Gilles Doisneau

Cyclopropane ring formation by an SmI2 mediated cyclisation of δ-halo-α,β-unsaturated esters

Abstract δ-Iodo- and δ-bromo-α,β-unsaturated esters with various substituents at the β- and γ-positions readily cyclise to cyclopropane compounds in the presence of samarium diiodide and a proton source.

Fast Access to Robust C‐Sialoside Multimers

Interactions between cell-surface glycoconjugates and receptors play a crucial role in a wide range of biological events with a presentation of glycans at cell surfaces as an ensemble of many different arrangements. This explains in part why most glycan-based interactions necessitate multivalency to achieve a biologically significant interaction. NAcetylneuraminic acid (Neu5Ac), the major member of the sialic acid family, is commonly located as an a-ketosidically linked terminal sugar on cell surface glycoconjugates. As a result of this external position within glycoconjugates, it is involved in numerous biological phenomena, including pathological interactions of human cells with bacteria and viruses. This has led to intense research interest in sialic acid chemistry, comprising the design of potent chemotherapeutic agents against the influenza virus or the elaboration of diagnostic tools that could facilitate fast and accurate virus detection. The stability of the diagnostic constructs to external conditions and to enzymatic activities of the target is often a serious and under-evaluated problem. In this context, we have developed a collection of new oligovalent C-sialosides attached to different scaffolds able to provide diverse combinations of valency and geometry that could effectively interact with various biological targets. The well-defined oligomeric C-sialoside structures were prepared by using a very short synthetic pathway combining two highyielding key steps: our recently reported samarium-mediated Reformatsky-coupling reaction by using anomeric acetates 1 (Scheme 1) and the copper(I)-catalyzed Huisgen cycloaddition of azide and alkyne, a model reaction of the “click” chemistry. This highly regioselective reaction introduces 1,4-disubstituted 1,2,3-triazole units linking, efficiently, sialic acid derivative monomers to various multivalent core compounds. With the intended cycloaddition reactions we envisioned two possible approaches for the construction of the multivalent species. The central multivalent core can present either alkyne or azide functionalities to react with C-sialoside monomers bearing the complementary functional group. Hence, the monomeric azide or alkyne C-sialosides required were promptly prepared from anomeric acetates 1. We previously showed that reductive samariation of 1 with cyclic ketones under Barbier conditions was a straightforward aselective and high yielding reaction. For the purpose of this study, the choice of a substituted piperidin-4-one, a symmetrical cyclic ketone, was essential to provide high-coupling efficiency without adding a new stereogenic center. Thus, treatment of an a/b diastereomeric mixture of pentaacetylated N-acetyl neuraminic acid methyl ester 1 and commercial NBoc protected piperidin-4-one (2 equiv) with a freshly prepared 0.1 m SmI2 THF solution (3 equiv), furnished, after the usual aqueous work-up and flash chromatography, the intermediate a-C-glycoside 2 in 95 % yield (Scheme 1). This reaction conducted on a gram scale exemplifies well the efficiency of this procedure with a cyclic ketone as an electrophile. Trifluoroacetic acid-mediated de[a] C. Papin, Dr. G. Doisneau, Prof. J.-M. Beau Universit Paris-Sud 11 Institut de Chimie Mol culaire et des Mat riaux associ au CNRS Laboratoire de Synth se de Biomol cules 91405 Orsay Cedex (France) Fax: (+33) 1-6985-3715 E-mail : jmbeau@icmo.u-psud.fr Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.200801810. Scheme 1. Synthesis of the C-sialoside monomers 3–5 by reductive samariation.

Radical dimerization of glycosyl 2-pyridylsulfones with samarium (II) iodide in the presence of HMPA

Abstract Reduction of glycosyl 2-pyridylsulfones by samarium (II) iodide in the presence of HMPA leads to glycosyl dimers in up to 74% yield. This is rationalized by a free-radical mechanism.

Anomeric Samarium(III) Intermediates of N-Acetylneuraminic Acid from Anomeric 2-Pyridylsulfides

Treatment of the anomeric 2-thiopyridyl derivative of N-acetylneuraminic acid (sialic acid or Neu5Ac) with samarium diiodide in the presence of aldehydes or ketones provides the corresponding C-sialylated derivatives in excellent yields. The efficiency of the reductive samariation of the anomeric 2-pyridylsulfide moiety in the Neu5Ac series does not require any cosolvent or additive. This samarium Reformatsky-like reaction from anomeric 2-pyridylsulfide derivatives of Neu5Ac provides an efficient and highly stereoselective access to a-2,6-C-disaccharides.

Direct Umpolung of Glycals and Related 2,3‐Unsaturated N‐Acetylneuraminic Acid Derivatives Using Samarium Diiodide

The umpolung of glycals with samarium diiodide offers a simple route to novel carbohydrate-derived nucleophilic reagents in a single step using a readily available reductant. The corresponding allyl samarium reagent that arises from the hexose series reacts with ketones at the C3 position with high stereoselectivity; carbon-carbon bond formation takes place only anti to the substituent at the C4 position of the dihydropyran ring. For the sialic acid series, the completely regio- and stereoselective coupling process of the samarium reagent occurs at the anomeric carbon atom and provides a new approach to the α-C-glycosides of N-acetyl neuraminic acid.

Synthesis of 1,2-trans C-glycosyl compounds by reductive samariation of glycosyl iodides

Reductive samariation of per-O-trimethylsilyl or benzyl glycopyranosyl iodides in the presence of carbonyl compounds provides the corresponding 1,2-trans-C-glycosyl compounds in good yields.

Characterization of Protonated Model Disaccharides from Tandem Mass Spectrometry and Chemical Dynamics Simulations

The fragmentation mechanisms of prototypical disaccharides have been studied herein by coupling tandem mass spectrometry (MS) with collisional chemical dynamics simulations. These calculations were performed by explicitly considering the collisions between the protonated sugar and the neutral target gas, which led to an ensemble of trajectories for each system, from which it was possible to obtain reaction products and mechanisms without pre-imposing them. The β-aminoethyl and aminopropyl derivatives of cellobiose, maltose, and gentiobiose were studied to observe differences in both the stereochemistry and the location of the glycosidic linkage. Chemical dynamics simulations of MS/MS and MS/MS/MS were used to suggest some primary and secondary fragmentation mechanisms for some experimentally observed product ions. These simulations provided some new insights into the fundamentals of the unimolecular dissociation of protonated sugars under collisional induced dissociation conditions.