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Preparation of a 4′‐Thiouridine Building‐Block for Solid‐Phase Oligonucleotide Synthesis

Benckendorff, Caecilie M. M.; Sanghvi, Yogesh S.; Miller, Gavin J.

Authors

Yogesh S. Sanghvi



Abstract

Starting from a commercially available thioether, we report a nine‐step synthesis of a 4′‐thiouridine phosphoramidite building‐block. We install the uracil nucleobase using Pummerer‐type glycosylation of a sulfoxide intermediate followed by a series of protecting group manipulations to deliver the desired phosphite. Notably, we introduce a 3′,5′‐O‐di‐tert‐butylsilylene protecting group within a 4′‐thiosugar framework, harnessing this to ensure regiospecific installation of the 2′‐O‐silyl protecting group. We envisage this methodology will be generally applicable to other 4′‐thionucleosides and duly support the exploration of their inclusion within related nucleic acid syntheses. © 2023 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: (2R,3S,4R)‐2,3‐O‐Isopopropylidene‐5‐O‐tert‐butyldiphenylsilyl‐1‐(4‐sulfinyl)cyclopentane: Sulfoxidation Basic Protocol 2: 2′,3′‐O‐Isopropylidene‐5′‐O‐tert‐butyldiphenylsilyl‐4′‐thiouridine: Pummerer glycosylation Basic Protocol 3: 4′‐Thiouridine: Deprotection Basic Protocol 4: 2′‐O‐tert‐Butyldimethylsilyl‐3′,5′‐di‐tert‐butylsiloxy‐4′‐thiouridine: 2′,3′,5′‐O‐silylation Basic Protocol 5: 2′‐O‐tert‐Butyldimethylsilyl‐4′‐thiouridine: Selective 3′‐5′‐desilylation Basic Protocol 6: 2′‐O‐tert‐Butyldimethylsilyl‐5′‐O‐dimethoxytrityl‐4′‐thiouridine: 5′‐O‐dimethoxytritylation Basic Protocol 7: 2′‐O‐tert‐butyldimethylsilyl‐3′‐O‐[(2‐cyanoethoxy)(N, N‐diisopropylamino)phosphino]‐5′‐O‐dimethoxytrityl‐4′‐thiouridine: 3′‐O‐phosphitylation

Journal Article Type Article
Acceptance Date Sep 1, 2023
Online Publication Date Sep 25, 2023
Publication Date Sep 1, 2023
Deposit Date Oct 9, 2023
Publicly Available Date Oct 9, 2023
Journal Current Protocols
Print ISSN 1934-8576
Publisher Wiley
Peer Reviewed Peer Reviewed
Volume 3
Issue 9
Pages e878
DOI https://doi.org/10.1002/cpz1.878
Keywords thiosugar, protecting group, phosphoramidite, 4′‐thionucleoside

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