The synthesis of difluoromethylene-linked C-glycosides and C-disaccharides

doi:10.1016/S0957-4166(00)86305-3

Tetrahedron: Asymmetry

Volume 5, Issue 11, November 1994, Pages 2269-2282

https://doi.org/10.1016/S0957-4166(00)86305-3 Get rights and content

Abstract

Novel difluoromethylene linked C-glycosides and C-disaccharides were prepared by intermolecular addition of nucleophilic and electrophilic radicals to carbohydrate gem-difluoroenol ethers.

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References (20)

R.D. Chambers et al.
Tetrahedron
(1989)
J.S. Houlton et al.
Tetrahedron
(1993)
B. Giese et al.
Tetrahedron
(1989)
J.M. Tedder et al.
Tetrahedron
(1980)
A.L.J. Beckwith et al.
Tetrahedron
(1985)
M.H.D. Postema
Tetrahedron
(1992)
O.R. Martin et al.
J. Org. Chem.
(1993)
P. Vogel et al.
J. Org. Chem.
(1992)
A. Chénéde et al.
Synlett
(1994)
A.G. Myers et al.
J. Am. Chem. Soc.
(1994)

There are more references available in the full text version of this article.

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Substitution with a carbon or a sulfur atom of the oxygen that in saccharides links one sugar unit to another sugar or to an aglycon generates compounds defined as C-glycosides and S-glycosides, respectively. The interest in these classes of compounds lies in the metabolic stability of the glycosidic linkage, as useful characteristic for potential drugs (inhibitors, agonists, antagonists) of glycosidic nature. After a brief introduction on the biological relevance of C-glycosides and S-glycosides, the chapter describes the different approaches for the synthesis of both classes of compounds, defining the general strategies and the recent applications. C-glycosides have been synthesized not only taking advantage of the electrophilic character of the anomeric center of the sugar, but also converting it into an electrophile or a radical. Not only carbon nucleophiles, such as organometallic reagents, carbanions, silyl enolethers, or allylsilanes, but also electrophilic carbons such as aldehydes, or carbon radical scavengers such as acrylates, can be used. The synthesis of S-glycosides is much simpler and well defined, due to the strong nucleophilic character of thiols that well combines with the electrophilic character of the anomeric center.
Regioselective Synthesis of Difluorinated C-Furanosides Involving a Debenzylative Cycloetherification
2019, Organic Letters
A highly regioselective synthesis of valuable gem-difluorinated C-furanosides from unprotected aldoses via a debenzylative cycloetherification (DBCE) reaction induced by diethylaminosulfur trifluoride is descibed. The scope and limitations of this DBCE reaction are described using a series of commercially available pentoses and hexoses to afford, without selective protection/deprotection sequences, the corresponding gem-difluorinated C-furanosides in moderate to good yields.
Biological Impacts of Fluorination: Pharmaceuticals Based on Natural Products. Pharmaceuticals Based on Natural Products.
2008, Fluorine and Health: Molecular Imaging, Biomedical Materials and Pharmaceuticals
This chapter focuses on the recent advances in the fluorinated analogues of natural products developed as pharmaceuticals. These mainly concern fluorine-substituted nucleosides, alkaloids, macrolides, steroids, amino acids, and prostaglandins. Among the numerous marketed pharmaceuticals in the world, more than 150 drugs are fluorinated compounds. The specific properties of the fluorine atom, such as its strong electronegativity, small size, and low polarisability of the C–F bond, can have considerable impact on the behavior of a small molecule in a biological environment. The introduction of fluorine atoms into a molecule has an impact on the physical and chemical properties of this molecule, with deep consequences on the biological properties. The absorption, distribution, recognition, and interaction or reaction processes with the biological target, as well as the metabolism and the elimination of this molecule, are affected. This possibility to modify or to modulate the pharmacological profile of a molecule by inserting fluorine atoms clearly explains why bioorganic and medicinal chemistry of fluorine has become so important, and why many drugs and pesticides are fluorinated compounds. Fluorinated groups (F, CF2, etc.) are isosteric or isopolar of various functional groups; they can mimic them in the interaction processes with biological macromolecules. They can also interact afterwards with the target, because of the specific reactivity of the fluorinated molecule. This explains the important role played by the incorporation of fluorine atoms in the design of receptor ligands and enzyme inhibitors: substrate analogues, transition state analogues, and based-mechanism inhibitors.
Biological Impacts of Fluorination: Pharmaceuticals Based on Natural Products
2008, Fluorine and Health
This chapter focuses on the recent advances in the fluorinated analogues of natural products developed as pharmaceuticals. These mainly concern fluorine-substituted nucleosides, alkaloids, macrolides, steroids, amino acids, and prostaglandins. Among the numerous marketed pharmaceuticals in the world, more than 150 drugs are fluorinated compounds. The specific properties of the fluorine atom, such as its strong electronegativity, small size, and low polarisability of the C–F bond, can have considerable impact on the behavior of a small molecule in a biological environment. The introduction of fluorine atoms into a molecule has an impact on the physical and chemical properties of this molecule, with deep consequences on the biological properties. The absorption, distribution, recognition, and interaction or reaction processes with the biological target, as well as the metabolism and the elimination of this molecule, are affected. This possibility to modify or to modulate the pharmacological profile of a molecule by inserting fluorine atoms clearly explains why bioorganic and medicinal chemistry of fluorine has become so important, and why many drugs and pesticides are fluorinated compounds. Fluorinated groups (F, CF2, etc.) are isosteric or isopolar of various functional groups; they can mimic them in the interaction processes with biological macromolecules. They can also interact afterwards with the target, because of the specific reactivity of the fluorinated molecule. This explains the important role played by the incorporation of fluorine atoms in the design of receptor ligands and enzyme inhibitors: substrate analogues, transition state analogues, and based-mechanism inhibitors.
Synthesis and conformational behavior of the difluoromethylene linked C-glycoside analog of β-galactopyranosyl-(1↔1)-α-mannopyranoside
2007, Carbohydrate Research
Citation Excerpt :
The J values for the ring protons indicate that all the pyranose chairs adopt the usual 4C1 chair (Table 2). The intermediate observed values for the C5–C6 lateral chains are in agreement with equilibria between the tg:gt conformers for the Gal ring and the gg:gt conformers for the Man moiety.28 The anomeric protons of both Gal and Man residues show scalar couplings to the fluorine atoms at the pseudoglycosidic linkage.
C-Glycosides in which the pseudoglycosidic substituent is a methylene group have been advertised as hydrolytically stable mimetics of their parent O-glycosides. While this substitution assures greater stability, the lower polarity and increased conformational flexibility in the intersaccharide linker brought about by this change may compromise biological mimicry. In this regard, C-glycosides, in which the pseudoanomeric methylene is replaced with a difluoromethylene group, are interesting because the CF₂ group is more of an isopolar replacement for oxygen than CH₂. In addition, the CF₂ residue is expected to instill conformational bias into the intersaccharide torsions. Herein is described the synthesis and conformational behavior of the difluoromethylene linked C-glycoside of β-d-galactopyranosyl-(1↔1)-α-d-mannopyranoside. The synthesis centers on the formation of the galactose residue via an oxocarbenium ion–enol ether cyclization. Conformational analysis, using a combination of molecular mechanics, dynamics, and NMR spectroscopy, suggests that the difluoro-C-glycoside populates the non-exo-Gal/exo-Man conformer to a major extent (ca 50%), with a minor contribution (∼15%) from the exo-Gal/exo-Man conformer that corresponds to the ground sate of the parent O-glycoside.
Synthesis of C- and S-Glycosides
2007, Comprehensive Glycoscience: From Chemistry to Systems Biology

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The synthesis of difluoromethylene-linked C-glycosides and C-disaccharides

Abstract

Tetrahedron

Tetrahedron

Tetrahedron

Tetrahedron

Tetrahedron

Tetrahedron

J. Org. Chem.

J. Org. Chem.

Synlett

J. Am. Chem. Soc.