummerer‐type and Vorbrüggen condensation, respectively. © 2017 by John Wiley & Sons, Inc.

Keywords: Pummerer‐type reaction; seleno‐Michael; Vorbrüggen condensation; 4′‐selenonucleoside

     
 
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Table of Contents

  • Introduction
  • Basic Protocol 1: Preparation of 4‐Selenosugar Intermediate
  • Basic Protocol 2: Synthesis of 5′‐Homo‐4′‐Selenouridine
  • Basic Protocol 3: Synthesis of 5′‐Homo‐4′‐Selenoadenosine
  • Commentary
  • Literature Cited
  • Figures
     
 
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Materials

Basic Protocol 1: Preparation of 4‐Selenosugar Intermediate

  Materials
  • D‐Ribose
  • Acetone (anhydrous or HPLC grade)
  • Nitrogen gas
  • Sulfuric acid (H 2SO 4), concentrated
  • Dichloromethane (CH 2Cl 2), anhydrous or HPLC grade
  • Methanol
  • Sodium bicarbonate (NaHCO 3)
  • Celite
  • Sodium hydroxide (NaOH)
  • Sodium borohydride (NaBH 4)
  • Acetic acid
  • Sodium periodate (NaIO 4)
  • Ethyl acetate (EtOAc)
  • Toluene, anhydrous or HPLC grade
  • Magnesium sulfate (MgSO 4), anhydrous
  • 2,2,2‐Trifluoroethanol
  • (Carbethoxymethylene)triphenylphosphorane
  • Methanesulfonyl chloride (MsCl)
  • Triethylamine (TEA)
  • Hexane
  • Ammonium chloride (NH 4Cl)
  • Brine
  • Silica gel 60
  • Selenium powder
  • Ethanol
  • Tetrahydrofuran (THF), anhydrous
  • Trifluoroacetic acid (TFA)
  • 2,2‐Dimethoxypropane
  • p‐Toluenesulfonic acid
  • 500‐mL and 2‐L round‐bottom flasks
  • 25‐ to 50‐μm glass filter
  • Rotary evaporator
  • Addition funnel
  • 500‐mL and 2‐L separatory funnels
  • 4 × 40– and 5 × 40–cm chromatography columns
  • Reflux condenser
  • 400‐mL glass filter
  • Additional reagents and equipment for TLC and flash chromatography

Basic Protocol 2: Synthesis of 5′‐Homo‐4′‐Selenouridine

  Materials
  • Lithium aluminum hydride (LiAlH 4)
  • Tetrahydrofuran (THF), anhydrous
  • Nitrogen gas
  • 4‐Selenosugar 4 (see protocol 1)
  • Hexane
  • Ethyl acetate (EtOAc)
  • Diethyl ether
  • Water (deionized)
  • 15% (w/v) sodium hydroxide (NaOH)
  • Magnesium sulfate (MgSO 4), anhydrous
  • Celite
  • Triethylamine (TEA)
  • 4‐Dimethylaminopyridine (DMAP)
  • tert‐Butylchlorodiphenylsilane (TBDPSCl)
  • Silica gel 60
  • Dichloromethane (CH 2Cl 2), anhydrous
  • 3‐Chloroperbenzoic acid (mCPBA)
  • Methanol
  • Sodium bicarbonate (NaHCO 3)
  • Brine
  • Uracil
  • Toluene, anhydrous
  • Trimethylsilyl trifluoromethanesulfonate (TMSOTf)
  • Silica gel 60
  • Trifluoroacetic acid (TFA)
  • 25‐, 50‐, 100‐, and 250‐mL round‐bottom flasks
  • Rotary evaporator
  • 5 × 40– and 2 × 30–cm chromatography columns
  • 100‐mL separatory funnels
  • 400‐mL glass filter
  • Cannula
  • Additional reagents and equipment for TLC and column chromatography

Basic Protocol 3: Synthesis of 5′‐Homo‐4′‐Selenoadenosine

  Materials
  • 4‐Selenosugar 7 (see protocol 2)
  • Dichloromethane (CH 2Cl 2), anhydrous
  • Nitrogen gas
  • 3‐Chloroperbenzoic acid (mCPBA)
  • Hexane
  • Ethyl acetate (EtOAc)
  • Methanol
  • Sodium bicarbonate (NaHCO 3)
  • Brine
  • Magnesium sulfate (MgSO 4), anhydrous
  • Acetic anhydride (Ac 2O)
  • Silica gel 60
  • 6‐Chloropurine
  • Toluene, anhydrous
  • N,O‐Bis(trimethylsilyl)acetamide (BSA)
  • Trimethylsilyl trifluoromethanesulfonate (TMSOTf)
  • tert‐Butanol
  • tert‐Butanol/ammonia solution: prepare fresh by bubbling ammonia gas (NH 3) into tert‐butanol at 0°C
  • Trifluoroacetic acid (TFA)
  • Diethyl ether
  • 50‐mL, 100‐mL, 250‐mL, and 1‐L round‐bottom flasks
  • 100‐ and 250‐mL separatory funnels
  • 400‐mL glass filter
  • Rotary evaporator
  • 2 × 30– and 2 × 40–cm chromatography columns
  • 50‐mL steel bomb (autoclave)
  • Additional reagents and equipment for TLC and column chromatography
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Figures

Videos

Literature Cited

Literature Cited
  Jayakanthan, K., Johnston, B. D., & Pinto, B. M. (2008). Stereoselective synthesis of 4′‐selenonucleosides using the Pummerer glycosylation reaction. Carbohydrate Research, 343, 1790–1800. doi: 10.1016/j.carres.2008.02.014.
  Jeong, L. S., Tosh, D. K., Choi, W. J., Lee, S. K., Kang, Y.‐J., Choi, S., … Kim, H. O. (2009). Discovery of a new template for anticancer agents: 2′‐Deoxy‐2′‐fluoro‐4′‐selenoarabinofuranosyl‐cytosine (2′‐F‐4′‐seleno‐ara‐C). Journal of Medicinal Chemistry, 52, 5303–5306. doi: 10.1021/jm900852b.
  Jeong, L. S., Tosh, D. K., Kim, H. O., Wang, T., Hou, X., Yun, H. S., … Zhao, L. X. (2008). First synthesis of 4′‐selenonucleosides showing unusual Southern conformation. Organic Letters, 10, 209–212. doi: 10.1021/ol7025558.
  Kim, G., Choi, Y., Sahu, P. K., Yu, J., Qu, S., Lee, D., & Jeong, L. S. (2015). Stereoselective synthesis of D‐5‐homo‐4‐selenoribose as a versatile intermediate for 4′‐selenonucleosides. Organic Letters, 17, 4636–4639. doi: 10.1021/acs.orglett.5b02393.
  Qu, S., Kim, G., Yu, J., Sahu, P. K., Choi, Y., Naik, S. D., Jeong, L. S. (2016). Synthesis and anti‐HIV activity of 5′‐homo‐2′,3′‐dideoxy‐2′,3′‐didehydro‐4′‐selenonucleosides (5′‐homo‐4′‐Se‐d4 Ns). Asian Journal of Organic Chemistry, 5, 735–741. doi: 10.1002/ajoc.201600154.
  Sahu, P. K., Kim, G., Yu, J., Ahn, J. Y., Song, J., Choi, Y., … Jeong, L. S. (2014). Stereoselective synthesis of 4′‐selenonucleosides via seleno‐Michael reaction as potent antiviral agents. Organic Letters, 16, 5796–5799. doi: 10.1021/ol502899b.
  Sahu, P. K., Naik, S. D., Yu, J., & Jeong, L. S. (2015). 4′‐Selenonucleosides as next‐generation nucleosides. European Journal of Organic Chemistry, 2015, 6115–6124. doi: 10.1002/ejoc.201500429.
  Shah, R. H. (1986). A convenient synthesis of L‐erythrose. Carbohydrate Research, 155, 212–216. doi: 10.1016/S0008‐6215(00)90148‐4.
  Yu, J., Kim, J.‐H., Lee, H. W., Alexander, V., Ahn, H.‐C., Choi, W. J., … Jeong, L. S. (2013). New RNA purine building blocks, 4′‐selenopurine nucleosides: First synthesis and unusual mixture of sugar puckerings. Chemistry European Journal, 19, 5528–5532. doi: 10.1002/chem.201300741.
  Yu, J., Sahu, P. K., Kim, G., Qu, S., Choi, Y., Song, J., … Jeong, L. S. (2015). Design, synthesis and cellular metabolism study of 4′‐selenonucleosides. Future Medicinal Chemistry, 7, 1643–1655. doi: 10.4155/fmc.15.102.
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