Gérard Simonneaux

Optically active ruthenium porphyrins: chiral recognition and asymmetric catalysis

Abstract The current applications of ruthenium porphyrins in stoichiometric and catalytic asymmetric reactions are reported. Chiral recognition of racemic phosphines, isocyanides and amino esters has been studied by 1H-NMR. Experimental investigations of the oxidation mechanism of racemic phosphines and amino esters are described. The stereochemistry of catalytic asymmetric oxidation and cyclopropanation of olefins with optically active ruthenium porphyrins are also discussed.

Cyclopropanation of Alkenes, N–H and S–H Insertion of Ethyl Diazoacetate Catalysed by Ruthenium Porphyrin Complexes

Abstract Product yields, stereoselectivities and regioselectivities for cyclopropanation reactions of ethyl diazoacetate with styrene derivatives and α-heteroatom alkenes, catalysed by ruthenium porphyrins, are reported and compared with observed stereoselectivities for cyclopropanation reactions catalysed with other metalloporphyrin catalysts. Linear correlations are observed when the rates for competitive cyclopropanation or product stereoisomer ratio are plotted against Hammet constants of various ring-substituted groups on styrenes. Isomeric distribution for the cyclopropanation of isoprene and 1,3-pentadiene with ethyl diazoacetate and competition studies of the cyclopropanation and diazo insertion into heteroatom–hydrogen bonds are also reported. All these results agree with a major electronic and steric influence on both the regiochemical and stereochemical control in the catalytic cyclopropanation and diazo insertion reactions.

Asymmetric cyclopropanation of alkenes and diazocarbonyl insertion into SH bonds catalyzed by a chiral porphyrin Ru(II) complex

Abstract A homochiral porphyrin ruthenium(II) complex catalyzes the cyclopropanation of styrene derivatives with ethyl diazoacetate with good yields and moderate enantiomeric excesses (46–52 %). The catalyst is also active for diazocarbonyl compound insertion into SH bonds, but with low ee.

First enantioselective iron-porphyrin-catalyzed sulfide oxidation with aqueous hydrogen peroxide

The asymmetric oxidation of sulfides by H(2)O(2) to give optically active sulfoxides (ee up to 90%) was carried out in methanol and water using chiral water-soluble iron porphyrins as catalysts.

Synthesis, and in vitro and in vivo evaluation of a diphenylchlorin sensitizer for photodynamic therapy.

This paper reports the synthesis of a new diphenylchlorin photosensitizer, 2,3-dihydro-5,15-di(3,5-dihydroxyphenyl)porphyrin (SIM01). The photodynamic properties, cell uptake and localization of SIM01 were compared with those of structurally related meso-tetra(hydroxyphenyl)chlorin (m-THPC). In vitro studies were conducted on rat glioma cells (C6) and human adenocarcinoma (HT-29), and in vivo studies on human colon adenocarcinoma cells (HT-29) and human prostate adenocarcinoma cells (PC3). Both dyes showed an absorption maximum at around 650 nm, with a molar extinction coefficient of 13017 M(-1) cm(-1) for SIM01 and 22718 M(-1) cm(-1) for m-THPC. Their capacity to generate singlet oxygen was identical, but differences in partition coefficients indicated that SIM01 was slightly more hydrophilic. In vitro, SIM01 was slightly more phototoxic than m-THPC for C6 cells (4.8 vs. 6.8 microg ml(-1)). However, phototoxicities were nearly identical for HT29 cells (0.45 microg ml(-1) for 5 h incubation followed by 300 mW, 20 J cm(-2)). Pharmacokinetics in vivo in mice, as determined by fibre spectrofluorimetry, showed that the SIM01 fluorescence signal in the tumor was maximal between 6 and 12 h after injection, as compared to 72 h for m-THPC. With a 2 mg kg(-1) dye dose and laser irradiation at 300 J cm(-2) (650 nm, 300 mW), the optimal PDT response occurred when the interval between injection and irradiation was 6 h for SIM01 and 24 h for m-THPC. For SIM01 with 5 mg kg(-1) injection, the optimal PDT response occurred with a 12 h delay and with the same irradiation parameters as described above, in this case the tumor response showing 40% growth. Considering the tumor volume doubling time, the value was 6.5 days in the control group and increased to 13.5 days with SIM01. Thus, SIM01 may be a powerful sensitizer characterized by strong in vitro and in vivo phototoxicity and faster tissue uptake and elimination than m-THPC.

Enantioselective Manganese-Porphyrin-Catalyzed Epoxidation and C–H Hydroxylation with Hydrogen Peroxide in Water/Methanol Solutions

The asymmetric epoxidation of alkene and hydroxylation of arylalkane derivatives by H(2)O(2) to give optically active epoxides (enantiomeric excess (ee) up to 68%) and alcohols (ee up to 57%), respectively, were carried out in water/methanol solutions using chiral water-soluble manganese porphyrins as catalysts.

Catalytic asymmetric syntheses. : Part III. Asymmetric hydrogenation of piperitenone catalysed by chiral ruthenium hydrides : An example of a catalytic kinetic resolution1

Abstract Piperitenone has been hydrogenated in the presence of chiral ruthenium catalysts to give piperitone, menthone and isomenthone. Starting from piperitone (42 % e.e.) excellent selectivity (⋍80 % e.e.) was obtained with menthone. The mechanism of the reaction, a double asymmetric synthesis, is discussed with respect to kinetic resolution of piperitone as well as the effect of the chiral center in the substrate on the catalytic asymmetric induction.

Ruthenium–porphyrin-catalyzed carbenoid addition to allylic compounds: application to [2,3]-sigmatropic rearrangements of ylides

Abstract The catalytic effectiveness of ruthenium porphyrins for ylide generation in reactions of ethyl diazoacetate and diisopropyl diazomethylphosphonate with allylic amines, sulfides and iodides is described for the first time. These reactions result mainly in products of the [2,3]-sigmatropic rearrangement of intermediate allylic ylides.

Hydroporphyrins as tumour photosensitizers: synthesis and photophysical studies of 2,3-Dihydro-5,15-di(3,5-dihydroxyphenyl) porphyrin

The synthesis and characterization of 2,3-dihydro-5,15-di(3,5-dihydroxyphenyl) porphyrin is reported. The phototoxicity on C6 cell lines and the pharmacokinetics are also reported as preliminary results showing a very high tumor to skin ratio and short retention time in tissues, and thus promising activity in photodynamic therapy.

Biological and Biophysical Properties of the Histone Deacetylase Inhibitor Suberoylanilide Hydroxamic Acid Are Affected by the Presence of Short Alkyl Groups on the Phenyl Ring

Inhibition of histone deacetylases (HDACs) leads to growth arrest, differentiation, or apoptosis of tumor cell lines, suggesting HDACs as promising targets for cancer therapy. At present, only one HDAC inhibitor (HDACi) is used in therapy: suberoylanilide hydroxamic acid (SAHA). Here, we describe the synthesis and biological evaluation of a new series of compounds derived from SAHA by substituting short alkyl chains at various positions of the phenyl ring. Such modifications induced variable effects ranging from partial loss of activity to increased potency. Through molecular modeling, we describe a possible interaction between HDAC7 proline 809, a residue that is strictly conserved within class 2 enzymes only, and the amide group of HDACi, while nuclear magnetic resonance experiments indicated that dimethyl m-substitution may stabilize the inhibitor in the active site. Our data provide novel information on the structure-activity relationship of HDACi and suggest new ways for developing second generation SAHA-like molecules.