Helicenic N-heterocyclic carbenes (helicenic NHCs) : synthesis and study of the physico-chemical and catalytic properties

Cette thèse de doctorat est centrée sur la chimie des carbènes N-hétérocycliques (NHC) hélicoïdaux, combinant ainsi deux domaines de recherche que sont la chimie des hélicènes et des carbènes N-hétérocycliques. L'objectif principal est de développer un nouveau type de ligands NHCs hélicéniques basés sur la plateforme imidazo[1,5-a]pyridin-3-ylidène (IPy) fonctionnalisée en position 5 de l'hétérobicycle par des entités hélicéniques adéquates. La fonctionnalisation en position 5 de la structure bicyclique rigide IPy conduit à des ligands NHC hélicoïdaux en forme de “L” dont l'arrangement spatial devrait être bien adapté à la catalyse asymétrique à l'or(I). La synthèse, l'étude des propriétés physico-chimiques et catalytiques des nouveaux NHC hélicoïdaux sont présentées. Tout d'abord, une nouvelle voie de synthèse de molécules C2-symétriques du type [5] et [7]- hélicènes dérivées du fluorényle (flu[n]hélicènes) est décrite. Cette voie d'accès aux flu[5]- et flu[7]hélicènes comprend trois étapes de synthèse et a été optimisée à l'échelle de plusieurs grammes. Premièrement, les 1,5-dicétones symétriques sont préparées par condensation de formaldéhyde avec deux équivalents de α-tétralone ou de 3,4-dihydrophénanthrén-4-one en présence de base. Ensuite, une réaction de McMurry intramoléculaire entre les deux fonctions carbonyles des 1,5-dicétones conduit aux fluoréno[5]- et fluoréno[7]hélicènes partiellement hydrogénés (ou saturés) avec une liaison C=C tétra-substituée. La séparation chirale et la caractérisation structurelle des différents diastéréoisomères des fluoréno[5]- et [7]hélicènes sont présentées ainsi que leurs propriétés chiroptiques. Les molécules cibles du type [5] et [7]-hélicènes dérivées du fluorényle sont obtenues lors d’une dernière étape d'aromatisation déshydrogénante des fluoréno[5]- et fluoréno[7]hélicènes saturés avec un rendement global de 43% et 22% respectivement. Les flu[5]- et flu[7]hélicènes préparés ont ensuite été greffés sur les sels de bromure de 5-bromoimidazo[1,5-a]pyridinium via une réaction de substitution nucléophile aromatique (SNAr) pour donner les sels d'imidazopyridinium hélicéniques en forme de L fonctionnalisés en position C5 de la plateforme IPy. Ces précurseurs sont monodéprotonés pour générer des composés fluorénure-imidazopyridinium zwitterioniques ou doublement déprotonés pour donner les NHC anioniques libres stables correspondants. La coordination de ces derniers sur l'or(I) a conduit aux complexes anioniques d'or(I) in situ qui peuvent être soit transformés en un complexe hélicoïdal zwitterionique d'or(I) par addition de triphénylphosphine, soit reprotonés sur la partie hélicoïdale avec un acide pour donner les complexes NHCs hélicoïdaux d’or(I). L'étude détaillée des conformères cinétiques et thermodynamiques de ces complexes d'or(I) est présentée, suggérant une possible interaction Au---H-C entre le proton acide du cycle cyclopentadiène de l’hélicène et le centre métallique. Les résultats préliminaires obtenus en cycloisomérisation des 1,6-énynes ont montré une faible activité catalytique, qui pourrait être due à la présence du proton hélicoïdal acide du cycle cyclopentadiène dans le complexe d'or(I). Afin d'éviter l'effet délétère de ce proton acide présent sur le cyclopentadiène de l'entité hélicénique, la substitution de cette dernière par un groupe alkyle a été développée. Selon la méthode de synthèse utilisée, le groupe alkyle a été introduit soit sur la position centrale apicale, soit sur un carbone du bord intérieur du cycle cyclopentadiène, créant un nouveau centre de chiralité sur la partie hélicoïdale et induisant de ce fait une chiralité axiale et hélicoïdale. Ces complexes NHC hélicoïdaux d’or(I) ont été préparés à l'échelle de la centaine de mg et ont été résolus par HPLC chirale. Leur activité a été évaluée dans des transformations asymétriques catalysées à l'or(I), notamment en cycloisomérisation des 1,6-énynes.This PhD thesis is focused on the chemistry of helicenic N-heterocyclic carbenes (NHCs) thus merging two domains of intense research, namely the chemistries of helicenes and of N-heterocyclic carbenes. The main objective is to develop new classes of helicenic NHC ligands based on the imidazo[1,5-a]pyridin-3-ylidene (IPy) platform functionalised in position 5 of the heterobicycle with adequate helicenic moieties. The functionalisation of the rigid bicyclic IPy structure in position 5 provides L-shaped helicenic NHC ligands which are expected to be well-suited for asymmetric gold(I) catalysis. The synthesis, the study of physico-chemical and catalytic properties of new helicenic NHCs are displayed. First the novel synthesis of C2-symmetric fluorenyl-derived [5] and [7] helicene-like molecules (flu[n]helicenes) is described. The developed synthetic pathway to access flu[5]- and flu[7]helicenes comprises three synthetic steps and has been optimised on a multi-gram scale. Firstly, the symmetrical 1,5-diketones are prepared by base-assisted condensation of formaldehyde with two equivalents of α-tetralone or 3,4-dihydrophenanthren-4-one. Then an intramolecular McMurry reaction between the two carbonyl moieties of 1,5-diketones affords the partially-hydrogenated (or saturated) fluoreno[5]- and fluoreno[7]helicenes with an internal tetra-substituted, overcrowded C=C bond. The chiral separation and structural characterisation of the different diastereomers are presented as well as their chiroptical properties. The desired fluorenyl-derived [5] and [7] helicene-like molecules are obtained in a final dehydrogenative aromatisation of the saturated fluoreno[5]- and fluoreno[7]helicenes with overall yields of 43% and 22% respectively. The prepared flu[5]- and flu[7]helicenes were then grafted on the 5-bromoimidazo[1,5-a]pyridinium bromide salts via a nucleophilic aromatic substitution (SNAr) to afford the L-shaped helicenic imidazopyridinium salts functionalised at the C5 position of the IPy platform. The latter precursors were monodeprotonated to generate zwitterionic fluorenide-imidazopyridinium compounds or deprotonated twice to yield the corresponding stable free anionic NHCs. The latter were cleanly coordinated to gold(I) centre generating in situ anionic gold(I) complexes, which could be further transformed into a zwitterionic helicenic gold(I) complex by addition of triphenylphosphine, or reprotonated on the helicenic moiety with an acid affording the helicenic NHC-gold(I) complexes. The detailed study of the kinetic and thermodynamic conformers of these gold(I) complexes is presented indicating a possible Au···H-C contact between the acidic helicene proton of the cyclopentadiene ring and the AuI centre. The preliminary results obtained in cycloisomerisation of 1,6-enynes showed low catalytic activity, which might be due to the presence of the acidic helicenic proton of the cyclopentadiene ring in the gold(I) complex. In order to avoid this deleterious acidic proton on the fluorenyl-derived helicenic moiety, the latter was derivatized by alkylation. Depending on the protocol, the alkyl moiety was either installed on the central apical position or on one carbon of the inner rim of the cyclopentadiene ring creating a new centre of chirality on the helicene moiety and inducing axial and helical chirality. The derivatized helicenic NHC-gold(I) complexes were prepared in hundreds of mg and were resolved by chiral HPLC. Their activity in the asymmetric gold(I)-catalysed transformations notably in cycloisomerisation of 1,6-enynes is presented

Manganese catalyzed α-methylation of ketones with methanol as a C1 source

International audienceThe direct α-methylation of ketones with methanol under hydrogen borrowing conditions using a well-defined manganese PN3P complex as a pre-catalyst was, for the first time, achieved. The reactions typically proceed at 120 °C for 20 h with 3 mol% pre-catalyst loading and in the presence of NaOtBu (50 mol%) as base. The scope of the reaction was extended to the α-methylation of esters

Cover Feature: Phosphorescent Cationic Heterodinuclear Ir III

n/

Phosphorescent cationic heterodinuclear IrIII/MI complexes (M = CuI, AuI) with a hybrid Janus-type N-heterocyclic carbene bridge

A novel class of phosphorescent cationic heterobimetallic IrIII/MI complexes, where MI = CuI (4) and AuI (5), is reported. The two metal centers are connected by the hybrid bridging 1,3-dimesityl-5-acetylimidazol-2-ylidene-4-olate (IMesAcac) ligand that combines both a chelating acetylacetonato-like and a monodentate N-heterocyclic carbene site coordinated onto an IrIII and a MI center, respectively. Complexes 4-5 have been prepared straightforwardly by a stepwise site-selective metalation with the zwitterionic [(IPr)MI(IMesAcac)] metalloproligand (IPr = 1,3-(2,6-diisopropylphenyl)-2H-imidazol-2-ylidene) and they have been fully characterized by spectroscopical, electrochemical and computational investigation. Complexes 4-5 display intense red emission arising from a low-energy lying excited state that is located onto the "Ir(C^N)" moiety featuring an admixed triplet ligand centered/metal-to-ligand charge transfer (3IL/1MLCT) character. Comparison with the benchmark mononuclear complexes reveals negligible electronic coupling between the two distal metal centers at the electronic ground state. The bimetallic systems display enhanced photophysical properties in comparison with the parental congeners. Noteworthy, similar nonradiative rate constant has been determined along with a two-fold increase of radiative rate, yielding brightly red-emitting cyclometallating IrIII complexes. This finding is ascribed to the increased MLCT character of the emitting state in complexes 4-5 due to the smaller energy gap between the 3IL and 1MLCT manifolds, which mix via spin-orbit coupling

N‐Heterocyclic Carbenes as Key Intermediates in the Synthesis of Fused, Mesoionic, Tricyclic Heterocycles

International audienceCoupling between 5-bromoimidazo[1,5-a]pyridinium salts and malonate or arylacetate esters leads to a facile and straightforward access to the new mesoionic, fused, tricyclic system of imidazo[2,1,5-cd]indolizinium-3-olate. Mechanistic studies show that the reaction pathway consists of nucleophilic aromatic substitution on the cationic, bicyclic heterocycle by an enolate-type moiety and in the nucleophilic attack of a transient free N-heterocyclic carbene (NHC) species on the ester group; the relative order of these two steps depends on the nature of the starting ester. This work highlights the valuable implementation of free NHC species as key intermediates in synthetic chemistry, beyond their classical use as stabilizing ligands or organocatalysts

Helical chiral N‐heterocyclic carbene ligands in enantioselective gold catalysis

International audienceThe first chiral helicene-NHC gold(I) complexes efficient in enantioselective catalysis were prepared. The L-shaped chiral ligand is composed of an imidazo[1,5-a]pyridin-3-ylidene (IPy) scaffold laterally-substituted by a configurationally stable [5]-helicenoid unit. The chiral information was introduced in a key post-functionalization step of a NHC-gold(I) complex bearing a symmetrical anionic fluoreno[5]helicene substituent, leading to a racemic mixture of complexes featuring three correlated elements of chirality, namely central, axial and helical chirality. After HPLC enantiomeric resolution, X-ray crystallography and theoretical calculations enabled structural and stereochemical characterization of these configurationally stable NHC-gold(I) complexes. The high potential in asymmetric catalysis is demonstrated in the benchmark cycloisomerization of N-tethered 1,6-enynes with up to 95:5 er

Synthesis and Properties of Partially Saturated Fluorenyl-Derived [n]helicenes Featuring an Overcrowded Alkene

International audienceThe straightforward, multigram-scale synthesis of the partially saturated H -fluoreno[n]helicenes (n=5 or 7) featuring a central, overcrowded alkene is described. The key cyclization step was based on an intramolecular McMurry reaction from the corresponding 1,5-diketones. Chiral stationary phase HPLC analysis and isomer separation indicate that each helicenic compound is constituted of three diastereoisomers at room temperature, i. e. the configurationally stable (R,R,P)/(S,S,M) pair of enantiomers and an apparently achiral compound resulting from the rapid interconversion between the (R,S,P) and (S,R,M) enantiomers. The partially saturated H -fluoreno[n]helicenes are oxidatively aromatized to give an efficient access to the corresponding fluoreno[n]helicenes. The chiroptical properties (vibrational and electronic circular dichroism) of the chiral, enantiopure compounds have been measured and analyzed by quantum-chemical calculations, confirming their helicoidal nature

Integrated Activity and Genetic Profiling of Secreted Peptidases in Cryptococcus neoformans Reveals an Aspartyl Peptidase Required for Low pH Survival and Virulence.

The opportunistic fungal pathogen Cryptococcus neoformans is a major cause of mortality in immunocompromised individuals, resulting in more than 600,000 deaths per year. Many human fungal pathogens secrete peptidases that influence virulence, but in most cases the substrate specificity and regulation of these enzymes remains poorly understood. The paucity of such information is a roadblock to our understanding of the biological functions of peptidases and whether or not these enzymes are viable therapeutic targets. We report here an unbiased analysis of secreted peptidase activity and specificity in C. neoformans using a mass spectrometry-based substrate profiling strategy and subsequent functional investigations. Our initial studies revealed that global peptidase activity and specificity are dramatically altered by environmental conditions. To uncover the substrate preferences of individual enzymes and interrogate their biological functions, we constructed and profiled a ten-member gene deletion collection of candidate secreted peptidases. Through this deletion approach, we characterized the substrate specificity of three peptidases within the context of the C. neoformans secretome, including an enzyme known to be important for fungal entry into the brain. We selected a previously uncharacterized peptidase, which we term Major aspartyl peptidase 1 (May1), for detailed study due to its substantial contribution to extracellular proteolytic activity. Based on the preference of May1 for proteolysis between hydrophobic amino acids, we screened a focused library of aspartyl peptidase inhibitors and identified four high-affinity antagonists. Finally, we tested may1Δ strains in a mouse model of C. neoformans infection and found that strains lacking this enzyme are significantly attenuated for virulence. Our study reveals the secreted peptidase activity and specificity of an important human fungal pathogen, identifies responsible enzymes through genetic tests of their function, and demonstrates how this information can guide the development of high affinity small molecule inhibitors

Integrated Activity and Genetic Profiling of Secreted Peptidases in <i>Cryptococcus neoformans</i> Reveals an Aspartyl Peptidase Required for Low pH Survival and Virulence

<div><p>The opportunistic fungal pathogen <i>Cryptococcus neoformans</i> is a major cause of mortality in immunocompromised individuals, resulting in more than 600,000 deaths per year. Many human fungal pathogens secrete peptidases that influence virulence, but in most cases the substrate specificity and regulation of these enzymes remains poorly understood. The paucity of such information is a roadblock to our understanding of the biological functions of peptidases and whether or not these enzymes are viable therapeutic targets. We report here an unbiased analysis of secreted peptidase activity and specificity in <i>C</i>. <i>neoformans</i> using a mass spectrometry-based substrate profiling strategy and subsequent functional investigations. Our initial studies revealed that global peptidase activity and specificity are dramatically altered by environmental conditions. To uncover the substrate preferences of individual enzymes and interrogate their biological functions, we constructed and profiled a ten-member gene deletion collection of candidate secreted peptidases. Through this deletion approach, we characterized the substrate specificity of three peptidases within the context of the <i>C</i>. <i>neoformans</i> secretome, including an enzyme known to be important for fungal entry into the brain. We selected a previously uncharacterized peptidase, which we term <b>M</b>ajor <b>a</b>spart<b>y</b>l peptidase 1 (May1), for detailed study due to its substantial contribution to extracellular proteolytic activity. Based on the preference of May1 for proteolysis between hydrophobic amino acids, we screened a focused library of aspartyl peptidase inhibitors and identified four high-affinity antagonists. Finally, we tested <i>may1Δ</i> strains in a mouse model of <i>C</i>. <i>neoformans</i> infection and found that strains lacking this enzyme are significantly attenuated for virulence. Our study reveals the secreted peptidase activity and specificity of an important human fungal pathogen, identifies responsible enzymes through genetic tests of their function, and demonstrates how this information can guide the development of high affinity small molecule inhibitors.</p></div