Nucleophile‐Directed Stereocontrol Over Glycosylations Using Geminal‐Difluorinated Nucleophiles

Abstract

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.

Acceptor reactivity in glycosylation reactions

“…While the reactive primary alcohol 156 provided a b-selective reaction, the weaker nucleophile 157 mainly provided the a-product (Scheme 4). 75 By tweaking the reaction temperature and solvent, nearly complete aor b-stereoselectivity could be obtained. 76 A variety of different donors provided a similar reactivity-stereoselectivity trend.…”

Mapping the Relationship between Glycosyl Acceptor Reactivity and Glycosylation Stereoselectivity

“…[4] Ther eactivity of acceptor glycosides is less well understood and systematic studies investigating this important reaction parameter are extremely scarce. [6] Often, this is done in atime consuming,trial-anderror manner since well-defined guidelines on how to tune the reactivity of an acceptor and how this effects the glycosylation reaction are absent. [6] Often, this is done in atime consuming,trial-anderror manner since well-defined guidelines on how to tune the reactivity of an acceptor and how this effects the glycosylation reaction are absent.…”

“…[5] At the same time,i ti sc ommon practice to change protecting groups on the acceptor building block to influence the yield or change the stereoselectivity of ag lycosylation reaction. [6] Often, this is done in atime consuming,trial-anderror manner since well-defined guidelines on how to tune the reactivity of an acceptor and how this effects the glycosylation reaction are absent. [7] Recently,w eh ave shown that the reactivity of the acceptor can have aprofound influence on the stereochemical outcome of ag lycosylation reaction.…”

Dreyfus Prize in the Chemical Sciences: M. Parrinello / FCI Dozentenpreis: J. Strunk / Stifterverband Science Prize: P. H. Seeberger / Günther Laukien Prize: B. Reif / Humboldt, Siemens, and Bessel Research Awards 2016/2017

“…Seeberger was honored for his work on automated sugar synthesis for the development of vaccines, therapies, and diagnostics. He has reported in Angewandte Chemie on nucleophile‐directed stereocontrol over glycosylation reactions, and is co‐author of a report in ChemPlusChem on glucose‐modified silica nanoparticles . Seeberger is on the Editorial Advisory Board of ChemBioChem .…”