18 F-Fluorination of a supported 2-(aryl-di-tert-butylsilyl)-N-methyl-imidazole for indirect 18 F-labeling of a VH H single-variable domain.

Anchoring an imidazole-di-tert-butyl-arylsilane possessing an azido group to a polystyrene resin provided a heterogeneous precursor that was radiolabeled easily using aqueous [18 F]fluoride. After optimizing the conditions (i.e., using DMSO as solvent and heating at 160°C for 15 min), the desired [18 F]fluorosilane was obtained in 24% radiochemical yield (RCY) and 78% radiochemical purity (RCP) using solid-phase extraction as sole purification. Then, this compound was conjugated by strain-promoted alkyne-azide cycloaddition to a model single-variable domain possessing a cyclooctyne tag, yielding to the desired 18 F-labeled bioconjugate in 2% RCY and >95% RCP after purification by a size exclusion chromatography.

Brønsted Acid-Catalyzed Enantioselective Cycloisomerization of Arylalkynes.

The first example of an enantioselective carbocyclization of an alkyne-containing substrate catalyzed by chiral Brønsted acids was achieved. The use of the 2-hydroxynaphthyl substituent on the alkyne as a directing group constituted the key parameter enabling both efficient regioselective protonation of the carbon-carbon triple bond and chiral induction. The key cationic intermediate could be depicted either as a cationic vinylidene ortho-quinone methide or a stabilized vinyl cation. Atropoisomeric phenanthrenes derivatives were produced in high yields and good enantioselectivities under mild, metal-free reaction conditions in the presence of chiral N-triflylphosphoramide catalysts. The carbenic nature of the cationic intermediate was also exploited to describe an example of alkyne/alkane cycloisomerization.

Last-Step Pd-Mediated [11C]CO Labeling of a Moxestrol-Conjugated o-Iodobenzyl Alcohol: From Model Experiments to in Vivo Positron Emission Tomography Studies.

The fast, efficient, and functional group tolerant last-step radiolabeling of bioconjugates is crucial for positron emission tomography (PET) applications. In this context, o-iodobenzyl alcohol based structures were identified as ideal tags for an easy Pd-catalyzed carbonylation after bioconjugation, and a moxestrol-conjugated precursor was chosen as the model compound for the further studies. Despite scale and time constraints, conditions developed with [12C]CO and [13C]CO were easily transferred to the 11C isotope, and the desired radioactive product was obtained in amounts up to 740 MBq with radiochemical purities higher than 99%. Radio-high-performance liquid chromatography analyses of rat blood samples demonstrated excellent in vivo stability within the time of the acquisition. MicroPET-magnetic resonance imaging showed excretion pathways similar to moxestrol, and molecular modeling was also performed to evaluate the potential ability of this conjugate to bind estrogen receptors α. Thus, being both synthetically and biologically suitable, this strategy clears the path to potential novel biotracers for preclinical PET imaging.

Diastereoselective three-component vinylogous Mannich reaction of nitrogen heterocycles, acyl/sulfonyl chlorides, and silyloxyfurans/pyrroles.

A one-step, 3-component vinylogous Mannich reaction of trimethylsilyloxyfuran or N-protected tert-butyldimethylsilyloxypyrrole with a variety of nitrogen-containing heterocycles in the presence of diverse electrophiles is described. The reaction products were generally obtained in high yields and as a single diastereoisomer having the (R*,R*) relative configuration based on crystallographic studies of several derivatives. Several azaheterocycles were successfully used for this reaction, such as isoquinolines, quinoline, phenanthridine, quinazoline, phthalazine, and ß-carboline, and electrophiles included acetyl chloride, methyl chloroformate, methyl chloromalonate, 2-bromobutanoyl chloride, and arylsulfonyl chlorides. The products of the vinylogous Mannich reactions were subjected to further transformations, leading to highly functionalized and stereochemically defined tetracyclic derivatives that are valuable building blocks for the preparation of natural products or medicinal agents.

Ex Situ Generation of 18O2 and 17O2 from Endoperoxides for *O-Labeling and Mechanistic Studies of Oxidations by Dioxygen.

Near-stoichiometric amounts of 18O2 and 17O2 were generated ex situ from endoperoxides in a two-chamber glassware to oxidize various substrates. This strategy gave [*O2]endoperoxides, [*O1]quinones, [*O1]phenols, and [*Ox]artemisin in moderate to good yields and high isotopic enrichments (up to 84%) at affordable costs. Moreover, mass spectrometry and 17O NMR of the [*O]products provided valuable information about the chemical mechanisms involved.

Last-step 18F-fluorination of supported 2-(aryl-di-tert-butylsilyl)-N-methyl-imidazole conjugates for applications in positron emission tomography.

Aiming for potential applications in positron emission tomography, fully automated productions of 18F-labelled bioconjugates were achieved using heterogenous precursors obtained by anchoring imidazole-di-tert-butyl-arylsilanes to a polystyrene resin. The reactions were performed using either "batch" or "flow" procedures, avoiding both the time-consuming azeotropic drying and HPLC purifications usually required.

Ex situ generation of stoichiometric and substoichiometric 12CO and 13CO and its efficient incorporation in palladium catalyzed aminocarbonylations.

A new technique for the ex situ generation of carbon monoxide (CO) and its efficient incorporation in palladium catalyzed carbonylation reactions was achieved using a simple sealed two-chamber system. The ex situ generation of CO was derived by a palladium catalyzed decarbonylation of tertiary acid chlorides using a catalyst originating from Pd(dba)(2) and P(tBu)(3). Preliminary studies using pivaloyl chloride as the CO-precursor provided an alternative approach for the aminocarbonylation of 2-pyridyl tosylate derivatives using only 1.5 equiv of CO. Further design of the acid chloride CO-precursor led to the development of a new solid, stable, and easy to handle source of CO for chemical transformations. The synthesis of this CO-precursor also provided an entry point for the late installment of an isotopically carbon-labeled acid chloride for the subsequent release of gaseous [(13)C]CO. In combination with studies aimed toward application of CO as the limiting reagent, this method provided highly efficient palladium catalyzed aminocarbonylations with CO-incorporations up to 96%. The ex situ generated CO and the two-chamber system were tested in the synthesis of several compounds of pharmaceutical interest and all of them were labeled as their [(13)C]carbonyl counterparts in good to excellent yields based on limiting CO. Finally, palladium catalyzed decarbonylation at room temperature also allowed for a successful double carbonylation. This new protocol provides a facile and clean source of gaseous CO, which is safely handled and stored. Furthermore, since the CO is generated ex situ, excellent functional group tolerance is secured in the carbonylation chamber. Finally, CO is only generated and released in minute amounts, hence, eliminating the need for specialized equipment such as CO-detectors and equipment for running high pressure reactions.

Synthesis and [*C]CO-labelling of (C,N) gem-dimethylbenzylamine-palladium complexes for potential applications in positron emission tomography.

Various aryl-palladium complexes were synthesised from gem-dimethylbenzylamine derivatives by C-H activation under extremely mild conditions. Interestingly, these highly stable structures reacted with [13C]carbon monoxide to produce the desired labelled lactams in 29% to 51% yields over the C-H activation/carbonylation steps. As representative examples, a non-natural amino acid and an estradiol-based conjugate were prepared and labelled in model experiments with [13C]CO in homogeneous or heterogeneous conditions. Especially, the latter was radiolabelled with [11C]CO using a convenient procedure from the resin-supported palladium complex precursor. Thus, these results strongly suggest that cyclometallated palladium complexes obtained from gem-dimethylbenzylamine moieties are promising precursors for the practical synthesis of new [11C]tracers for Positron Emission Tomography.

Bioconjugated arylpalladium complexes on solid supports for a convenient last-step synthesis of 11C-labelled tracers for positron emission tomography.

Arylpalladium complexes prepared from o-iodobenzylalcohol-biomolecule conjugates and triphenylphosphine linked on polystyrene beads provided convenient supported and stable precursors. These heterogeneous substrates could react smoothly with [11C]CO, affording the corresponding 11C-labelled bioconjugates with isolated radiochemical yields ranging from 4% to 71%, and excellent radiochemical purities from 86% to >98% after a simple filtration. Thus, this method opens up a new pathway for an easier automation of Pd-catalysed syntheses of PET tracers.

Mechanistic and asymmetric investigations of the Au-catalysed cross-coupling between aryldiazonium salts and arylboronic acids using (P,N) gold complexes.

In order to explore the different mechanisms possibly occurring in the Au-catalysed cross-coupling of ArN2BF4 and ArB(OH)2 in the presence of CsF, various stoichiometric experiments were performed on gold complexes with (P,N) ligands. Employing 2-pyridylphenyl-diphenylphosphine allowed us to suggest three different mechanistic pathways, starting either with a transmetallation step, via two consecutive single electron transfers, or by implying a transmetallation between Au(i) and Au(iii) species. Moreover, when using commercially available chiral (P,N) ligands, the asymmetric formation of atropoisomeric biaryls from suitable aryldiazonium salts and arylboronic acids could be achieved with e.e. up to 26%.

Highly hindered 2-(aryl-di-tert-butylsilyl)-N-methyl-imidazoles: a new tool for the aqueous 19F- and 18F-fluorination of biomolecule-based structures.

A new class of silicon-based fluoride acceptors with a C-linked heterocycle as the leaving group was synthesized in one step from commercial chemicals, and linked to biomolecules. The resulting conjugates were efficiently 19F-fluorinated in aqueous mixtures, and switching to 18F-labelling provided nucleoside- and peptide-based bioconjugates with excellent molar activities suitable for biological applications.

Gold-catalysed cross-coupling between aryldiazonium salts and arylboronic acids: probing the usefulness of photoredox conditions.

The synthesis of biaryl compounds from aryldiazonium salts and arylboronic acids was achieved using PPh3AuCl as catalyst, CsF as base and acetonitrile as solvent. Combined to photosensitizers, irradiation by blue LEDs allowed accelerating the reaction and expanding its scope. Various functional groups were compatible including bromoaryls, iodoaryls, aldehydes and alcohols. A 2-iodobenzyl alcohol moiety was smoothly introduced by this method, enabling its consecutive isotopic labelling by a Pd-catalysed alkoxycarbonylation.

Precise localization of metal nanoparticles in dendrimer nanosnakes or inner periphery and consequences in catalysis.

Understanding the relationship between the location of nanoparticles (NPs) in an organic matrix and their catalytic performances is essential for catalyst design. Here we show that catalytic activities of Au, Ag and CuNPs stabilized by dendrimers using coordination to intradendritic triazoles, galvanic replacement or stabilization outside dendrimers strongly depends on their location. AgNPs are found at the inner click dendrimer periphery, whereas CuNPs and AuNPs are encapsulated in click dendrimer nanosnakes. AuNPs and AgNPs formed by galvanic replacement are larger than precursors and only partly encapsulated. AuNPs are all the better 4-nitrophenol reduction catalysts as they are less sterically inhibited by the dendrimer interior, whereas on the contrary CuNPs are all the better alkyne azide cycloaddition catalysts as they are better protected from aerobic oxidation inside dendrimers. This work highlights the role of the location in macromolecules on the catalytic efficiency of metal nanoparticles and rationalizes optimization in catalyst engineering.

General last-step labeling of biomolecule-based substrates by [12C], [13C], and [11C] carbon monoxide.

Alkaloid-, steroid-, biotin-, carbohydrate-, nucleoside-, and peptide-based bioconjugates are easily labeled with CO by a last-step palladium-catalyzed carbonylation. The choice of the [(12)C], [(13)C], or [(11)C] isotope opens the way to a new class of potential tracers or ligands easily available for various applications.

GABA(A) receptor subtype-selectivity of novel bicuculline derivatives.

GABA(A) receptors are the major inhibitory neurotransmitter receptors in the central nervous system and are targets of clinically important drugs modulating GABA induced ion flux by interacting with distinct allosteric binding sites. ROD 185 is a previously investigated structural analogue of the GABA site antagonist bicuculline, and a positive allosteric modulator acting via the benzodiazepine binding site. Here, we investigated 13 newly synthesized structural analogues of ROD 185 for their interaction with rat GABA(A) receptors. Using [(3)H]flunitrazepam binding assays, we identified four compounds exhibiting a higher affinity for the benzodiazepine binding site than ROD 185. Two electrode voltage clamp electrophysiology at recombinant GABA(A) receptors indicated that most of these compounds positively modulated GABA-induced currents at these receptors. Additionally, these experiments revealed that this compound class not only interacts with the benzodiazepine binding site at αßγ receptors but also with a novel, so far unidentified binding site present in αß receptors. Compounds with a high affinity for the benzodiazepine binding site stimulated GABA-induced currents stronger at αßγ than at αß receptors and preferred α3ß3γ2 receptors. Compounds showing equal or smaller effects at αßγ compared to αß receptors differentially interacted with various αß or αßγ receptor subtypes. Surprisingly, five of these compounds interacting with αß receptors showed a strong stimulation at α6ß3γ2 receptors. The absence of any direct effects at GABA(A) receptors, as well as their potential selectivity for receptor subtypes not being addressed by benzodiazepines, make this compound class to a starting point for the development of drugs with a possible clinical importance.

Carbonylative Heck reactions using CO generated ex situ in a two-chamber system.

A carbonylative Heck reaction of aryl iodides and styrene derivatives employing a two-chamber system using a stable, crystalline, and nontransition metal based carbon monoxide source is reported. By applying near-stoichiometric amounts of the carbon monoxide precursor, an effective exploitation of the hazardous CO gas is obtained affording chalcone derivatives in good yields. Application to isotope labeling, incorporating (13)CO, was further established.

Highly diastereoselective three-component vinylogous Mannich reaction between isoquinolines, acyl/sulfonyl chlorides, and silyloxyfurans.

Reaction of an isoquinoline, a silyloxyfuran, and an acyl or sulfonyl chloride provides easy access to a wide variety of isoquinolinobutyrolactones with excellent yields and diastereoselectivites (R*,R* isomer), even in the case of formation of quaternary centers (i.e., R(3) or R(4) = Me). Moreover, the use of a chiral auxiliary allowed formation of a single stereoisomer in 96% yield. This represents the first examples of asymmetric vinylogous Mannich reactions on isoquinolinium salts.