The influence of acceptor nucleophilicity on the glycosylation reaction mechanism

Vorm, Stefan van der; Hansen, Thomas; Overkleeft, Herman S.; Marel, Gijsbert A. van der; Codée, Jeroen D. C.

doi:10.1039/c6sc04638j

Cited by 136 publications

(130 citation statements)

References 78 publications

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“…The presence of the cyano moiety was found to be critical for 1,2‐ cis product formation, which was proposed to form hydrogen bonding with the acceptor hydroxyl group for intramolecular delivery favoring the generation of α glycoside. The nucleophilicities of acceptors have also been found by Codée and co‐workers to directly influence the stereoselectivities of glycosylations without 2‐cyanobenzyl ether moiety especially for benzylidene‐protected glucose donors …”

Section: Effect Of Protective Group On C‐2 Positionmentioning

confidence: 80%

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Pre‐Activation‐Based Stereoselective Glycosylations

Yang

Ramadan

et al. 2018

Eur J Org Chem

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Due to the wide presence of carbohydrates in nature and their crucial roles in numerous important biological processes, oligosaccharides have attracted a lot of attention in synthetic organic chemistry community. Many innovative synthetic methods have been developed for oligosaccharide synthesis, among which the pre-activation based glycosylation is particularly noteworthy. Traditionally, glycosylation reactions are carried out when the glycosyl donor and the acceptor are both present when the promoter is added. In comparison, the pre-activation based glycosylation is unique, where the glycosyl donor is activated by the promoter in the absence of the acceptor. Upon complete donor activation, the acceptor is added to the reaction mixture enabling glycosylation. The key step in any oligosaccharide synthesis is the stereoselective formation of the glycosidic bond. As donor activation and acceptor glycosylation are temporally separated, pre-activation based glycosylation can bestow unique stereochemical control. This review systematically discusses factors impacting the stereochemical outcome of a pre-activation based glycosylation reaction including substituents on the glycosyl donor, reaction solvent, and additives. Applications of pre-activation based stereoselective glycosylation in assembly of complex oligosaccharides are also discussed.

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Section: Effect Of Protective Group On C‐2 Positionmentioning

confidence: 80%

“…The nucleophilicities of acceptors have also been found by Codée and co-workers to directly influence the stereoselectivities of glycosylations without 2-cyanobenzyl ether moiety especially for benzylidene-protected glucose donors. [64]…”

Section: Effect Of Protective Group On C-2 Positionmentioning

confidence: 99%

Pre‐Activation‐Based Stereoselective Glycosylations

Yang

Ramadan

et al. 2018

Eur J Org Chem

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“…[43] Allyl-TMS and [D]TES are poor nucleophiles and are ideal acceptors to study the S N 1r eaction pathways of the glycosylations at hand. [15,16,[44][45][46] The results of theseglycosylations together with results obtained previously for the tri-O-benzyl series (i.e., donors 57-60)a re listed in Table 2. As previously described, the reactions in the tri-O-benzyl series proceed with good to excellent 1,2-cis selectivityf or all four configurations.…”

Section: Glycosylationsmentioning

confidence: 88%

Furanosyl Oxocarbenium Ion Conformational Energy Landscape Maps as a Tool to Study the Glycosylation Stereoselectivity of 2‐Azidofuranoses, 2‐Fluorofuranoses and Methyl Furanosyl Uronates

Vorm

Hansen

Rijssel

et al. 2019

Chemistry A European J

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The 3D shape of glycosyl oxocarbenium ions determines their stability and reactivity and the stereochemical course of S N 1 reactions taking place on these reactive intermediates is dictated by the conformation of these species. The nature and configuration of functional groups on the carbohydrate ring affect the stability of glycosyl oxocarbenium ions and control the overall shape of the cations. We herein map the stereoelectronic substituent effects of the C2‐azide, C2‐fluoride and C4‐carboxylic acid ester on the stability and reactivity of the complete suite of diastereoisomeric furanoses by using a combined computational and experimental approach. Surprisingly, all furanosyl donors studied react in a highly stereoselective manner to provide the 1,2‐ cis products, except for the reactions in the xylose series. The 1,2‐ cis selectivity for the ribo ‐, arabino ‐ and lyxo ‐configured furanosides can be traced back to the lowest‐energy 3 E or E 3 conformers of the intermediate oxocarbenium ions. The lack of selectivity for the xylosyl donors is related to the occurrence of oxocarbenium ions adopting other conformations.

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“…[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. [8] Through the use of ap anel of partially fluorinated ethanol derivatives (ethanol, mono-, di-and trifluoro ethanol) [5c] we revealed how the stereochemical outcome of ag lycosylation depends on acceptor nucleophilicity as ar esult of as hift mechanism, with weaker nucleophiles requiring am ore dissociative reaction mechanism (with more S N 1c haracter) than reactive acceptors,w hich can engage more readily in an S N 2-type displacement reaction (Scheme 1). [8] Through the use of ap anel of partially fluorinated ethanol derivatives (ethanol, mono-, di-and trifluoro ethanol) [5c] we revealed how the stereochemical outcome of ag lycosylation depends on acceptor nucleophilicity as ar esult of as hift mechanism, with weaker nucleophiles requiring am ore dissociative reaction mechanism (with more S N 1c haracter) than reactive acceptors,w hich can engage more readily in an S N 2-type displacement reaction (Scheme 1).…”

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confidence: 99%

Mapping the Relationship between Glycosyl Acceptor Reactivity and Glycosylation Stereoselectivity

et al. 2018

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The reactivity of both coupling partners-the glycosyl donor and acceptor-is decisive for the outcome of ag lycosylation reaction, in terms of both yield and stereoselectivity.W here the reactivity of glycosyl donors is well understood and can be controlled through manipulation of the functional/protecting-group pattern, the reactivity of glycosyl acceptor alcohols is poorly understood. We here present an operationally simple system to gauge glycosyl acceptor reactivity,which employs two conformationally locked donors with stereoselectivity that critically depends on the reactivity of the nucleophile.Awide arrayo fa cceptors was screened and their structure-reactivity/stereoselectivity relationships established. By systematically varying the protecting groups,t he reactivity of glycosyl acceptors can be adjusted to attain stereoselective cis-glucosylations. Scheme 1. General glycosylation mechanism, showing the equilibrium of reactive species. Pg = protecting group. Figure 1. Donors A and B and C-4-OH glucosyl acceptors 1-20.

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The influence of acceptor nucleophilicity on the glycosylation reaction mechanism

Abstract: The acceptor dependence on the glycosylation stereoselectivity is revealed by a systematic study employing model acceptors of gradually changing nucleophilicity.

Cited by 136 publications

References 78 publications

Pre‐Activation‐Based Stereoselective Glycosylations

Pre‐Activation‐Based Stereoselective Glycosylations

Furanosyl Oxocarbenium Ion Conformational Energy Landscape Maps as a Tool to Study the Glycosylation Stereoselectivity of 2‐Azidofuranoses, 2‐Fluorofuranoses and Methyl Furanosyl Uronates

Mapping the Relationship between Glycosyl Acceptor Reactivity and Glycosylation Stereoselectivity

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