Synthesis of sp2-Iminosugar Selenoglycolipids as Multitarget Drug Candidates with Antiproliferative, Leishmanicidal and Anti-Inflammatory Properties

sp2-Iminosugar glycolipids (sp2-IGLs) represent a consolidated family of glycoconjugate mimetics encompassing a monosaccharide-like glycone moiety with a pseudoamide-type nitrogen replacing the endocyclic oxygen atom of carbohydrates and an axially-oriented lipid chain anchored at the pseudoanomeric position. The combination of these structural features makes them promising candidates for the treatment of a variety of conditions, spanning from cancer and inflammatory disorders to parasite infections. The exacerbated anomeric effect associated to the putative sp2-hybridized N-atom imparts chemical and enzymatic stability to sp2-IGLs and warrants total α-anomeric stereoselectivity in the key glycoconjugation step. A variety of O-, N-, C- and S-pseudoglycosides, differing in glycone configurational patterns and lipid nature, have been previously prepared and evaluated. Here we expand the chemical space of sp2-IGLs by reporting the synthesis of α-d-gluco-configured analogs with a bicyclic (5N,6O-oxomethylidene)nojirimycin (ONJ) core incorporating selenium at the glycosidic position. Structure–activity relationship studies in three different scenarios, namely cancer, Leishmaniasis and inflammation, convey that the therapeutic potential of the sp2-IGLs is highly dependent, not only on the length of the lipid chain (linear aliphatic C12 vs. C8), but also on the nature of the glycosidic atom (nitrogen vs. sulfur vs. selenium). The ensemble of results highlights the α-dodecylseleno-ONJ-glycoside as a promising multitarget drug candidate.

Light-Mediated Cross-Coupling of Anomeric Trifluoroborates

Stereoselective reactions at the anomeric carbon constitute the cornerstone of preparative carbohydrate chemistry. Here, we report the synthesis of axial C1 trifluoroborates and stereoselective C-arylation and etherification reactions under photoredox conditions. These reactions are characterized by high anomeric selectivities for 2-deoxysugars and broad substrate scope (24 examples), including disaccharides and trifluoroborates with free hydroxyl groups. Computational studies show that high axial selectivities for these reactions originate from a combination of kinetic anomeric effect of the intermediate C1 radical and stereoelectronic stabilization of Ni(III) through the metallo-anomeric effect. Taken together, this new class of carbohydrate reagents adds the palette of anomeric nucleophile reagents suitable for efficient installation C-C and Cheteroatom bonds.

Light-Mediated Cross-Coupling of Anomeric Trifluoroborates

Stereoselective reactions at the anomeric carbon constitute the cornerstone of preparative carbohydrate chemistry. Here, we report the synthesis of axial C1 trifluoroborates and stereoselective C-arylation and etherification reactions under photoredox conditions. These reactions are characterized by high anomeric selectivities for 2-deoxysugars and broad substrate scope (24 examples), including disaccharides and trifluoroborates with free hydroxyl groups. Computational studies show that high axial selectivities for these reactions originate from a combination of kinetic anomeric effect of the intermediate C1 radical and stereoelectronic stabilization of Ni(III) through the metallo-anomeric effect. Taken together, this new class of carbohydrate reagents adds the palette of anomeric nucleophile reagents suitable for efficient installation C-C and Cheteroatom bonds.

Stereoelectronic power of oxygen in control of chemical reactivity: the anomeric effect is not alone

The chameleonic properties of oxygen accounts for the diverse reactivity of O-functionalities and their profound role in organic synthesis.

Correction: Stereoelectronic power of oxygen in control of chemical reactivity: the anomeric effect is not alone

Correction for ‘Stereoelectronic power of oxygen in control of chemical reactivity: the anomeric effect is not alone’ by Igor V. Alabugin et al., Chem. Soc. Rev., 2021, DOI: 10.1039/d1cs00386k.

Probing the anomeric effect and mechanism of isomerization of oxazinane rings by DFT methods

Oxazinane rings can undergo isomerization or transformation to 5-membered rings tuned by the anomeric effect.

The contribution of non-classical CHax⋯OC hydrogen bonds to the anomeric effect in fluoro and oxa-methoxycyclohexanes

In this theory study the dominance of non-classical 1,3-diaxial CHax⋯OC hydrogen bonds (NCHBs) dictating anomeric effects in fluorinated methoxycyclohexanes and 2-methoxytetrahydropyrans is demonstrated, a phenomenon which is most often described as a consequence of hyperconjugation.

On the anomeric preference of the isothiocyanato group

Anomeric effect of the isothiocyanato group has been quantified for the first time in xylopyranose triacetates; both anomers being synthesized.

Anomeric effect, hyperconjugation and electrostatics: lessons from complexity in a classic stereoelectronic phenomenon

Like the tale of blind men and an elephant, discussions of the anomeric effect illustrate the danger of conclusions from a limited perspective. Stereoelectronic analysis addresses this challenge and remains the most useful in predicting reactivity.