Practical Synthesis of 4′‐Thioribonucleosides from L‐Arabinose via Novel Reductive Ring‐Contraction Reaction and Pummerer‐Type Thioglycosylation

Hideaki Wakamatsu1, Kozue Nitta1, Nozomi Shoji1, Yoshihiro Natori1, Yukako Saito1, Yuichi Yoshimura1

1 Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, Sendai
Publication Name:  Current Protocols in Nucleic Acid Chemistry
Unit Number:  Unit 1.43
DOI:  10.1002/cpnc.45
Online Posting Date:  December, 2017
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Abstract

The detailed practical synthesis of 4′‐thionucleosides starting from L‐arabinose is described here. 1,4‐Anhydro‐2,3‐O‐isopropylidene‐4‐thioribitol, which is the key intermediate for the synthesis of 4′‐thionucleosides, is obtained from L‐arabinose in several steps, including a novel reductive ring‐contraction reaction. After oxidation of the key intermediate, the sulfoxide is subjected to Pummerer‐type thioglycosylation in the presence of persilylated nucleobases to obtain the 4′‐thioribonucleosides in good yield and β‐selectively. © 2017 by John Wiley & Sons, Inc.

Keywords: 4‐thioribonucleosides; 4‐thiosugar; L‐arabinose; Pummerer reaction; reductive ring contraction

     
 
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Table of Contents

  • Introduction
  • Basic Protocol 1: Preparation of 5‐Thioarabinoside
  • Basic Protocol 2: Preparation of 5‐O‐Silylated Sulfoxide
  • Basic Protocol 3: Synthesis of 4′‐Thioribonucleosides
  • Commentary
  • Literature Cited
  • Figures
     
 
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Materials

Basic Protocol 1: Preparation of 5‐Thioarabinoside

  Materials
  • Acetyl chloride (AcCl), 95.0% (Nacalai Tesque)
  • Dry methanol (MeOH), 99.8%, super dehydrated (Wako Pure Chemical Industries)
  • L‐arabinose, 98% (Sigma‐Aldrich)
  • Argon
  • Acetyl chloride (AcCl), 95.0% (Nacalai Tesque)
  • Sodium bicarbonate (NaHCO 3), 99.5% (Nacalai Tesque)
  • MeOH, 99.6% (Junsei Chemical)
  • Chloroform (CHCl 3), 99% (Junsei Chemical)
  • Dry pyridine, 99.5%, super dehydrated (Kanto Chemical)
  • Toluene sulfonyl chloride (TsCl), 99% (Tokyo Chemical Industry)
  • Acetic anhydride (Ac 2O), 97% (Wako Pure Chemical Industries)
  • Ethanol (EtOH), 99.5% (Junsei Chemical)
  • Ethyl acetate (EtOAc), 99% (Junsei Chemical)
  • 35% (w/v) hydrochloric acid (HCl; Nacalai Tesque) solution in water
  • Sodium chloride (NaCl)
  • Sodium sulfate (Na 2SO 4), 98.5% (Nacalai Tesque)
  • N,N‐Dimethylformamide (DMF), 99.5%, super dehydrated (Kanto Chemical)
  • Potassium thioacetate (KSAc), 97% (Tokyo Chemical Industry)
  • Water (H 2O)
  • Hexane, 95% (Kanto Chemical)
  • Potassium carbonate (K 2CO 3), 99.5% (Nacalai Tesque)
  • Dry acetone, 99.5%, dehydrated (Wako Pure Chemical Industries)
  • 2,2‐Dimethoxypropane (DMP), 97% (Nacalai Tesque)
  • p‐Toluenesulfonic acid (TsOH), monohydrate, 99.0% (Nacalai Tesque)
  • 200‐ and 300‐mL round‐bottom flasks
  • Magnetic stir plate and magnetic stirrer bar
  • Celite (Nacalai Tesque)
  • Rotary evaporator
  • Chromatography columns
  • Silica Gel 60N (spherical, neutral; Kanto Chemical, cat. no. 37560‐84)
  • TLC Silica gel 60 F 254 (Merck, cat. no. 1.05715.0001)
  • Separatory funnels
  • Additional reagents and equipment for column chromatography ( appendix 3E; Meyers, 2001) and thin‐layer chromatography (TLC; appendix 3D; Meyers and Meyers, )

Basic Protocol 2: Preparation of 5‐O‐Silylated Sulfoxide

  Materials
  • Dry tetrahydrofuran (THF), 99.5%, super dehydrated, stabilizer free (Kanto Chemical)
  • Triethylamine (Et 3N), 99.5% (Sigma‐Aldrich)
  • Methanesulfonyl chloride (MsCl), 99% (Nacalai Tesque)
  • Sodium borohydride (NaBH 4), 92% (Nacalai Tesque)
  • Ethanol (EtOH), 99.5% (Junsei Chemical)
  • Water (H 2O)
  • Acetic acid
  • Chloroform (CHCl 3), 99% (Junsei Chemical)
  • Sodium bicarbonate (NaHCO 3), 99.5% (Nacalai Tesque)
  • Sodium chloride (NaCl)
  • Sodium sulfate (Na 2SO 4), 98.5% (Nacalai Tesque)
  • Hexane, 95% (Kanto Chemical)
  • Imidazole, 98% (Tokyo Chemical Industry)
  • Dry dichloromethane (CH 2Cl 2), 99.5%, super dehydrated (Kanto Chemical)
  • tert‐Butyldimethylchlorosilane (TBDMSCl), 98% (Tokyo Chemical Industry)
  • Argon
  • Ethyl acetate (EtOAc), 99% (Junsei Chemical)
  • 65% (w/w) m‐chloroperbenzoic acid (mCPBA; Nacalai Tesque) in CH 2Cl 2
  • 10% (w/v) sodium thiosulfate (Na 2S 2O 3) (Nacalai Tesque) in water
  • 50‐ and 100‐mL round‐bottom flasks
  • Magnetic stir plate and magnetic stirrer bar
  • Separatory funnels
  • Rotary evaporator
  • Chromatography columns
  • Silica Gel 60N (spherical, neutral; Kanto Chemical, cat. no. 37560‐84)
  • TLC Silica gel 60 F 254 (Merck, cat. no. 1.05715.0001)
  • Additional reagents and equipment for column chromatography ( appendix 3E; Meyers, 2001) and thin‐layer chromatography (TLC; appendix 3D; Meyers and Meyers, )

Basic Protocol 3: Synthesis of 4′‐Thioribonucleosides

  Materials
  • N‐acetylcytosine, 98% (Tokyo Chemical Industry)
  • Dry dichloromethane (CH 2Cl 2), 99.5%, super dehydrated (Kanto Chemical)
  • N,O‐Bis(trimethylsilyl)acetamide (BSA), 80% (Tokyo Chemical Industry)
  • Argon
  • Trimethylsilyl trifluoromethanesulfonate (TMSOTf), 98% (Tokyo Chemical Industry)
  • Triethylamine (Et 3N), 99.5% (Sigma‐Aldrich)
  • Dry toluene, 99.5%, super dehydrated (Kanto Chemical)
  • Sodium bicarbonate (NaHCO 3), 99.5% (Nacalai Tesque)
  • Chloroform (CHCl 3), 99% (Junsei Chemical)
  • Sodium chloride (NaCl)
  • Sodium sulfate (Na 2SO 4), 98.5% (Nacalai Tesque)
  • Hexane, 95% (Kanto Chemical)
  • Ethyl acetate (EtOAc), 99% (Junsei Chemical)
  • MeOH, 99.6% (Junsei Chemical)
  • 28% (w/v) ammonia (NH 3; Nacalai Tesque) in water
  • Ethanol (EtOH), 99.5% (Junsei Chemical)
  • DOWEX 50W X8 (H + form; Sigma‐Aldrich)
  • Chromatorex (Fuji Silysia Chemical Ltd.)
  • Water (H 2O)
  • Bis(TMS)uracil (Shin‐Etsu Chemical)
  • Trimethylsilyl trifluoromethanesulfonate (TMSOTf), 98% (Tokyo Chemical Industry)
  • iPr 2NEt (Nacalai Tesque)
  • 10‐, 20‐, and 50‐mL round‐bottom flasks
  • Magnetic stir plate and magnetic stirrer bar
  • Celite (Nacalai Tesque)
  • Separatory funnels
  • Rotary evaporator
  • Chromatography columns
  • Silica Gel 60N (spherical, neutral; Kanto Chemical, cat. no. 37560‐84)
  • TLC Silica gel 60 F 254 (Merck, cat. no. 1.05715.0001)
  • Additional reagents and equipment for column chromatography ( appendix 3E; Meyers, 2001) and thin‐layer chromatography (TLC; appendix 3D; Meyers and Meyers, )
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Figures

Videos

Literature Cited

Literature Cited
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