A flexible and scalable synthesis of 4′-thionucleosides
4'-Thionucleosides (thNAs) are synthetic nucleoside analogues that have attracted attention as leads for drug discovery in oncology and virology. Here we report a <i>de novo</i> thNA synthesis that relies on a scalable α-fluorination and aldol reaction of α-heteroaryl acetaldehydes followed by a streamlined process involving carbonyl reduction, mesylate formation and a double displacement reaction using NaSH. We demonstrate the multigram preparation of 4'-thio-5-methyluridine and highlight the production of purine and pyrimidine thNAs as well as C2'-modified thNAs.
Authors
- Matthew B. Nodwell
- Robert Britton (ORCID: https://orcid.org/0000-0002-9335-0047)
- Steven M. Silverman (ORCID: https://orcid.org/0000-0003-0792-7071)
- Louis‐Charles Campeau (ORCID: https://orcid.org/0000-0002-2373-802X)
- Callum Lucas
- B.P. Singh (ORCID: https://orcid.org/0009-0000-4640-8237)
- Ethan Fung
Institutions
- Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
- Simon Fraser University (CA)
Publication Details
- Journal
- Chemical Science
- Published
- 2024-11-27
- DOI
- https://doi.org/10.1039/d4sc05679e
- Citations
- 6
- Primary Topic
- HIV/AIDS drug development and treatment
- Type
- article
- Field-Weighted Citation Impact
- 2.33
Funders
- Québec Consortium for Drug Discovery
- Natural Sciences and Engineering Research Council of Canada
- Canadian Glycomics Network