Nucléophile | EPFL Graph Search

En chimie, un nucléophile (littéralement qui aime les noyaux, donc qui aime les charges positives) est une espèce chimique attirée par les espèces chargées positivement, par opposition à une espèce électrophile. Un nucléophile réagit en donnant des électrons à des composés électrophiles pour former une liaison chimique. Parce que les nucléophiles donnent des électrons, ils sont par définition des bases de Lewis. Cependant il convient de bien différencier ces deux caractères : l'un intervient uniquement dans les réactions sous contrôle thermodynamique (basicité), l'autre dans les réactions sous contrôle cinétique. Toutes les molécules, ou ions, qui possèdent un doublet non liant peuvent agir comme des nucléophiles, même si les anions sont plus réactifs que les composés neutres. Lorsque les liaisons mettent en jeu un composé nucléophile neutre, par exemple un alcool (R–OH) ou l'eau (HOH), on parle généralement de solvatation. La liaison peut alors être une véritable liaison chimique (c

New access to long-chain polyketides and spiroketals by umpolung of electron rich dienes with sulfur dioxide

Freddy Fonquerne

Natural polyketides show important biological activity. The inherent stereochemical complexity present in this class of molecules has captured the imagination of organic chemists. Their stereocontrolled, asymmetric total synthesis is a permanent and stimulating area of research. Previous efforts in our group demonstrated that the Umpolung of electron rich 1,3-dienes with SO2 could represent an efficient synthetic strategy to polyketides. Under appropriate conditions sulfur dioxide reacts with 1,3-dienes in the hetero-Diels-Alder fashion. In the case of 1-alkoxy-1,3-dienes, the 6-alkoxy-3,6-dihydro-1,2-oxatiin-2-oxides (sultines) so-obtained can be ionized in the presence of a Lewis or protic acid. The resulting zwitterionic intermediates can be trapped with enoxysilanes (oxyallylation) to generate the corresponding substituted alkenylsulfinates. Desilylation of the latter under acidic conditions leads to allylsulfinic acid intermediates, which, after retro-ene desulfitation, produce 4-alkoxyhepta-6-en-2-one core, a valuable fragment in polyketide natural product synthesis. This new SO2 cascade reaction, hetero-Diels-Alder addition/oxyallylation/retro-ene desulfitation (Vogel's cascade) has been extended to 1-alkoxy-3-acyloxy-1,3-pentadienes. Their use in this cascade reaction allowed the generation of 1,3-polyols array containing keto and enol ester functions, suitable for further chain elongation. In addition, this work highlights the extension of this methodology to other types of p-nucleophiles. The use of carefully elaborated allylsilanes allowed the preparation in a single operation (one pot double oxyallylation reaction) of long chain polyketides of 13 carbons units. Finally, a new route to the spiroketals A/B and C/D and of Spongistatins is presented in order to demonstrate the utility and the versatility of this approach.

EPFL2005

Ring-Opening Reactions of Aminocyclopropanes and Aminocyclobutanes

Mingming Wang

Nitrogen-containing compounds are an important class of molecules in medicinal chemistry, chemical biology, biochemistry, material sciences or environmental sciences. Organic nitrogen occurs in many forms, ranging from small building blocks such as urea, amino acids, nucleotides, to complex natural products, drug molecules, proteins, nucleic acids, among others. The transformation of easily-accessed nitrogen-containing building blocks into more complex nitrogen-containing structures is therefore important for the synthesis of bioactive compounds or functional materials. Interested in donor-acceptor aminocyclopropanes and aminocyclobutanes, we first developed a Lewis-acid catalyzed formal [4+1] cycloaddition of donor-acceptor aminocyclobutanes with isocyanides, which resulted in the formation of cyclopentene-1,2-diamines. We then attempted to develop a formal [3+2] cycloaddition of donor-acceptor aminocyclopropanes with electron-deficient alkenes, which was mechanistically inspired by the Morita-Baylis-Hillman reaction. Apart from the donor-acceptor system, we were also attracted by simple aminocyclopropanes without electron-withdrawing group at vicinal position. We anticipated that the incorporation of cyclopropylamine into carboxylic-containing compounds followed by ring opening functionalization reactions could be used for the synthesis of more complex products. Therefore, we first disclosed an oxidative ring-opening strategy to transform acyl, sulfonyl or carbamate protected aminocyclopropanes into 1,3-dielectrophilic carbon intermediates bearing a halide atom (Br, I) and a N,O-acetal. Replacing the alkoxy group of the N,O-acetal was achieved under acidic conditions via an elimination-addition pathway, while substitution of the halides by nucleophiles was done under basic conditions via a SN2 pathway, generating a wide range of 1,3-difunctionalized propylamines. Based on the transformation described above, we further discovered an efficient synthesis of 4-amino thiochromans starting from simple aminocyclopropanes and thiophenols through a formal [3+3] annulation reaction. Next, we developed an oxidative ring-opening strategy to transform cyclopropylamides and cyclobutylamides into fluorinated imines. The imines can be isolated in their more stable hemiaminal form, with the fluorine atom installed selectively at the terminal position. Both cheap benzophenone with UV A light or organic and inorganic dyes with blue light could be used as photoredox catalysts to promote this process. Various fluorinated amines were then obtained by nucleophilic attack on the hemiaminals in one pot, giving access to a broad range of useful building blocks for medicinal chemistry. Finally, we turned our attention to the synthesis of diamines, which are essential building blocks for the synthesis of agrochemicals, drugs and organic materials, yet their synthesis remains challenging, as both nitrogen moieties need to be differentiated and diverse substitution patterns (1,2-, 1,3 or 1,4) are required. We described a new strategy giving access to 1,2-, 1,3- and 1,4- amido azides as orthogonally protected diamines based on the nitrogen-directed diazidation of alkenes, cyclopropanes and cyclobutanes.Other unsuccessful efforts over the last four years have also been described, together with some preliminary results of ring-opening cyanation and arylation reactions.

EPFL2022

Tosyloxybenziodoxolone: A Platform for Performing the Umpolung of Alkynes in One-Pot Transformations

Julien Aymeric Borrel, Jérôme Waser

Ethynylbenziodoxolones (EBXs) are commonly encountered reagents for the electrophilic alkynylation of nucleophiles. Herein, we report a one-pot, two-step process for EBX generation and their direct application in substrate functionalization. Our approach enables us to bypass the originally mandatory isolation and purification of the reagents, resulting in a more efficient synthesis. We could apply this process to seven different transformations involving both two- and one-electron nucleophiles to obtain a large variety of alkynylated products.

AMER CHEMICAL SOC2021

Ring-Opening Reactions of Aminocyclopropanes and Aminocyclobutanes

Mingming Wang

EPFL2022