Noureddine Khiar

Inositolphosphoglycan Mediators Structurally Related to Glycosyl Phosphatidylinositol Anchors: Synthesis, Structure and Biological Activity

The preparation of the pseudopentasaccharide 1a, an inositol-phosphoglycan (IPG) that contains the conserved linear structure of glycosyl phosphatidylinositol anchors (GPI anchors), was carried out by using a highly convergent 2+3-block synthesis approach which involves imidate and sulfoxide glycosylation reactions. The preferred solution conformation of this structure was determined by using NMR spectroscopy and molecular dynamics simulations prior to carrying out quantitative structure--activity relationship studies in connection with the insulin signalling process. The ability of 1a to stimulate lipogenesis in rat adipocytes as well as to inhibit cAMP dependent protein kinase and to activate pyruvate dehydrogenase phosphatase was investigated. Compound 1a did not show any significant activity, which may be taken as a strong indication that the GPI anchors are not the precursors of the IPG mediators.

Axial Chirality Control During Suzuki−Miyaura Cross-Coupling Reactions: The tert-Butylsulfinyl Group as an Efficient Chiral Auxiliary

An efficient route to a new family of axially chiral biaryl ligands by a Suzuki-Miyaura cross-coupling reaction between ortho,ortho-disubstituted aryl iodides bearing in ortho position a tert-butyl or p-tolylsulfinyl group and ortho-substituted phenyl boronic acids or esters is described. The comparison between the t-BuSO and p-TolSO groups as chiral controllers is reported. The modularity of the approach is demonstrated by the preparation of a variety of enantiopure axially chiral mixed S/N and S/P ligands.

A generalization of the base effect on the diastereoselective synthesis of sulfinic and phosphinic esters

Abstract Various chiral secondary alcohols have been used to study the dependence of the stereochemical outcome of sulfinate and phosphinate ester synthesis on the nature of the base used to catalyse the reaction. From this study it has been shown that the achiral stereodirecting base effect determined in the DAG methodology is a general behaviour in the asymmetric synthesis of sulfinate and phosphinate esters.

Enantioselective synthesis of optically pure s-isoserine

Abstract KF-promoted addition of nitromethane on (−)-8-phenylmenthyl glyoxylate monohydrate affords, after one purification, optically pure (−)S isoserine in about 50% yield.

A new promoter system for the sulfoxide glycosylation reaction

Abstract Sulfinylglycosides are efficiently activated by the system TfOH/TEP in the glycosylation reaction to afford disaccharides in good yields.

A short enantiodivergent synthesis of d-erythro and l-threo sphingosine

A new, short (6 steps) and efficient enantiodivergent route to both D-erythro and L threo-sphingosine I and II is disclosed. The high diastereoselection (100% de) reached in the creation of the C-3 stereocenter relies on the use of a sulfoxide as chiral controlling agent in the reduction of the common precursor β-keto sulfoxide 3. The desired E-alkene of sphingosines has been constructed by the Schlosser modification of the Wittig reaction between the aldehyde 8 and the phosphonium salt 9. The reported methodology can easily be extended to the synthesis of a large number of optically pure syn and anti amino alcohols starting from commercially available amino acids.

The solution conformation of glycosyl inositols related to inositolphosphoglycan (IPG) mediators

Abstract The preferred solution conformation of the pseudodisaccharides 7 – 15 , containing the structural motifs that have been proposed for the putative inositolphosphoglycan (IPG) mediators of intracellular signalling processes, have been investigated using NMR spectroscopy and molecular mechanics calculations. The results indicate that the different structural motifs (α and β 1–6 or α and β 1–4 glucosaminyl -d- myo -inositol; α and β 1–6 glucosaminyl -d- chiro -inositol) adopt various three-dimensional shapes that may modulate their biological properties.

Synthesis and Structure of 1‐D‐6‐O‐(2‐Amino‐2‐deoxy‐α‐ and ‐β‐D‐gluco‐ and ‐galactopyranosyl)‐3‐O‐methyl‐D‐chiro‐inositol

A convenient preparative synthesis of 1-D-6-O-(2-amino-2-deoxy-α-D-glucopyranosyl)-3-O-methyl-chiro-inositol (Ia), 1D-6-O-(2-amino-2-deoxy-β-D-glucopyranosyl)-3-O-methylchiro-inositol (Ib), 1-D-6-O-(2-amino-2-deoxy-α-D-galactopyranosyl)-3-O-methyl-chiro-inositol (IIa), and 1-D-6-O-(2-amino-2-deoxy-β-D-galactopyranosyl)-3-O-methyl-chiro-inositol (IIb) from 3-O-methyl-D-chiro-inositol (pinitol) as starting material is reported. These compounds contain some of the basic structural motifs proposed for insulin mediators. The three-dimensional structures of these compounds have been determined by NMR spectroscopy and molecular dynamics simulations.