Abstract
Nucleoside analogs are valuable commodities in the development of antisense oligonucleotides or as stand-alone antiviral and anticancer therapies. Syntheses of nucleoside analogs are typically challenged by a reliance on chiral pool starting materials and inefficient synthetic routes that are not readily amenable to diversification. The novel methodology described in this protocol addresses several longstanding challenges in nucleoside analog synthesis by enabling flexible and selective access to nucleoside analogs possessing variable nucleobase substitution, D- or L-configuration, selective protection of C3′/C5′ alcohols and C2′ or C4′ derivatizations. This protocol provides direct access to C3′/C5′ protected nucleoside analogs in three steps from simple, achiral starting materials and is described on both research (2.8 g) and process (30 g) scales for the synthesis of C3′/C5′-acetonide protected uridine. Using this protocol, proline catalyzes the fluorination of simple heteroaryl-substituted aldehyde starting materials, which are then directly engaged in a one-pot enantioselective aldol reaction with a dioxanone. Reduction, followed by intramolecular annulative fluoride displacement, forges the nucleoside analog. The three-step parent protocol can be completed in ~5 d by using simple mix-and-stir reaction procedures and standard column chromatographic purification techniques.
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Data availability
The data described in Anticipated results were obtained from the materials prepared by using the protocol described herein and are concordant with the data that we have previously reported for compounds 4a/b, 5a/b and 1 (ref. 9).
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Acknowledgements
The authors acknowledge Michael Smith Health Research BC for financial support in the form of a Research Trainee Award (E.K.D.). R.B. acknowledges support from the Canadian Glycomics Network (Strategic Initiatives Grant CD-81); the Consortium de Recherche Biopharmaceutique (CQDM Quantum Leap Grant); Merck & Co., Inc.; and the Natural Sciences and Engineering Research Council (NSERC) of Canada (Discovery Grant, RGPIN-2019-064680).
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E.K.D. optimized the research-scale protocol and wrote the manuscript and supporting information. D.A.P. optimized the process-scale protocol and wrote the associated procedures. M.M. carried out initial discovery efforts for this protocol. M.B.N. optimized the synthesis of the aldehyde precursors. S.M.S., L.-C.C. and R.B. supervised the project.
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Simon Fraser University and Merck & Co., Inc. have filed a patent application describing the synthesis of nucleoside analogs via the process presented in this manuscript—U.S. provisional patent application No. 62/994,349.
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Nature Protocols thanks Yongguirobin Chi and Henning Jacob Jessen for their contribution to the peer review of this work.
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Key reference using this protocol
Meanwell, M. et al. Science 369, 725–730 (2020): https://www.science.org/doi/10.1126/science.abb3231
Supplementary information
Supplementary Information
Supplementary Fig. 1; Supplementary Procedures, Troubleshooting table and Anticipated results; and Supplementary Figs. 2–7 (spectra).
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Davison, E.K., Petrone, D.A., Meanwell, M. et al. Practical and concise synthesis of nucleoside analogs. Nat Protoc 17, 2008–2024 (2022). https://doi.org/10.1038/s41596-022-00705-7
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DOI: https://doi.org/10.1038/s41596-022-00705-7
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