Ferrier/Aza-Wacker/Epoxidation/Glycosylation (FAWEG) Sequence to Access 1,2-Trans 3-Amino-3-deoxyglycosides.

3-Amino-3-deoxyglycosides constitute an essential class of nitrogen-containing sugars. Among them, many important 3-amino-3-deoxyglycosides possess a 1,2-trans relationship. In view of their numerous biological applications, the synthesis of 3-amino-3-deoxyglycosyl donors giving rise to a 1,2-trans glycosidic linkage is thus an important challenge.

Preparation of propargyl 1,2-orthoesters of carbohydrates: From side reactions in dichloromethane to optimized reaction conditions in acetonitrile.

In this note, supercritical fluid chromatography coupled to high-resolution mass spectrometry (SFC-HRMS) has been used to identify a chloro glycoside formed during the preparation of propargyl 1,2-orthoesters in dichloromethane. Additional studies revealed that 20-40% of this side-product was obtained depending on the source of anhydrous solvent, and that tetrabutylammonium iodide amplifies this side-reaction. Finally, a reliable procedure was developed in acetonitrile to prepare these glycosyl donors from perbenzoylated bromo glycosides in manno, gluco and galacto series in 63-74% yield.

Zirconium-Catalyzed Hydroalumination of C═O Bonds: Site-Selective De--acetylation of Peracetylated Compounds and Mechanistic Insights.

An unprecedented hydroalumination of C ═ O bonds catalyzed by zirconocene dichloride is reported herein and applied to the site-selective deprotection of peracetylated functional substrates. A mixed metal hydride, with 1:1 zirconium/aluminum stoichiometry, is also shown to be the reductive species. A catalytic cycle is finally proposed for this transformation with no precedent in the field of zirconium catalysis.

Hydrozirconation/bromination, followed by a Michaelis-Arbuzov reaction, as a convenient approach towards polyfunctional glycosylphosphonates.

In this note, an hydrozirconation/bromination/Michaelis-Arbuzov sequence was developped to introduce a trimethylene phosphonate unit on ketopyranosides. Performed on polyfunctional substrates bearing orthogonal protecting groups, this new approach provided a straightforward entry towards a large diversity of glycophosphomimetics having a quaternary anomeric position.

Functionalization of GlucoPyranosides at position 5 by 1,5 C-H insertion of Rh(II)-Carbenes: Dramatic influence of the anomeric configuration.

Herein, a C-H bond functionalization approach is reported as a new route towards non-natural glycosides having a quaternary position 5. The development of this transformation furthermore reveals that insertion of Rh(II)-carbenes into the C-H bond is controlled by remote stereoelectronic effects induced by the axial or equatorial orientation of the aglycone.

Regio- and Chemoselective Deprotection of Primary Acetates by Zirconium Hydrides.

A combination of DIBAL-H and CpZrCl is shown to promote the regioselective cleavage of primary acetates on a broad scope of substrates, ranging from carbohydrates to terpene derivatives, with a high tolerance toward protecting groups and numerous functionalities found in natural products and bioactive compounds. Apart from providing highly valuable building blocks in only two steps from biosourced raw materials, this selective de- O-acetylation should also be strongly helpful to solve selectivity issues in organic synthesis.

Carbene-Mediated Quaternarization of the Anomeric Position of Carbohydrates: Synthesis of Allylic Ketopyranosides, Access to the Missing α-Gluco and β-Manno Stereoisomers, and Preparation of Quaternary 2-Deoxy 2-Acetamido Sugars.

Following our work on the C-H functionalization of carbohydrates by the 1,5 insertion of metal-carbenes, we report herein the robust and scalable conversion of sugar γ-lactones into highly valuable glycosides having a quaternary anomeric position substituted by an allyl chain ready for further functionalization. A divergent synthetic approach furthermore provided a straightforward access to ketopyranosides with a large chemo- and stereodiversity at position 2.

Substitution of the Participating Group of Glycosyl Donors by a Halogen Atom: Influence on the Rearrangement of Transient Orthoesters Formed during Glycosylation Reactions.

Substitution of the participating group of glycosyl donors by a halogen atom is shown to specifically induce degradation of transient orthoesters formed during glycosylation reactions, depending on the nature of the acceptor, and to affect the protonation profile of those intermediates. Following these findings, bromo- and chloroacetates, which are major protecting groups in glycochemistry because they are orthogonal to other esters, should be considered with care as participating groups in the future.

A systematic investigation of iminosugar click clusters as pharmacological chaperones for the treatment of Gaucher disease.

A series of 18 mono- to 14-valent iminosugars with different ligands, scaffolds, and alkyl spacer lengths have been synthesized and evaluated as inhibitors and pharmacological chaperones of β-glucocerebrosidase (GCase). Small but significant multivalent effects in GCase inhibition have been observed for two iminosugar clusters. Our study provides strong confirmation that compounds that display the best affinity for GCase are not necessarily the best chaperones.

Rescue of functional CFTR channels in cystic fibrosis: a dramatic multivalent effect using iminosugar cluster-based correctors.

Cystic fibrosis is caused by a mutation in the gene for the cystic fibrosis transmembrane conductance regulator (CFTR) protein. N-butyl 1-deoxynojirimycin (N-Bu DNJ), a clinical candidate for the treatment of cystic fibrosis, is able to act as a CFTR corrector by overcoming the processing defect of the mutant protein. To explore the potential of multivalency on CFTR correction activity, a library of twelve DNJ click clusters with valencies ranging from 3 to 14 were synthesized.

The multivalent effect in glycosidase inhibition: probing the influence of valency, peripheral ligand structure, and topology with cyclodextrin-based iminosugar click clusters.

In view of recent reports of a strong multivalent effect in glycosidase inhibition, a library of β-CD-based multivalent iminosugars has been efficiently synthesized by way of Cu(I) -catalyzed azide-alkyne cycloaddition (CuAAC). In combination with the first application of isothermal titration calorimetry (ITC) experiments to the study of multivalent iminosugar-enzyme interactions, the inhibition properties of these click clusters were evaluated on a panel of glycosidases. The structural parameters that were varied include valency, peripheral ligand structure, and topology.

Use of cleavable coordinating rings as protective groups in the synthesis of a rotaxane with an axis that incorporates more chelating groups than threaded macrocycles.

A new methodology allowing preparation of a linear "unsaturated" [3]rotaxane consisting of an axis incorporating more coordination sites than threaded rings was developed. It was based on the preliminary synthesis of a "saturated" [5]rotaxane consisting of a four-chelating site axis threaded through four macrocyclic components, two of them being cleavable rings incorporating a lactone function and the two others being "secure" non-cleavable rings. The stoppering reaction was based on click chemistry.

Palladium(II)-catalyzed oxidative cyclization of allylic tosylcarbamates: scope, derivatization, and mechanistic aspects.

A highly selective oxidative palladium(II)-catalyzed (Wacker-type) cyclization of readily available allylic tosylcarbamates is reported. This operationally simple catalytic reaction furnishes tosyl-protected vinyl-oxazolidinones, common precursors to syn-1,2-amino alcohols, in high yield and excellent diasteroselectivity (>20:1). It is demonstrated that both stoichiometric amounts of benzoquinone (BQ) as well as aerobic reoxidation (molecular oxygen) is suitable for this transformation.

Copper(I)-assembled [3]rotaxane whose two rings act as flapping wings.

A new copper-complexed [3]rotaxane consisting of two coordinating 30-membered rings threaded by a two-binding-site axis has been prepared in good yield from relatively simple organic fragments. The main specificity of the system originates from the stoppering reaction, based on "click" chemistry, and thus from the presence of two triazole groups at positions next to the bidentate chelates of the axis central part. The geometry of the coordinating atoms belonging to the axis is such that the triazole groups can either be part of the coordinating fragments when the metal center is 5-coordinate or be not at all involved in coordination to the metal when the latter is 4-coordinate.

Diastereoselective access to trans-2-substituted cyclopentylamines.

A highly diastereoselective synthesis of trans-2-substituted cyclopentylamines via a tandem hydrozirconation/Lewis acid-mediated cyclization sequence applied to butenyl oxazolidines is described. The method allows an easy preparation of diversely substituted cyclopentylamines which appear to be useful synthetic intermediates. This was further illustrated by the syntheses of (±)-Rodocaine, (±)-trans-pentacin, and enantiomerically enriched trans-cyclopentane-1,2-diamine.

Stereoselective synthesis of pyrrolidines from N-allyl oxazolidines via hydrozirconation-cyclization.

[reaction: see text] A new diastereoselective synthesis of pyrrolidines from readily available chiral N-allyl oxazolidines is presented. The construction of the pyrrolidine ring is achieved via a tandem hydrozirconation-stereoselective Lewis acid mediated cyclization sequence.