Didier Dubreuil

Complexation of lanthanides(III), americium(III), and uranium(VI) with bitopic N,O ligands: an experimental and theoretical study.

New functionalized terpyridine-diamide ligands were recently developed for the group actinide separation by solvent extraction. In order to acquire a better understanding of their coordination mode in solution, protonation and complexation of lanthanides(III), americium(III), and uranium(VI) with these bitopic N,O-bearing ligands were studied in homogeneous methanol/water conditions by experimental and theoretical approaches. UV-visible spectrophotometry was used to determine the protonation and stability constants of te-tpyda and dedp-tpyda. The conformations of free and protonated forms of te-tpyda were investigated using NMR and theoretical calculations. The introduction of amide functional groups on the terpyridine moiety improved the extracting properties of these new ligands by lowering their basicity and enhancing the stability of the corresponding 1:1 complexes with lanthanides(III). Coordination of these ligands was studied by density functional theory and molecular dynamics calculations, especially to evaluate potential participation of hard oxygen and soft nitrogen atoms in actinide coordination and to correlate with their affinity and selectivity. Two predominant inner-sphere coordination modes were found from the calculations: one mode where the cation is coordinated by the nitrogen atoms of the cavity and by the amide oxygen atoms and the other mode where the cation is only coordinated by the two amide oxygen atoms and by solvent molecules. Further simulations and analysis of UV-visible spectra using both coordination modes indicate that inner-sphere coordination with direct complexation of the three nitrogen and two oxygen atoms to the cation leads to the most likely species in a methanol/water solution.

Focus on the Controversial Activation of Human iNKT Cells by 4-Deoxy Analogue of KRN7000

4-Deoxy-alpha-GalCer analogues are considered weaker agonists than KRN7000 for the stimulation of human iNKT cells, but this remains strongly debated. In this work, we described a strategy toward 4-deoxy-alpha-GalCers with, as a key step, a metathesis reaction allowing sphingosine modifications from a single ethylenic alpha-galactoside precursor. The 4-deoxy-KRN7000 derivative 2, described here, induced potent cytokinic responses, comparable to those of KRN7000, both from human iNKT cells in vitro and from their murine counterpart in vivo.

Stereoselective synthesis of 6-deoxy and 3,6-dideoxy-D-myo-inositol precursors of deoxy-myo-inositol phosphate analogues from D-galactose

The synthesis of chiral protected D-6-deoxy-myo-inositol derivatives from D-galactose is described. Ferrier rearrangement of hexenogalactopyranosides has been employed to produce the corresponding 6-deoxy-cyclohexanone polyols. The stereoselectivity of the carbocyclic transformation was discussed on the basis of the experimental data and a mechanism has been proposed. From deoxy-inososes, the access to a variety of 6-deoxy and 3,6-dideoxy-myo-inositol was performed to prepare suitable monool, diol and triol precursors for the synthesis of D-deoxy-myo-inositol phosphate analogues.

Synthesis and reactivity of N-selenoacylamidines precursors of selenoheterocycles

Abstract A new synthesis and the reactivity of stable selenaazadienes are discussed. Their dienic, electrophilic and nucleophilic character are used to prepare five and six membered selenoheterocycles. The easy access to selenazine, selenazinone, selenopyran, selenazoline, selenazole and selenophene heterocycles from N-selenoacylamidines is described. An interpretation of the reactivity of the selenaazadiene systems, experimentaly compared to their thia analogues, is based on their physico-chemical parameters and correlated to the theoretical calculations of their frontier molecular orbital energy levels.

STEREOSELECTIVE SYNTHESIS OF INOSITOL MONO, BIS AND TRISPHOSPHATE ANALOGUES FROM 6-DEOXY-D-INOSITOL PRECURSORS

Abstract The synthesis of opticaly pure deoxy- myo -inositol mono, bis and trisphosphate analogues is described from 4- O -benzyl-2,3-di- O -cyclohexylidene-6-deoxy- myo -inositol and corresponding 1,5 epimer chiro -inositol. These precursors, which derive from galactose, are used to accede to a variety of cyclitol intermediates employing protection/deprotection sequence. The phosphorylation procedure was performed to produce free and original substituted phosphate derivatives aimed to be incorporated through the lipidic cell membrane for in vivo evaluation.

Solvent-free benzylation of polyols by phase-transfer catalysis or supported reagent methods

Abstract Solvent-free techniques were successfully and efficiently applied under mild conditions to the perbenzylation of methyl α- d -glucopyranoside and methyl 6-bromo(and 6-chloro)-6-deoxy-α- d -glucopyranoside, and to the selective monobenzylation of diethyl (R,R)-tartrate. Selective 2-O- or 3-O-benzylation of methyl 4,6-O-benzylidene-α- d -galactopyranoside, requiring CH2Cl2 as solvent, was observed depending on the nature of the ammonium catalyst.

Stereoselective synthesis of myo-inositol-1,3,4,5-tetrakisphosphate analogues from 6-deoxy d-inositol precursors

Abstract The synthesis of 6-deoxy-D-myo-inositol-1,3,4,5-tetrakisphosphates is described. The access to opticaly pure Ins(1,3,4,5)P4 analogues was carried out from deoxy myo inositol precursors derived from d -galactose. Modification of Ins(1,3,4,5)P4 analogues by lipophilic substituents has been investigated in order to produce neutral phosphate derivatives aimed to be incorporated in cell membrane for in vivo evaluation.

Enantioselective synthesis of inositols as intermediates for the preparation of deoxy-inositol phosphates from D-galactose

Abstract Optically pure 6-deoxy-inososes, 6-deoxy-inositols and 6-deoxy-inositol-1,4,5-trisphosphates were synthesized from D-galactose by the carbohydrate-inosose Ferrier rearrangement. 6-Deoxy-inositolphosphates exhibit a tight binding to the Ins-P 3 -receptor making such compounds an interesting tool for studying the intracellular signalling. It is now well established that receptor stimulated hydrolysis of inositol phospholipids is a common mechanism for transmembrane signalling when cells respond to external stimuli such as hormones, neurotransmitters, antigens, light, growth factors and insulin 1 . It was also shown that phosphatidylinositol-4,5-bisphosphate [(Ptd)Ins(4,5)P 2 ] is a major inositol lipid hydrolysed by activated phospholipase C, resulting into the simultaneous generation of two “second messengers”, D- myo -inositol-1,4,5-trisphosphate [Ins(1,4,5)P 3 ] and diacylglycerol (DG) 2 . Ins(1,4,5)P 3 triggers the mobilization of Ca ++ from intracellular stores and DG stimulates protein phosphorylation via the activation of protein kinase C 3,4 . In addition (Ptd)Ins(4,5)P 2 contains a high percentage of arachidonic acid in the sn-2 position, which is released for lipoxygenase and cyclooxygenase pathways. These “second messengers” and their metabolites control and modulate vital physiological processes by their independent, additive and synergestic effects. 5 Therefore, it is conceivable that inhibitors of the key enzymes of the phosphoinositide cascade could be of medicinal interest and could be also useful tools to elucidate the individual role of the inositol metabolites in regulation of cell functions. 6,7 In view of difficulties in the isolation of inositol phosphate metabolites from natural sources and the need for structural analogues, several synthetic studies have been reported 8 . However, these have employed mostly the optically inactive myo inositol as a logical and cheap starting material. The crucial role of the phosphate esters at positions 1, 3, 4, and 5 of the myo inositol nucleus in the “second messengers” Ins(1,4,5)P 3 and Ins(1,3,4,5)P 4 is well established. For analogue synthesis, modifications of the centers C-1, C-3, C-4 and C-5 or alteration of the hydroxyl functions at neighboring carbons (C-2 or C-6), not involved at first glance in cellular processes, seemed justified. With these considerations in mind we have initiated a synthetic program aimed to proxide access to the hitherto unknown partially protected 6-deoxy-cyclitols 8 and 9, appropriate precursors of a variety of chiral deoxy-inositol phosphates 9 . Our approach to the deoxy-inositols 8 and 9 has been envisaged from the chiral deoxy-inososes 6 and 7 which could be obtained by mercury(II) mediated carbohydrate-inosose Ferrier rearrangement 10 from hex-5- ene -pyranoside 5. Olefin 5 was readily prepared in a four steps sequence from methyl-β-D-galactopyranoside 1 in 60% overall yield 11 . Treatment of 1 with 1,1-dimethoxycyclohexane in DMF in presence of sulfuric acid afforded acetal 2 in 90% yield. The latter was selectively brominated with triphenylphosphine-carbontetrabromide, leading to 3 (m.p. 122–123°C). Benzylation of 3 by a phase transfer process (powdered KOH, benzyltriethylammonium chloride, benzyl bromide in CH 2 Cl 2 ) furnished benzyl ether 4 (m.p. 94–95°C,[ α ] rmD 20 + 46). Access to olefin 5 (m.p. 61–62°C, [ α ] rmD 20 − 55) was achieved by two methods. Initially the bromo compound 4 was dehydrobrominated with sodium hydride in DMF (3h, 100°C) giving 5 in 90% yield 12. An alternative route for the

1-Oxo-1H-phenalene-2,3-dicarbonitrile heteroaromatic scaffold: revised structure and mechanistic studies.

Synthesis of the originally proposed 8-oxo-8H-acenaphtho[1,2-b]pyrrol-9-carbonitrile led to a structural revision, and the product has now been identified as unknown compound 1-oxo-1H-phenalene-2,3-dicarbonitrile. The structural assignment was corroborated by detailed NMR studies and unambiguously confirmed by X-ray diffraction. A mechanism is proposed to explain the formation of this original heterocyclic scaffold. In addition, some new chemical transformations involving this compound are presented.

Theoretical Study of the Structures and Hydrogen-Bond Properties of New Alternated Heterocyclic Compounds

The conformational preferences of a new bis-pyrrole derivative and its bis-pyridazine precursor have been investigated through quantum chemistry calculations (HF, DFT(MPWB1K), LMP2) and observations in the solid state. The global energetic minima are planar for both structures, with the conformational preferences being explained by pi-electronic conjugation between the aromatic systems and the occurrence of intramolecular hydrogen bonds (HB). For the bis-pyridazine derivative, the all-anti preferred conformation results from CH...Nsp(2) HB whereas the all-syn conformation of the bis-pyrrole is partly due to NH...Nsp(2) HB. For both systems, the validity of the theoretical conformational features is confirmed through the excellent agreement with the experimental data available. Calculations of electrostatic potential computed on the molecular surface of the various structures and their building blocks allow the variations to be rationalized in terms of molecular structure and are used to analyze the HB donor and acceptor sites of the compounds. The HB interaction sites predicted from the quantum chemical calculations are confirmed through the HB interactions observed in relevant crystal structures.