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<p>C4′-modified nucleoside analogs continue to attract global attention for treating infectious diseases and as components in oligonucleotide therapeutics. Current preparations mostly employ lengthy semi-synthetic approaches that do not allow for the efficient exploration of the chemical space associated with this valuable nucleoside subclass. Here we describe the pilot-scale (250 mg) and process-scale (85 g) preparation of 4′-methyl-ribothymidine (4′,5-dimethyluridine) using a de novo strategy. Both <span>l</span>- and <span>d</span>-nucleoside analogs are accessible, and 10 different C4′ modifications and 20 different nucleobases can be used interchangeably to create new analogs. This protocol involves the use of an enantioselective proline-catalyzed aldol between 2,2-dimethoxyacetaldehyde and a dioxanone. A 1,2-addition into the aldol product installs the C4′ modification. Subsequent cyclization via intramolecular <i>trans</i>-acetalization delivers the modified ribose core of the nucleoside analog. Peracetylation, followed by Vorbrüggen glycosylation, completes the route. The pilot- and process-scale protocols can be completed in ~5 and ~7 d, respectively, to deliver C4′-modified nucleoside analogs in good yields and excellent enantiopurity.</p>

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Preparation of C4′-modified nucleoside analogs

  • 期刊论文

  • 发表日期：

    2026年4月27日

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  • Thirupathi Nuligonda,
  • Gautam Kumar,
  • Jason W. Wang,
  • Lara K. Mahal,
  • Michael W. Meanwell

摘要

C4′-modified nucleoside analogs continue to attract global attention for treating infectious diseases and as components in oligonucleotide therapeutics. Current preparations mostly employ lengthy semi-synthetic approaches that do not allow for the efficient exploration of the chemical space associated with this valuable nucleoside subclass. Here we describe the pilot-scale (250 mg) and process-scale (85 g) preparation of 4′-methyl-ribothymidine (4′,5-dimethyluridine) using a de novo strategy. Both l- and d-nucleoside analogs are accessible, and 10 different C4′ modifications and 20 different nucleobases can be used interchangeably to create new analogs. This protocol involves the use of an enantioselective proline-catalyzed aldol between 2,2-dimethoxyacetaldehyde and a dioxanone. A 1,2-addition into the aldol product installs the C4′ modification. Subsequent cyclization via intramolecular trans-acetalization delivers the modified ribose core of the nucleoside analog. Peracetylation, followed by Vorbrüggen glycosylation, completes the route. The pilot- and process-scale protocols can be completed in ~5 and ~7 d, respectively, to deliver C4′-modified nucleoside analogs in good yields and excellent enantiopurity.