An Enantioselective and Modular Platform for C4'-modified Nucleoside Analogue Synthesis Enabled by Intramolecular Trans-acetalizations

Overview

Journal Nat Commun

Specialty Biology

Date 2024 Aug 16

PMID 39152141

Authors

Thirupathi Nuligonda

Gautam Kumar

Jason W Wang

Dinithi Rajapaksha

Ismael A Elayan

Ramiz Demir

Neil J Meanwell

Sherrie F Wang

Lara K Mahal

Alex Brown

Michael W Meanwell

Affiliations

Soon will be listed here.

Abstract

C4'-modified nucleoside analogues continue to attract global attention for their use in antiviral drug development and oligonucleotide-based therapeutics. However, current approaches to C4'-modified nucleoside analogues still involve lengthy (9-16 steps), non-modular routes that are unamenable to library synthesis. Towards addressing the challenges associated with their syntheses, we report a modular 5-step process to a diverse collection of C4'-modified nucleoside analogues through a sequence of intramolecular trans-acetalizations of readily assembled polyhydroxylated frameworks. Overall, the 2-3 fold reduction in step-count compares favorably to even recently reported biocatalytic approaches and should ultimately enable new opportunities in drug design around this popular chemotype.

Citing Articles

Unmasking the halide effect in diastereoselective Grignard reactions applied to C4´ modified nucleoside synthesis.

Muir G, Caballero-Garcia G, Muilu T, Nodwell M, Park Y, Huxley C Nat Commun. 2025; 16(1):1679.

PMID: 39956836 PMC: 11830774. DOI: 10.1038/s41467-025-56895-7.

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