Nucleophile-Directed Stereocontrol Over Glycosylations Using Geminal-Difluorinated Nucleophiles

The glycosylation reaction is the key transformation in oligosaccharide synthesis, but it is still difficult to control in many cases. Stereocontrol during cis‐glycosidic linkage formation relies almost exclusively on tuning the glycosylating agent or the reaction conditions. Herein, we use nucleoph...

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Bibliographic Details
Published in:Angewandte Chemie (International ed.) 2016-11, Vol.55 (46), p.14431-14434
Main Authors: Schumann, Benjamin, Parameswarappa, Sharavathi G., Lisboa, Marilda P., Kottari, Naresh, Guidetti, Fabio, Pereira, Claney L., Seeberger, Peter H.
Format: Article
Language:English
Subjects:
Alcohol
diastereoselectivity
fluorine
glycosylation
microarrays
nucleophilicity
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Summary:The glycosylation reaction is the key transformation in oligosaccharide synthesis, but it is still difficult to control in many cases. Stereocontrol during cis‐glycosidic linkage formation relies almost exclusively on tuning the glycosylating agent or the reaction conditions. Herein, we use nucleophile‐directed stereocontrol to manipulate the stereoselectivity of glycosylation reactions. Placing two fluorine atoms in close proximity to the hydroxy group of an aliphatic amino alcohol lowers the oxygen nucleophilicity and reverses the stereoselectivity of glycosylations to preferentially form the desired cis‐glycosides with a broad set of substrates. This concept was applied to the design of a cis‐selective linker for automated glycan assembly. Fluorination of an amino alcohol linker does not impair glycan immobilization and lectin binding as illustrated by glycan microarray experiments. These fluorinated linkers enable the facile generation of α‐terminating synthetic glycans for the formation of glycoconjugates. Flirting with fluorine: Lowering the nucleophilicity of aliphatic amino alcohols by difluorination drastically increases the 1,2‐cis‐stereoselectivity in glycosylations to produce conjugation‐ready glycans that are suitable for biological evaluation. Bn=benzyl, Cbz=benzyloxycarbonyl, LG=leaving group.
ISSN:1433-7851
1521-3773
DOI:10.1002/anie.201606774