Origins of the diastereoselectivity in hydrogen bonding directed Diels-Alder reactions of chiral dienes with achiral dienophiles: a computational study

In this study, the origins of diastereoselectivity in the hydrogen bonding assisted Diels-Alder reactions of chiral dienes with achiral dienophiles have been investigated with density functional methods. The distortion/interaction model has been applied to shed light on the origins of selectivity. C9-Substituted chiral anthracene templates (R = (CH(3))(OCH(3))(H), R = (CH(3))(OH)(H), R = (CH(3))(CH(2)CH(3))(H) and R = (-CH(2)-C(CH(3))(OCH(3))(H)) are used to rationalize the role of a stereogenic center and H-bonding on the product distribution ratio. Even though hydrogen bonding increases the reactivity of the diene, the stereoselectivity is reduced because of the hydrogen bonding capacity of both diastereomeric transition states. The interaction energies of the studied anthracene templates with N-methyl maleimide at the transition state correlate linearly with an increase in reactivity. The selectivity is determined by both favorable distortion and interaction energies. The π-facial selectivity induced by the presence of a chiral auxiliary in 1-substituted 1,3-pentadienes (R1 = (CH(3))(OCH(3))(H) and R1 = (CH(3))(OH)(H)) has also been modeled in order to rationalize the role of the stereogenic center and H-bonding on the stereoselectivity of an aliphatic diene. In both parts, the product distribution ratios calculated from Boltzmann distributions based on Gibbs free energies are in reasonable agreement with the experimental results. Finally the role of OH-substituted five-membered pyrrolidine on C9 of anthracene is investigated since the successful usage of the conformationally rigid pyrrolidines in asymmetric synthesis is well known. Overall, both in the acyclic system and in anthracene, the facilitation due to H-bonding is reflected in the interaction energies: the higher the difference in interaction energies in the transition structures of the two diastereomers, the more selective the H-bonding assisted Diels-Alder reaction is.     

Elaboration of vinblastine hybrids using a reactive in situ generated N-carboxyanhydride

Hybrids of vinblastine and phomopsin, designed by a molecular modelling study, were elaborated in order to target tubulin. The key step of the synthesis (fragmentation and insertion of vindoline) was mediated by an internal N-carboxyanhydride (or O-acylcarbamate). This reaction was diastereospecific and addition of silver salts could reverse the diastereoselectivity. Even if the synthesized compounds are inactive, this synthesis represents an original example of a C-N fragmentation mediated by a N-carboxyanhydride.     

Synthesis of novel chromene scaffolds for adenosine receptors

A one-pot procedure was developed for the synthesis of novel 3-[amino(methoxy)methylene]-2-oxo-3,4-dihydro-2H-chromen-4-yl)-3-cyanoacetamides and chromeno[3,4-c]pyridine-1-carbonitriles from the reaction of 2-oxo-2H-chromene-3-carbonitriles and cyanoacetamides. These chromene derivatives were identified as new scaffolds for adenosine receptors and the hits 3a, 3c, 5a, and 5b were found.     

New access to (η(5)-cyclohexadienyl)Mn(CO)3 and cationic (η(6)-arene)Mn(CO)3 complexes by Suzuki-Miyaura reaction

First Suzuki-Miyaura coupling reactions applied to (η(5)-chloro-cyclohexadienyl)Mn(CO)3 complexes are described and lead to the syntheses of (η(5)-aryl-cyclohexadienyl)Mn(CO)3 and of cationic (η(6)-arene)Mn(CO)3 complexes after rearomatization. The structures of two of the new complexes have been investigated by X-ray diffraction study.     

New chiral cyclooctatriene-based polycyclic architectures

The synthesis and properties of new chiral polycyclic architectures that display both helicity and a saddle-type shape are described. The enantiomers have been separated, and their absolute configuration was determined by VCD and ECD. The unprecedented molecular architecture is based on a cyclooctatriene core surrounded by an association of benzo[c]fluorene and ortho-phenylene units.     

Highly efficient one-pot access to functionalized arylboronic acids via noncryogenic bromine/magnesium exchanges

A general and convenient protocol for the electrophilic borylation of aryl Grignard reagents prepared from arylbromides by direct insertion of magnesium in the presence of LiCl or by Mg/Br exchange with (i)PrMgCl·LiCl has been developed. Various aryl boronic acids were synthesized in a straightforward manner in excellent yields at 0 °C.     

Synthesis of the tetracyclic core of daphnilactone B-type and yuzurimine-type alkaloids

The core of daphnilactone B-type and yuzurimine-type alkaloids was synthesized in only 16 steps from a known β-allyl-γ-butyrolactone. The key sequence of Vilsmeier-Haack cyclization and intramolecular azomethine ylide cycloaddition allowed the construction of, in a single step, three of the five rings common to all alkaloids found in both of these classes with perfect chemocontrol.     

Stereoselective synthesis of both stereoisomers of β-fluorostyrene derivatives from a common intermediate

The stereoselective synthesis of both cis- and trans-β-fluorostyrene derivatives from a common intermediate, (Z)-1-aryl-2-fluoro-1-(trimethylsilyl)ethenes, is described. The trans isomers are obtained by a stereospecific replacement of the silyl group in the presence of water and a fluoride source, whereas the preparation of the cis isomers is achieved by a bromination/desilicobromination sequence followed by reduction of the newly created C-Br bond. A stereoselective transformation of both stereoisomers of β-fluorostyrene is also presented.     

L-arginine binding to human inducible nitric oxide synthase: an antisymmetric funnel route toward isoform-specific inhibitors?

Nitric oxide (NO) is an important signaling molecule produced by a family of enzymes called nitric oxide synthases (NOS). Because NO is involved in various pathological conditions, the development of potent and isoform-selective NOS inhibitors is an important challenge. In the present study, the dimer of oxygenase domain of human iNOS (iNOSoxy) complexed to its natural substrate L-arginine (L-Arg) and both heme and tetrahydro-L-biopterin (BH4) cofactors was studied through multiple molecular dynamics simulations. Starting from the X-ray structure available for that complex (PDB: 1NSI ), a 16 ns equilibration trajectory was first obtained. Twelve dynamics of slow extraction of L-Arg out from the iNOSoxy active site were then performed. The steered molecular dynamics (SMD) approach was used starting from three different points of the reference trajectory for a total simulation time of 35 ns. A probable unbinding/binding pathway of L-Arg was characterized. It was suggested that a driving force directed the substrate toward the heme pocket. Key intermediate steps/residues along the access route to the active site were identified along this "funnel shape" pathway and compared to existing data. A quasi-normal mode analysis performed on the SMD data suggested that large collective motions of the protein may be involved in L-Arg binding and that opening the route to the active site in one monomer promoted an inverse, closing motion in the second monomer. Finally, our findings might help to rationalize the design of human iNOS isoform competitive inhibitors.     

Determination of organophosphorous pesticides in the ppq range using a simple solid-phase extraction method combined with dispersive liquid-liquid microextraction

Solid-phase extraction combined with dispersive liquid-liquid microextraction (SPE-DLLME) was applied for the extraction of six organophosphorous pesticides (OPPs) in water samples. The analytes considered in this study were determined by gas chromatography with mass spectrometry and included prophos, diazinon, chlorpyrifos methyl, methyl parathion, fenchlorphos and chlorpyrifos. Several extraction conditions (extraction solvent and elution/dispersion solvents nature, extraction solvent volume, elution solvent volume, water volume and sample volume) were tested for SPE-DLLME with these analytes and the best results were obtained using carbon tetrachloride as the extraction solvent and acetone as the elution/dispersion solvent. Calibration curves for the determination of OPPs in water samples were constructed in the concentration range of 10-100 ng/L. Limits of detection (LODs) ranged from 38 to 230 pg/L values that are below the maximum admissible level for drinking water (100 ng/L). Relative standard deviations (RSD) were between 8.6 and 10.4% for a fortification level of 100 ng/L. At the same fortification level, the relative recoveries (R.R.) of tap, well and irrigation water samples were in the range of 30.2-97.1%.