Frédéric Guillen

Ionic Liquids: New Targets and Media for α-Amino Acid and Peptide Chemistry

CNRS-UMR 5068, LSPCMIB, Universite Paul Sabatier, 118 route de Narbonne, F-31062 Toulouse Cedex 9, France, Laboratoire de Chimie Moleculaire et Thio-organique, ENSICAEN, Universite de Caen Basse-Normandie, FR CNRS 3038, 6 boulevard du Marechal Juin, F-14050 Caen, France, CNRS-UMR 6014, IRCOF, Universite de Rouen, rue Tesniere, F-76821 Mont-Saint-Aignan Cedex, France, and URCOM, EA 3221 FR CNRS 3038, Universite du Havre, 25 rue Ph. Lebon, BP 540, F-76058 Le Havre Cedex, France

Multicomponent reactions in ionic liquids: convenient and ecocompatible access to the 2,6-DABCO core

Herein we describe the use of ionic liquids as complementary new media for multicomponent reactions leading to the 2,6-diazabicyclo[2.2.2]octane core. The reaction took place efficiently in ionic liquid solvents instead of toluene, giving overall better results (faster rate, higher concentration) and allowing generalization to hitherto unreactive substituted Michael acceptors. In these cases, the use of molecular sieves, acting as a heterogeneous catalyst in the preliminary study in molecular solvents, could be totally excluded thanks to the promoting properties of the ionic liquid solvent, which could be recycled and reused up to five times. Complete diastereoselectivity was observed at one of the bridge positions, as assigned by X-ray analysis.

Structure–Binding Effects: Comparative Binding of 2-Anilino-6-naphthalenesulfonate by a Series of Alkyl- and Hydroxyalkyl-Substituted β-Cyclodextrins

Cyclodextrins (CDs) are the most widely used organic hosts for the inclusion of guest molecules. CDs can be readily modified through substitutions of the hydroxyl groups, and these modified CDs can have different host binding properties compared to those of parent CDs. However, only relatively few systematic studies of the effects of chemical substitution on CD binding ability have been reported thus far. In this paper, we report the study of the binding properties of five different analytically pure modified β-cyclodextrin (β-CD) hosts (substituted with alkyl and/or hydroxyalkyl groups) with 2-anilino-6-naphthalenesulfonate (2,6-ANS) as guest. Binding constants for the formation of the inclusion complex between 2,6-ANS and each CD were determined using both fluorescence spectroscopy and capillary electrophoresis. Addition of modified CDs to an aqueous solution of 2,6-ANS resulted in significant enhancement of the fluorescence intensity of 2,6-ANS, as well as a significant spectral blue shift, indicative of inclusion. Inclusion of 2,6-ANS within the CD cavity was confirmed by NMR spectroscopy. Substitution at position 3 decreased the magnitude of the binding constants, while alkyl or hydroxylalkyl substitution of the primary hydroxyl at position 6 increased the magnitude of the binding constant in all cases, in relation with increasing length of the alkyl chain linker. In addition, binding constants decreased with solvent polarity when increasing amounts of methanol were added. Structure-binding correlations for CDs based on these binding constant results are presented and discussed.

Synthesis of phosphoantigens: scalable accesses to enantiomers of BrHPP and studies on N-HDMAPP synthesis.

Phosphoantigens enable the access to a new anti-tumoral and anti-infectious therapeutic pathway, based on innate immunity through the selective activation of Tγ9δ2 lymphocytes. The first proof of concept of this new immunotherapy approach was demonstrated with the synthetic phosphoantigen named bromohydrin pyrophosphate (BrHPP, IPH 1101) which was administrated in racemic form to about 200 patients in six clinical trials with good safety and promising early signals of efficacy in type C viral hepatitis and follicular non-Hodgkins lymphoma. Enantiopure samples of BrHPP in gram scale are required for further studies on structure-bioactivity relationship. Thus we developed two complementary synthetic pathways, the first using transformation of a chiral compound and the second involving asymmetric synthesis starting from a prochiral building-block. The synthesis of a second-generation phosphoantigen, N-HDMAPP, which bears a phosphoramidate moiety, was also investigated.

1-Ethyl-3-methylimidazolium tartrate chiral ionic liquids: preparation, characterization and opportunities thereof

A unified acid/base synthetic access to tartrate-based chiral ionic liquids relying on the generation of cation hydroxide salts with AgOH was challenged with the preparation of sensitive 1-ethyl-3-methylimidazolium derivatives. Systematic variation of the starting tartaric acid stoichiometry and configuration led to eight stereoisomeric 1-ethyl-3-methylimidazolium hydrogen tartrate or di-(1-ethyl-3-methylimidazolium)tartrate entities. These salts were all characterised as proper ionic liquids. An unprecedented influence of the configuration ((2S,3S), or (2R,3R) vs. racemic or meso) on dynamic viscosity was observed. The relevance of such tartrate salts as task-specific ionic liquids was demonstrated in a synthetically useful base-promoted intramolecular cyclisation of a C2-symmetrical bis-epoxide en route to the total synthesis of phytofuran metabolites.