Miyaura borylation/Suzuki-Miyaura coupling (MBSC) sequence of 4-bromo-2,4'-bithiazoles with halides: straightforward access to a heterocylic cluster of d-series of thiopeptide GE2270.

Herein, palladium-catalyzed Miyaura borylation of 4-bromo-2,4'-bithiazoles followed by Suzuki-Miyaura cross-coupling reaction (named the MBSC process) with (hetero)aryl- and alkenyl halides is reported. This methodology offers rapid access to various 2',4-disubstituted 2,4'-bithiazole features including naturally-occurring 4-alkenylated and 4-pyridinylated 2,4'-bithiazoles. To prove its application, a concise approach for the synthesis of a heterocyclic cluster of the thiopeptide d-series antibiotic GE2270 is reported through a late-stage MBSC strategy.

Synthesis of the heterocyclic core of the D-series GE2270.

A straightforward enantiomerically pure synthesis of the heterocyclic core of the D-series GE2270 is reported. The synthetic strategy combines the Hantzsch thiazole's building condensation with a cross-coupling reaction including direct C-H hetarylation to build and connect step-by-step thiazolyl moieties to the 5-bromopicolinate as readily available starting material.

Dihydroquinoline Carbamate Derivatives as "Bio-oxidizable" Prodrugs for Brain Delivery of Acetylcholinesterase Inhibitors: [¹¹C] Radiosynthesis and Biological Evaluation.

With the aim of improving the efficiency of marketed acetylcholinesterase (AChE) inhibitors in the symptomatic treatment of Alzheimer's disease, plagued by adverse effects arising from peripheral cholinergic activation, this work reports a biological evaluation of new central AChE inhibitors based on an original "bio-oxidizable" prodrug strategy. After peripheral injection of the prodrug 1a [IC50 > 1 mM (hAChE)] in mice, monitoring markers of central and peripheral cholinergic activation provided in vivo proof-of-concept for brain delivery of the drug 2a [IC50 = 20 nM (hAChE)] through central redox activation of 1a. Interestingly, peripheral cholinergic activation has been shown to be limited in time, likely due to the presence of a permanent positive charge in 2a promoting rapid elimination of the AChE inhibitor from the circulation of mice. To support these assumptions, the radiosynthesis with carbon-11 of prodrug 1a was developed for additional ex vivo studies in rats. Whole-body biodistribution of radioactivity revealed high accumulation in excretory organs along with moderate but rapid brain uptake. Radio-HPLC analyses of brain samples confirm rapid CNS penetration of [(11)C]1a, while identification of [(11)C]2a and [(11)C]3a both accounts for central redox activation of 1a and pseudoirreversible inhibition of AChE, respectively. Finally, Caco-2 permeability assays predicted metabolite 3a as a substrate for efflux transporters (P-gp inter alia), suggesting that metabolite 3a might possibly be actively transported out of the brain. Overall, a large body of evidence from in vivo and ex vivo studies on small animals has been collected to validate this "bio-oxidizable" prodrug approach, emerging as a very promising strategy in the rational design of selective central AChE inhibitors.

Mechanism selection for regiocontrol in base-assisted, palladium-catalysed direct C-H coupling with halides: first approach for oxazole- and thiazole-4-carboxylates.

Both base-assisted non-concerted metallation-deprotonation (nCMD) and concerted metallation-deprotonation (CMD) have been identified as two potent operating mechanisms in palladium-catalysed direct C-H coupling of oxazole and thiazole-4-carboxylate esters with halides through base- and solvent-effect experiments. Novel C2- and C5-selective CMD direct arylation procedures in oxazole- and thiazole-4-carboxylate series were then designed by controlling the balance between electronic and steric factors. Notably, charge interactions between the palladium catalyst and substrate were identified as a parameter for controlling selectivity and reducing the impact of steric factors in the CMD reaction.

DPO and POPOP carboxylate-analog sensors by sequential palladium-catalysed direct arylation of oxazole-4-carboxylates.

Sequential palladium-catalysed direct (het)arylation of oxazole-4-carboxylates is achieved to give rapid access to DPO and POPOP (di)carboxylate-analogs. Three novel DPO- and POPOP-type sensors with unusual Stokes shifts and high quantum yields are discovered.

Evidence of benzilic rearrangement during the electrochemical oxidation of D-glucose to D-glucaric acid.

During the course of the 2,2,6,6-tetramethyl-1-piperidinyloxy free radical-catalyzed electrochemical oxidation of D-glucose to D-glucaric acid a new side-product was observed. This compound was isolated and identified as a tricarboxylic acid of unique structure, which was named maribersonic acid. Its structure was proven by different experiments coupled with several analytical methods, and its appearance during the electrochemical oxidation of D-glucose was rationalized through a thorough study.

Recent advances in direct C-H arylation: Methodology, selectivity and mechanism in oxazole series.

Catalytic direct (hetero)arylation of (hetero)arenes is an attractive alternative to traditional Kumada, Stille, Negishi and Suzuki-Miyaura cross-coupling reactions, notably as it avoids the prior preparation and isolation of (hetero)arylmetals. Developments of this methodology in the oxazole series are reviewed in this article. Methodologies, selectivity, mechanism and future aspects are presented.

Ortho-directed functionalization of arenes using magnesate bases.

Ortho-directed functionalisation of arenes using lithium alkylmagnesate bases were achieved, demonstrating the potential use of arylmagnesates as suitable arylanions, without a further transmetallation step, for challenging functionalizations such as fluorination, hydroxylation, arylation, vinylation and alkylation through epoxide ring-opening.

Design of silicon-based misonidazole analogues and (18)F-radiolabelling.

INTRODUCTION: Development of new (18)F-labeled tracers for positron emission tomography (PET) imaging is increasingly important. Herein, we described the synthesis of silicon analogues of [(18)F]fluoromisonidazole in order to develop new radiolabelled compounds for the detection of tumour hypoxic domain. Their stabilities and their in vivo biodistribution were evaluated. METHODS: (18)F-labeled silicon-based misonidazole analogues were synthesized by alkylating 2-nitroimidazole with alkyloxy-(3-chloropropyl)dialkyl or diarylsilane. These intermediates were labeled with [(18)F]F(-) with a mixture of K(18)F and Kryptofix (K222) in acetonitrile as standard condition. PET imaging was performed using a dedicated small animal PET scanner. RESULTS: (18)F-labeled silicon-based misonidazole analogues were easily synthesized in three steps. The hydrolytic and radiolytic stability of these new fluorosilanes depend on the steric hindrance at the silicon center. Indeed, partial uptake of dimethylfluorosilane [(18)F]2a(1-(3-(Fluorodimethylsilyl)propyl)-2-nitro-1H-imidazole) in tumor hypoxic area was observed but defluorination also appeared. Moreover, PET studies indicated that, owing to its high lipophilicity, the most stable dinaphtylfluorosilane [(18)F]2d is retained mainly by the lungs. CONCLUSION: We have described an efficient and versatile approach for the synthesis of (18)F-labeled, silicon-based misonidazole analogues. PET imaging of one of these compounds revealed that hypoxia could be detected. Controlling the biodistribution of (18)F-labeled silicon-based misonidazole analogues will require additional studies.

TBD-organocatalysed synthesis of pyrazolines.

It was found that TBD, a cheap and commercially available guanidine, easily catalysed the synthesis of biologically important 3,5-diarylpyrazolines from chalcones and acylhydrazines via a selective secondary amine alkylation.

Synthesis, radiosynthesis and biological evaluation of 1,4-dihydroquinoline derivatives as new carriers for specific brain delivery.

In spite of numerous reports dealing with the use of 1,4-dihydropyridines as carriers to deliver biological active compounds to the brain, this chemical delivery system (CDS) suffers from poor stability of the 1,4-dihydropyridine derivatives towards oxidation and hydration reactions seriously limiting further investigations in vivo. In an attempt to overcome these limitations, we report herein the first biological evaluation of more stable annellated NADH models in the quinoline series as relevant neuroactive drug-carrier candidates. The radiolabeled 1,4-dihydroquinoline [(11)C] was prepared to be subsequently peripherally injected in rats. The injected animals were sacrificed and brains were collected. The radioactivity measured in rat brain indicated a rapid penetration of the carrier [(11)C] into the CNS. HPLC analysis of brain homogenates showed that oxidation of [(11)C] into the corresponding quinolinium salt [(11)C] was completed in less than 5 min. An in vivo evaluation in mice is also reported to illustrate the potential of such 1,4-dihydroquinoline derivatives to transport a neuroactive drug in the CNS. For this purpose, gamma-aminobutyric acid (GABA), well known to poorly cross the brain blood barrier (BBB) was connected to this 1,4-dihydroquinoline-type carrier. After i.p. injection of 1,4-dihydroquinoline-GABA derivative in mice, a significant alteration of locomotor activity (LMA) was observed presumably resulting from an enhancement of central GABAergic activity. These encouraging results give strong evidence for the capacity of carrier-GABA derivative to cross the BBB and exert a pharmacological effect on the CNS. This study paves the way for further progress in designing new redox chemical delivery systems.

Highly efficient borylation Suzuki coupling process for 4-bromo-2-ketothiazoles: straightforward access to micrococcinate and saramycetate esters.

The first palladium-catalyzed borylation of 4-bromo-2-ketothiazoles followed by a Suzuki cross-coupling reaction with haloheteroaromatics using Buchwald's Cy-JohnPhos and XPhos ligands is reported. The methodology has allowed the fast preparation of highly valuable 4-pyridinyl- and 4-thiazolyl-2-ketothiazoles as common subunits of thiopeptide antibiotics. As direct applications, novel concise syntheses of a sulfomycinamate thio-analogue as well as micrococcinate and saramycetate esters are described.

Rational design of central selective acetylcholinesterase inhibitors by means of a "bio-oxidisable prodrug" strategy.

This work deals with the design of a bio-oxidisable prodrug strategy for the development of new central selective acetylcholinesterase inhibitors. This prodrug approach is expected to reduce peripheral anticholinesterase activity responsible for various side effects observed with presently marketed AChE inhibitors. The design of these new AChE inhibitors in quinoline series is roughly based on cyclic analogues of rivastigmine. The key activation step of the prodrug involves an oxidation of an N-alkyl-1,4-dihydroquinoline 1 to the corresponding quinolinium salt 2 unmasking the positive charge required for binding to the catalytic anionic site of the enzyme. The synthesis of a set of 1,4-dihydroquinolines 1 and their corresponding quinolinium salts 2 is presented. An in vitro biological evaluation revealed that while all reduced forms 1 were unable to exhibit any anticholinesterase activity (IC50 > 10(6) nM), most of the quinolinium salts 2 displayed high AChE inhibitory activity (IC50 ranging from 6 microM to 7 nM). These preliminary in vitro assays validate the use of these cyclic analogues of rivastigmine in quinoline series as appealing chemical tools for further in vivo development of this bio-oxidisable prodrug approach.

Product-catalyzed addition of alkyl nitriles to unactivated imines promoted by sodium aryloxide/ethyl(trimethylsilyl)acetate (ETSA) combination.

The first transition-metal-free addition of alkyl nitriles to unactivated imines was developed using a catalytic combination of 4-MeOC(6)H(4)ONa and TMSCH(2)CO(2)Et to promote the reaction. The corresponding beta-amino nitriles are obtained in good to almost quantitative isolated yields under mild conditions. A mechanism involving an autocatalytic pathway is proposed on the basis of experimental observations.

Direct palladium-catalyzed alkenylation, benzylation and alkylation of ethyl oxazole-4-carboxylate with alkenyl-, benzyl- and alkyl halides.

The ethyl oxazole-4-carboxylate was directly and regioselectively alkenylated, benzylated and alkylated with alkenyl-, benzyl-, allyl- and alkyl halides in the presence of catalytic amounts of palladium acetate with caesium carbonate using Buchwald's JohnPhos ligand.

Aminoacid-derived mercaptoimidazoles.

Starting from suitably protected amino acids, mercaptoimidazoles were synthesized either from the acid or including the amine nitrogen itself. A preliminary optimisation study led to efficient conditions for the obtention of the imidazole ring. These conditions are compatible with the presence of amino acid or dipeptide scaffolds.

Palladium-catalyzed direct (hetero)arylation of ethyl oxazole-4-carboxylate: an efficient access to (hetero)aryloxazoles.

A straightforward route toward 2-(hetero)arylated and 2,5-di(hetero)arylated oxazoles through regiocontrolled palladium-catalyzed direct (hetero)arylation of ethyl oxazole-4-carboxylate with iodo-, bromo-, and chloro(hetero)aromatics followed by a two-step hydrolysis/decarboxylation sequence was described. The method was applied here to a neat synthesis of two 2,5-di(hetero)aryloxazole natural products, balsoxin and texaline.

Direct C-2 arylation of alkyl 4-thiazolecarboxylates: new insights in synthesis of heterocyclic core of thiopeptide antibiotics.

The Pd(0)-catalyzed regioselective C-2 (hetero)arylation of tert-butyl 4-thiazolecarboxylate with a broad (hetero)aryl halide is reported, including the direct coupling of pyridinyl halides. The process has allowed the preparation of valuable 2-pyridynyl-4-thiazolecarboxylates which are components of the complex heterocyclic core of thiopeptides antibiotics. As a first application, a synthesis of a tert-butyl sulfomycinamate thio-analogue from tert-butyl 4-thiazolecarboxylate is here described through a three-step direct pyridinylation, halogenation, and Stille cross-coupling sequence.

A concise synthesis of lentiginosine derivatives using a pyridinium formation via the Mitsunobu reaction.

A four-step synthesis of (-)-lentiginosine and its epimers is described starting from 2-bromopyridine. The key step consisted of a quaternarization of a fully unprotected pyridinium-polyol unit using Mitsunobu methodology. Subsequent PtO(2)-catalyzed diastereoselective hydrogenation of the pyridinium ring proceeded smoothly and led to the expected dihydroxyindolizidines with excellent yields. This stereochemically flexible strategy has been illustrated by the concise total synthesis of non-natural products derivatives such as (-)-lentiginosine and its stereoisomers in high yields.