DS10 - Défi de tous les savoirs

Carbohydrates Nucleophiles, New Partners in Transition Metals Catalysis – CarNuCat

Carbohydrates Nucleophiles, New Partners in Transition Metals Catalysis

The current research project takes advantage of the extraordinary chemical complexity offered by saccharides to propose an original new way for the functionalization of saccharides under metal-catalyzed. Based on catalytic approaches with saccharides as nucleophilic partners, this proposal may led to the comprehension of new structure/reactivity relationships in the carbohydrate chemistry and propose an universal catalytic system for the construction of complex structures.

Main issues raised & general objectives

Our project deals with the use transition metal-catalyzed approaches to imagine and explore new ways to build glycoconjugates. The chemistry in this proposal involves the development of a series of processes concerning N-, S- , O- or C-glycosidic bonds forming reaction under transition metal catalysis by coupling saccharides as nucleophiles with various aglycons . These processes will involve Buchwald-Hartwig, Ullmann, Chan-Lam couplings and C-H activation using saccharides as nucleophiles.


603/5000
The Buchwald-Hartwig-Migita coupling (BHM) has become the most essential coupling in the creation of the C-heteroatom bond (S, N, O, P .. etc). This reaction has been used in the synthesis of several biologically active molecules and has been transposed on an industrial scale for the synthesis of active principles. On the other hand, the use of the sugar entities in this type of coupling has never been reported.
Furthermore, CH activation processes have become a highly studied synthetic alternative. In this context, very few studies report the CH activation of sugars.

We have identified, for the first time, coupling conditions of various thiosucers protected or completely deprotected with partners halogenated at ambient temperature. The reaction, which requires a minute amount of precatalyst (1 mol%), is extremely rapid (5 min) and tolerates various functions on the electrophilic partners. In addition, it is applied to deprotected mono, di and poly-thiosugars. This methodology was then extended to another family of sulfur nucleophiles: cysteine ??derivatives, and complex biomolecules (antibodies). We have shown that if one operates in water and at room temperature, peptides and proteins (antibody trastuzumab) with free cysteine ??(SH) can be selectively functionalized with various electrophiles.

Following the encouraging results obtained in 2013 on the reactivity of aminosugars in Chan-Lam-Evans reactions, recent interest has been focused on the intramolecular coupling of amidosugars. In this context, we have succeeded in carrying out a palladocatalyzed coupling of variously substituted Z-cinnamidosugars for direct access to highly functionalized and unpublished N-glycosylated quinolin-2-ones.

Finally, in the context of CH activation, very encouraging preliminary results have recently been obtained in the laboratory. Indeed, for the first time we have been able to show that when copper salts are used, thiosugars can be introduced onto a benzamide selectively at the C-2 position by a C-H activation process. The presence of the 8-aminoquinoline adjuvant regioselectively directs the ortho reaction of the amide function. These preliminary results open up enticing prospects for the use of sugars in C-H processes

In perspective for this second year, we will continue to explore other metallocatalysed couplings with sugars as nucleophiles. We will be interested in the coupling of sugars (OH) and 1-aminosugars which remain a challenge to be met.
We will also exploit with great interest the diastereoselective arylation processes of sugars.

T. T. H. Luong, S. Touchet, M. Alami and S. Messaoudi* “Selective Pd-Catalyzed Domino Heck/Buchwald-Hartwig Arylations of N-Glycosylcinnamamides: An Efficient Route to 4-Aryl N-Glycosyl Quinolin-2-ones” Adv. Synth. Catal. 2017, 359, 1320 – 1330 (IF: 6.453)
5. A. Chabrier, A. Bruneau, S. Benmahdjoub, B. Benmerad, S. Belaid, J.-D. Brion, M. Alami, and S. Messaoudi* «Stereoretentive copper catalyzed directed thioglycosylation of C(sp2)-H bonds of benzamidesc, Chem. Eur. J, 2016, 22, 15006-15010 (Hot Paper). (IF: 5.73)
4. R. Ahmed Atto Al-Shuaeeb, S. Kolodych, O. Koniev, S. Delacroix, S. Erb, S. Nicolaÿ, J-C. Cintrat, J.-D. Brion, S. Cianférani, M. Alami, A. Wagner and S. Messaoudi* «Palladium Catalyzed Chemoselective and Biocompatible Functionalization of Cysteine-Containing Molecules at Room Temperature«, Chem. Eur. J, 2016, 22, 11365 –11370. (IF: 5.73)
3. T. T. H.Luong, J.-B. Brion, E. Lescop, M. Alami,* S. Messaoudi* «Intramolecular Pd-Catalyzed Arylation of 1-Amidosugars : A New Route to N-Glycosyl Quinolin-2-ones«, Org. Lett. 2016, 18, 2126–2129. (IF: 6.73)
2. Al-Shuaeeb, R. A. A.; Galvani, G.; Bernadat, G.; Alami, M.*; Messaoudi, S*. «Diversty-oriented synthesis of fused thioglycosyl benzo[e][1,4]oxathiepin-5-ones and benzo[f][1,4]thiazepin-5(2H)-ones by a sequences of palladium-catalyzed glycosyl thiol arylation and deprotection-lactonization reactions«. Org. Biomol. Chem. 2015, 13, 10904-10916 (IF: 3.56).
1. Bruneau, A.; Roche, M.; Hamze, A.; Brion, J.-D.; Alami, M*.; Messaoudi, S.* «Stereoretentive Palladium-Catalyzed Arylation, Alkenylation and Alkynylation of 1-Thiosugars and Thiols Using Aminobiphenyl Palladacycle Precatalyst at Room Temperature«, Chem. Eur. J, 2015, 21, 8375 – 8379. (IF: 5.73)

The field of glycobiology has exploded in the last few decades, identifying glycoconjugates to serve critical roles in a wide range of biological processes. Most carbohydrates found in nature or used in therapeutics exist as glycoconjugates in which the sugars are attached to aglycones through N-, S- or O-glycosidic bonds. These units are important or essential for biological activity. The rapid expansion of knowledge surrounding the function of carbohydrates has led to increasing attention from biological, medicinal, and pharmacological study. To meet their demands, investigators require access to significant quantities of well-defined bioactive glycoconjugates. This necessity has prompted resurgence in the interest of synthesis, with a predominant focus on new approaches to the glycosidic bond.
The chemical synthesis of glycoconjugates usually involves the transformation of a sugar into a fully protected glycosyl donor with a leaving group at its anomeric center (eg. acetate, halides, trichloroacetimidates, thiols). Glycosylation of a suitably aglycone, which react as nucleophile, then follows. (In other words, the “glycosyl donor” transfers the glycosyl moiety (generally as an electrophile) to the “aglycon” (generally the nucleophile)). Hence, the leaving group of the glycosyl donor and the protecting groups are the most fundamental parameters with respect to the yield and anomeric selectivity of glycosidation reactions. These additional steps however, decrease the yield and selectivity, are costly in time, resources and produce waste.
Our project deals with the use transition metal-catalyzed approaches to imagine and explore new ways to build glycoconjugates. The chemistry in this proposal involves the development of a series of processes concerning N-, S- , O- or C-glycosidic bonds forming reaction under transition metal catalysis by coupling saccharides as nucleophiles with various aglycons such as (i) (hetero)aryl- and alkynylhalides (ii) halogenated aminoacids, peptides or proteins. These processes will involve Buchwald-Hartwig, Ullmann, Chan-Lam couplings and C-H activation using saccharides as nucleophiles. The use of these catalytic methods is conducive to achieving “greener” chemistry, where air and moisture tolerance, performance at room temperature, and enhanced synthetic efficiency through reduction of unnecessary waste is attained. Additionally, the ligand–transition metal complex system could provide stereocontrol during the glycosylation, rather than the nature of protecting groups on the substrate. This approach is, to our knowledge, unique and has never been explored in the world.

Based on the successful outcome of this project, an unlimited number of organic transformations will be possible in the future, and the development of such new sustainable methodologies will make a tremendous impact into routine organic synthesis of glycoconjugates and into selective late-stage modification of pharmaceuticals. This conceptually novel approach would provide chemists in both the academic and industrial worlds with new disconnection strategies that give access to molecules with original structures and properties in a simple, efficient, and ecological manner.

Project coordination

Samir MESSAOUDI (BioCIS (Biomolécules, Conception, Isolement et Synthèse))

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

BioCIS-UMR 8076 BioCIS (Biomolécules, Conception, Isolement et Synthèse)

Help of the ANR 158,704 euros
Beginning and duration of the scientific project: September 2015 - 24 Months

Useful links

Explorez notre base de projets financés

 

 

ANR makes available its datasets on funded projects, click here to find more.

Sign up for the latest news:
Subscribe to our newsletter