Delineating the physical organic profile of the 6-fluoro glycosyl donor

Santschi, Nico; Aiguabella, Nuria; Lewe, Vanessa; Gilmour, Ryan

doi:10.1016/j.jfluchem.2015.06.004

Cited by 6 publications

(8 citation statements)

References 66 publications

(15 reference statements)

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“…[22] sented in the Eyring plot that correspond to these measurements are parallel (Figure 4, black top set of lines). [22] sented in the Eyring plot that correspond to these measurements are parallel (Figure 4, black top set of lines).…”

Section: Resultsmentioning

confidence: 79%

“…Error bars are presented as 2 ϫ σЈ βα with σЈ βα = σ βα /r βα ; data for P4 included from ref. [22] sented in the Eyring plot that correspond to these measurements are parallel (Figure 4, black top set of lines). This Table 2.…”

Section: Resultsmentioning

confidence: 79%

“…That is, the set of lines repre- [19] [d] Values taken from ref. [22] rЈ βα = calculated selectivity. r βα = measured selectivity.…”

Section: Resultsmentioning

confidence: 99%

“…[21,22] Whereas the physical ramifications of the C2 [OH Ǟ F] substitution have found widespread application in molecular design, and synthetic routes to the target glyco structures have been developed, a comparative analysis based on experimentally derived reaction parameters would assist in delineating the enthalpic and entropic contributions that underpin the selectivity observed by this seemingly trivial structural adjustment. [21,22] Whereas the physical ramifications of the C2 [OH Ǟ F] substitution have found widespread application in molecular design, and synthetic routes to the target glyco structures have been developed, a comparative analysis based on experimentally derived reaction parameters would assist in delineating the enthalpic and entropic contributions that underpin the selectivity observed by this seemingly trivial structural adjustment.…”

Section: Introductionmentioning

confidence: 99%

“…can be derived by Eyring analysis. [21,22] Whereas the physical ramifications of the C2 [OH Ǟ F] substitution have found widespread application in molecular design, and synthetic routes to the target glyco structures have been developed, a comparative analysis based on experimentally derived reaction parameters would assist in delineating the enthalpic and entropic contributions that underpin the selectivity observed by this seemingly trivial structural adjustment. Herein, a variable-temperature glycosylation study of perbenzylated 2-deoxy-2-fluoro-dglucose and 2-deoxy-2-fluoro-d-galactose is reported by using iPrOH as a model glycosyl acceptor.…”

Section: Introductionmentioning

confidence: 99%

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Comparative Analysis of Fluorine‐Directed Glycosylation Selectivity: Interrogating C2 [OH → F] Substitution in d‐Glucose and d‐Galactose

Santschi

Gilmour

2015

Eur J Org Chem

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The influence of C2 [OH → F] substitution on the stereochemical course of chemical glycosylation was interrogated in both D‐glucose and its C4 epimer D‐galactose. Molecular editing at C2 and configurational inversion at C4 were simultaneously investigated by variable‐temperature glycosylation studies of both systems. Extrapolation of the differences in enthalpic (ΔΔHβα‡) and entropic (ΔΔSβα‡) contributions that discriminate these closely similar systems revealed that deoxofluorination at the C2 position induces an enthalpic bias that augments β‐stereoselection. Intriguingly, the enhanced stereoselectivity of the C4 epimer D‐galactose was found to be entropic in nature. Given the prominence of these scaffolds in chemical biology, delineating the factors that underpin selectivity will be critical in developing novel glycosylation methods and in rationalizing differences with the natural systems post facto.

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Section: Resultsmentioning

confidence: 79%

Section: Resultsmentioning

confidence: 79%

“…That is, the set of lines repre- [19] [d] Values taken from ref. [22] rЈ βα = calculated selectivity. r βα = measured selectivity.…”

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Comparative Analysis of Fluorine‐Directed Glycosylation Selectivity: Interrogating C2 [OH → F] Substitution in d‐Glucose and d‐Galactose

Santschi

Gilmour

2015

Eur J Org Chem

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Fluorine‐Directed Glycosylation Enables the Stereocontrolled Synthesis of Selective SGLT2 Inhibitors for Type II Diabetes

Sadurní

Kehr

Ahlqvist

et al. 2017

Chemistry A European J

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Inhibition of the sodium-glucose co-transporters (SGLT1 and SGLT2) is a validated strategy to address the increasing prevalence of type II diabetes mellitus. However, achieving selective inhibition of human SGLT1 or SGLT2 remains challenging. Orally available small molecule drugs based on the d-glucose core of the natural product Gliflozin have proven to be clinically effective in this regard, effectively impeding glucose reabsorption. Herein, we disclose the influence of molecular editing with fluorine at the C2 position of the pyranose ring of Phlorizin analogues Remogliflozin Etabonate and Dapagliflozin (Farxiga ) to concurrently direct β-selective glycosylation, as is required for biological efficacy, and enhance aspects of the physicochemical profile. Given the abundance of glycosylated pharmaceuticals in diabetes therapy that contain a β-configured d-glucose nucleus, it is envisaged that this strategy may prove to be expansive.

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Fluorine-directed 1,2-trans glycosylation of rare sugars

2016

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To reconcile the urgent need to access well defined β-configured 2,6-di-deoxypyranose analogues for chemical biology, with the intrinsic α-selectivity of the native system, the directing role of fluorine at C2 has been explored. Localised partial charge inversion (C-H(δ+)→ C-F(δ-)) elicits a reversal of the substrate-based α-stereoselectivity, irrespective of the protecting group electronics.

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Delineating the physical organic profile of the 6-fluoro glycosyl donor

Cited by 6 publications

References 66 publications

Comparative Analysis of Fluorine‐Directed Glycosylation Selectivity: Interrogating C2 [OH → F] Substitution in d‐Glucose and d‐Galactose

Comparative Analysis of Fluorine‐Directed Glycosylation Selectivity: Interrogating C2 [OH → F] Substitution in d‐Glucose and d‐Galactose

Fluorine‐Directed Glycosylation Enables the Stereocontrolled Synthesis of Selective SGLT2 Inhibitors for Type II Diabetes

Fluorine-directed 1,2-trans glycosylation of rare sugars

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Delineating the physical organic profile of the 6-fluoro glycosyl donor

Cited by 6 publications

References 66 publications

Comparative Analysis of Fluorine‐Directed Glycosylation Selectivity: Interrogating C2 [OH → F] Substitution in d‐­Glucose and d‐Galactose

Comparative Analysis of Fluorine‐Directed Glycosylation Selectivity: Interrogating C2 [OH → F] Substitution in d‐­Glucose and d‐Galactose

Fluorine‐Directed Glycosylation Enables the Stereocontrolled Synthesis of Selective SGLT2 Inhibitors for Type II Diabetes

Fluorine-directed 1,2-trans glycosylation of rare sugars

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Comparative Analysis of Fluorine‐Directed Glycosylation Selectivity: Interrogating C2 [OH → F] Substitution in d‐Glucose and d‐Galactose

Comparative Analysis of Fluorine‐Directed Glycosylation Selectivity: Interrogating C2 [OH → F] Substitution in d‐Glucose and d‐Galactose