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. Even though glycals are highly polyvalent donors, the synthesis and reactivity of 3-amino-3-deoxyglycals have been little studied. In this work, we describe a new sequence, involving a Ferrier rearrangement and subsequent aza-Wacker cyclization that allows the rapid synthesis of orthogonally protected 3-amino-3-deoxyglycals. Finally a 3-amino-3-deoxygalactal derivative was submitted for the first time to an epoxidation/glycosylation with high yield and great diastereoselectivity, highlighting FAWEG (Ferrier/Aza-Wacker/Epoxidation/Glycosylation) as a new approach to access 1,2-trans 3-amino-3-deoxyglycosides.

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-O-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.

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 C5-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 Cp2ZrCl2 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.

Straightforward Entry toward Highly Substituted 2,3-Dihydrobenz[ b]oxepines by Ring Expansion of Benzopyryliums with Donor-Acceptor Diazo Compounds.

Ylide-type reactivity of diazo compounds is exploited in a new way to prepare benzo[ b]oxepines thanks to the formation of three chemical bonds and two contiguous and highly substituted stereocenters in a single pot. This cationic reaction cascade first involves addition of a donor-acceptor-substituted diazo compound to a benzopyrylium. Selective 1,2 migration of the endocyclic C-C bond then results in a ring-expansion and generates a second oxocarbenium that is trapped by a nucleophile added sequentially.

Diastereoselective Ring Homologation of Bicyclic Hydrazines: Access to cis-1,3-Diaminocyclohexitols.

A sequence of oxidative cleavage/double nitroaldol condensation followed by a few simple synthetic transformations can lead to polyhydroxylated di- and triaminocyclohexanes from a readily available bicyclic hydrazine. This new synthetic route provides a simple and general access to densely substituted privileged scaffolds or fragments with a perfect control of their relative configuration.

Carbene-Mediated Quaternarization of the Anomeric Position of Carbohydrates: Synthesis of Allylic Ketopyranosides, Access to the Missing α-Gluco and ß-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.

Modular access to N-substituted cis-3,5-diaminopiperidines.

A sequence of oxidative cleavage/reductive amination/hydrogenolysis enables the preparation of N-substituted cis-3,5-diaminopiperidines from a readily available bicyclic hydrazine. This new synthetic route provides a simple and general access to RNA-friendly fragments with a good chemical diversity.

Carbene-mediated functionalization of the anomeric C-H bond of carbohydrates: scope and limitations.

Herein we investigate the scope and limitations of a new synthetic approach towards α- and ß-ketopyranosides relying on the functionalization of the anomeric C-H bond of carbohydrates by insertion of a metal carbene. A key bromoacetate grafted at the 2-position is the cornerstone of a stereoselective glycosylation/diazotransfer/quaternarization sequence that makes possible the construction of a quaternary center with complete control of the stereochemistry. This sequence shows a good tolerance toward protecting groups commonly used in carbohydrate chemistry and gives rise to quaternary disaccharides with good efficiency. In the case of a disaccharide with a more restricted conformation, this functionalization process can be hampered by the steric demand next to the targeted anomeric position. In addition, the formation of transient orthoesters during the glycosylation step may also reduce the overall efficiency of the synthetic sequence.

Direct synthesis of polysubstituted aluminoisoxazoles and pyrazoles by a metalative cyclization.

Alumino-heteroles are obtained from simple precursors in a fully chemo- and regioselective manner by a metalative cyclization. The carbon-aluminum bond is still able to react further with several electrophiles, without the need of transmetalation. This synthetic route provides a novel entry to heterocyclic organoaluminum reagents as well as a straightforward access to 3,4,5-trisubstituted isoxazoles and 1,3,4,5-tetrasubstituted pyrazoles.

Stereoselective synthesis of fluorinated 1,3-cis-diaminocyclopentanes.

Several fluorinated 1,3-diaminocyclopentanes, previously reported to be useful RNA structural probes, can be prepared in a diastereoselective manner from a single bicyclic hydrazine precursor, in 3 to 9 steps.

Rh(II) carbene-promoted activation of the anomeric C-H bond of carbohydrates: a stereospecific entry toward α- and ß-ketopyranosides.

In this communication we report a new strategy toward ketopyranosides based on a carbene-mediated activation of the anomeric C-H bond of carbohydrates. By forming a new carbon-carbon bond after a glycosylation step, this approach enables the preparation of both α- and ß-ketopyranosides from advanced precursors.

Fluorinated diaminocyclopentanes as chiral sensitive NMR probes of RNA structure.

The supramolecular chiral recognition between rac-2a and several structured RNA leads to a distinct (19)F NMR signal splitting. The (19)F NMR analysis of the diastereomeric pairs formed upon binding of this racemic probe delivers a topological footprint of the RNA. This phenomenon can be exploited to investigate dynamic events involving structural equilibria, as demonstrated in a melting experiment. This work provides a proof of concept that small fluorinated moderate binders can act as external probes of RNA structures.

Cyclodextrin tetraplexes: first syntheses and potential as cross-linking agent.

The first syntheses of two cyclic tetramers of cyclodextrins, dubbed tetraplexes, are described as well as the use of one of them to form a supramolecular assembly with a modified biopolymer.

Tether influence on the binding properties of tRNALys3 ligands designed by a fragment-based approach.

A small library of 1,5-triazole derivatives linking a diaminocyclopentadiol and aromatic ketones has been prepared and screened using NMR and fluorescent techniques against tRNA(Lys)(3), the HIV reverse transcription primer. The comparison of their binding properties to those of their 1,4-triazole isomers, previously discovered in a fragment-based approach, outlines the influence of the linker on affinity and binding selectivity in such an approach.

Focus on the controversial activation of human iNKT cells by 4-deoxy analogue of KRN7000.

4-Deoxy-alpha-GalCer analogues are considered weaker agonists than KRN7000 for the stimulation of human iNKT cells, but this remains strongly debated. In this work, we described a strategy toward 4-deoxy-alpha-GalCers with, as a key step, a metathesis reaction allowing sphingosine modifications from a single ethylenic alpha-galactoside precursor. The 4-deoxy-KRN7000 derivative 2, described here, induced potent cytokinic responses, comparable to those of KRN7000, both from human iNKT cells in vitro and from their murine counterpart in vivo.