Large-scale asymmetric synthesis of the bioprotective agent JP4-039 and analogs

JP4-039 is a novel nitroxide conjugate capable of crossing lipid bilayer membranes and scavenging reactive oxygen species (ROS). An efficient and scalable one-pot hydrozirconation-transmetalation-imine addition methodology has been developed for its asymmetric preparation. Furthermore, this versatile methodology allows for the synthesis of cyclopropyl and fluorinated analogs of the parent lead structure.     

Straightforward synthesis of (S)- and (R)-alpha-trifluoromethyl proline from chiral oxazolidines derived from ethyl trifluoropyruvate

[Structure: see text] A concise synthesis of both enantiomers of alpha-Tfm-proline and (S)-alpha-Tfm-prolinol from ethyl trifluoropyruvate is reported. The key step is a diastereoselective allylation reaction of ethyl trifluoropyruvate and (R)-phenylglycinol-based oxazolidines or imine. The lactone obtained by cyclization of the resulting hydroxy ester proved to be a valuable intermediate for the synthesis of (S)-alpha-Tfm-allylglycine and (S)-alpha-Tfm-norvaline in enantiopure form.     

X-ray-excited optical luminescence (XEOL) and X-ray absorption fine structures (XAFS) studies of gold(I) complexes with diphosphine and bipyridine ligands

Synchrotron techniques, X-ray-excited optical luminescence (XEOL) combined with X-ray absorption fine structures (XAFS), have been used to study the electronic structure and optical properties of a series of luminescent gold(I) complexes with diphosphine and bipyridine ligands using tunable X-rays (in the regions of the C and P K-edges and the Au L3-edge) and UV from synchrotron light sources. The effects of gold-ligand and aurophilic interactions on the luminescence from these gold(I) complexes have been investigated. It is found that the luminescence from these complexes is phosphorescence, primarily due to the decay of the Au (5d) --> PR3 (pi*), metal to ligand charge transfer (MLCT) excitation as well as contributions from the conjugated pi-system in the bipyridine ligands via the gold-nitrogen bond. The large Au 5d spin-orbit coupling enhances the intersystem crossing. The elongation of the hydrocarbon chain of the diphosphine ligand does not greatly affect the spectral features of the luminescence from the gold(I) complexes. However, the intensity of the luminescence was reduced significantly when the bipyridine ligand was replaced with 1,2-bis(4-pyridylamido)benzene. The aurophilic interaction, as investigated by EXAFS at the Au L3-edge, is shown to be only one of the factors that contribute to the luminescence of the complexes.     

Remodeling of ordered membrane domains by GPI-anchored intestinal alkaline phosphatase

Glycosylphosphatidyl-inositol (GPI)-anchored proteins preferentially localize in the most ordered regions of the cell plasma membrane. Acyl and alkyl chain composition of GPI anchors influence the association with the ordered domains. This suggests that, conversely, changes in the fluid and in the ordered domains lipid composition affect the interaction of GPI-anchored proteins with membrane microdomains. Validity of this hypothesis was examined by investigating the spontaneous insertion of the GPI-anchored intestinal alkaline phophatase (BIAP) into the solid (gel) phase domains of preformed supported membranes made of dioleoylphosphatidylcholine/dipalmitoylphosphatidylcholine (DOPC/DPPC), DOPC/sphingomyelin (DOPC/SM), and palmitoyloleoylphosphatidylcholine/SM (POPC/SM). Atomic force microscopy (AFM) showed that BIAP inserted in the gel phases of the three mixtures. However, changes in the lipid composition of membranes had a marked effect on the protein containing bilayer topography. Moreover, BIAP insertion was associated with a net transfer of phospholipids from the fluid to the gel (DOPC/DPPC) or from the gel to the fluid (POPC/SM) phases. For DOPC/SM bilayers, transfer of lipids was dependent on the homogeneity of the gel SM phase. The data strongly suggest that BIAP interacts with the most ordered lipid species present in the gel phases of phase-separated membranes. They also suggest that GPI-anchored proteins might contribute to the selection of their own microdomain environment.     

A 31P NMR Study of the Stability of Carboxyifosfamide and Carboxycyclophosphamide,Two Metabolites of Ifosfamide and Cyclophosphamide

Abstract

Ifosfamide (IF) and cyclophosphamide (CP) are two phosphorated anticancer agents used in the treatment of solid tumours. Several phosphorated metabolites, among them carboxyifosfamide (CXIF) and carboxycyclophosphamide (CXCP), were detected and quantified by ³¹P NMR in urine from patients treated with IF or CP. In agreement with other authors [1], we observed a great inter-patient variability in the urinary excretion of CXIF in patients treated with IF [2]. This variability was attributed to a genetic polymorphism of aldehyde dehydrogenase, the enzyme responsible for the formation of CXCP or CXIF [1,3]. Since CXCP and CXIF are unstable, we thought that the inter-individual variability could also be due to a degradation during the storage of urine samples. A ³¹P NMR study of the stability of CXIF and CXCP in urine as a function of time, pH (7 and 5.5) and storage temperature (25°C, 8°C, ?20°C, ?80°C) demonstrated that (i) CXCP and CXIF are more stable at pH 7 than at pH 5.5, (ii) CXCP is more stable than CXIF at both pH, (iii) the degradation decreases with temperature but still occurs at ?20°C and even ?80°C. For an accurate quantification of these compounds, the storage of urine samples must be done at ?80°C immediately after collection and not exceed 1 month at pH 7 whereas, at pH 5.5, the assay must be carried out in the few days following the sampling. To identify the degradation products of CXCP and CXIF, the time course of hydrolysis (between pH 2 and 7) of these compounds was monitored by ³¹P NMR. The structure of each compound formed was determined by mass spectrometry and ¹H and ¹³C NMR after their isolation (except compound A too unstable to be isolated). The results are reported in the following schemes.     

UN sustainable development goals: How can sustainable/green chemistry contribute? Green chemistry as a source of sustainable innovations in the cosmetic industry

Sustainable innovation is a key-objective for our Group that has recently integrated the principles of sustainable development into all stages of a product's life cycle, from its design to consumer use. The following ambitious commitment: 100% of its products should bring an environmental (or social benefit) by 2020, will be reached, in particular, by integrating and giving a constant privilege to renewable raw materials -or ingredients-that originate from sustainable resources that fully comply with the green chemistry rules. In this short review, integration of Green Chemistry principles by our Group, strategies to identify new performing ingredients through sustainable chemistry as well as illustrative examples of innovative raw materials will be presented. With regard to the crucial respect of the environment of our planet, sustainable chemistry has become an indispensable turning point for industrial groups highly devoted to innovation.     

Radical alkylphosphanylation of olefins with stannylated or silylated phosphanes and alkyl iodides

Intermolecular conjugate radical addition reactions of secondary and tertiary alkyl radicals derived from the corresponding alkyl iodides to activated olefins such as α,β-unsaturated esters, amides, imides, nitriles, and sulfones are described. The adduct radicals are trapped by either diphenyl(trimethylstannyl)phosphane or the commercially available diphenyl(trimethylsilyl)phosphane as chain transfer reagents to give the corresponding phosphanylated products in moderate to good yields. The overall process comprises a C-C followed by a C-P bond formation.     

Enantiomeric differentiation of acyclic terpenes by 13C NMR spectroscopy using a chiral lanthanide shift reagent

The 13C NMR behaviour of ten acyclic terpene alcohols was examined in the presence of a chiral lanthanide shift reagent (CLSR). For each alcohol, we measured the lanthanide-induced shift (LIS) on the signals of the carbons and the splitting of some signals, which allowed the enantiomeric differentiation. As expected, the LIS decreased with the number of bonds between the binding function and the considered carbon. The enantiomeric splitting is observed for several signals in the spectrum of each compound. The influence of the hindrance of the binding function (primary, secondary or tertiary alcohol) and that of the stereochemistry of the double bonds is discussed.