Corinne Fruit

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.

New family of peptidomimetics based on the imidazole motif.

Starting from amino acid esters, new peptidomimetics based on the imidazole scaffold were prepared. An efficient and rapid sequence consisting of two subsequent one-pot procedures was developed and applied to various aminoacids. As they provide more substitution patterns, these heterocyclic mimics are promising tools for structural and biological studies.

Ligand-Free Pd-Catalyzed and Copper-Assisted C–H Arylation of Quinazolin-4-ones with Aryl Iodides under Microwave Heating

A microwave-assisted method for the palladium-catalyzed direct arylation of quinazolin-4-one has been developed under copper-assistance. This method is applicable to a wide range of aryl iodides and substituted (2H)-quinazolin-4-ones. This protocol provides a simple and efficient way to synthesize biologically relevant 2-arylquinazolin-4-one backbones.

Design of silicon-based misonidazole analogues and 18F-radiolabelling

INTRODUCTIONnDevelopment 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.nnnMETHODSn(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.nnnRESULTSn(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.nnnCONCLUSIONnWe 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.

Pd-Catalyzed Decarboxylative Cross-Coupling of 2-Carboxyazine N-Oxides with Various (Hetero)aryl Halides

Decarboxylative cross-coupling reactions of substituted 2-carboxyazine N-oxides, with a variety of (hetero)aryl halides, by bimetallic Pd(0)/Cu(I) and Pd(0)/Ag(I) catalysis are reported. Two possible pathways, a conventional bimetallic-catalyzed decarboxylative arylation, as well as a protodecarboxylative/direct C-H arylation sequence have been considered. These methods provide the first general decarboxylative arylation methodology for the 2-carboxyazine series.

Regioselective Decarboxylative Cross-Coupling of Carboxy Isoquinoline N‑Oxides

A straightforward method for direct decarboxylative arylation of 1- and 3-carboxy isoquinaldic acid N-oxides with aryl iodides is reported. The reaction proceeded selectively at the carboxy function site to exclusively give the corresponding C-1 or C-3 arylated product. This methodology tolerates various aryl iodides substituted by electronically different groups. Combined with subsequent Reissert-Henze chlorination and SNAr amination, the decarboxylative arylation provides an efficient access to 1,3-functionalized isoquinoline-based antitumor agent.

Orthogonal Palladium-Catalyzed Direct C−H Bond Arylation of Heteroaromatics with Aryl Halides

Transition metal‐catalyzed direct C−H bond functionalization of heterocycles with halo(het)arenes has received considerable attention as synthetic alternative to standard cross‐coupling reactions regarding step‐ and atom‐economy in the preparation of heteroarylmetals intermediates and better chemo‐selectivity towards standard organic functions such as aldehyde, ketone, ester, cyanide, and amide. An additional major and poorly highlighted interest of such methodology is its unparalleled ability to open the chemical space of functionalization of heterocycles towards challenging unprecedented sites. This Review gives an overview of the advances in challenging orthogonal direct C−H arylation of heterocycles related to the wide variety of catalytic C−H bond metalation processes, most of them evaluated by DFT calculations.

Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) inhibitors: a survey of recent patent literature

ABSTRACT Introduction: Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) is a eukaryotic serine-threonine protein kinase belonging to the CMGC group. DYRK1A hyperactivity appears to contribute to the development of a number of human malignancies and to cognitive deficits observed in Down syndrome and Alzheimer’s disease. As a result, the DYRK1A kinase represents an attractive target for the synthesis and optimization of pharmacological inhibitors of potential therapeutic interest. Like most tyrosine kinase inhibitors developed up to the market, DYRK1A inhibitors are essentially acting by competing with ATP for binding at the catalytic site of the kinase. Areas covered: This paper reviews patent activity associated with the discovery of synthetic novel heterocyclic molecules inhibiting the catalytic activity of DYRK1A. Expert opinion: Despite the important role of DYRK1A in biological processes and the growing interest in the design of new therapeutic drugs, there are only few patented synthetic DYRK1A inhibitors and most of them were and are still developed by academic research groups, sometimes with industrial partners.

Pd-Catalyzed and Copper Assisted Regioselective Sequential C2 and C7 Arylation of Thiazolo[5,4-f]quinazolin-9(8H)-one with Aryl Halides.

A selective functionalization of thiazolo[5,4-f]quinazolin-9(8H)-one has been developed through sequential activation of C-H bonds to furnish diarylated compounds. This strategy allows the regioselective C2 and C7 arylation by a judicious choice of coupling partners and bases, requiring no additional ligands or directing groups. Differently substituted N(8)-benzylated-2,7-diaryl-thiazoloquinazolin-9(8H)-ones were thereby obtained in a facile manner. A one-pot procedure was also performed. These protocols provide a synthetically useful route for late-stage functionalization of this highly valuable scaffold, required in drug discovery.

Synthesis of Thiazolo[5,4-f]quinazolin-9(8H)-ones as Multi-Target Directed Ligands of Ser/Thr Kinases.

A library of thirty novel thiazolo[5,4-f]quinazolin-9(8H)-one derivatives belonging to four series designated as 12, 13, 14 and 15 was efficiently prepared, helped by microwave-assisted technology when required. The efficient multistep synthesis of methyl 6-amino-2-cyano- benzo[d]thiazole-7-carboxylate (1) has been reinvestigated and performed on a multigram scale. The inhibitory potency of the final products against five kinases involved in Alzheimer’s disease was evaluated. This study demonstrates that some molecules of the 12 and 13 series described in this paper are particularly promising for the development of new multi-target inhibitors of kinases.