Fragment-Based Ligand Discovery Applied to the Mycolic Acid Methyltransferase Hma (MmaA4) from : A Crystallographic and Molecular Modelling Study.

The mycolic acid biosynthetic pathway represents a promising source of pharmacological targets in the fight against tuberculosis. In , mycolic acids are subject to specific chemical modifications introduced by a set of eight S-adenosylmethionine dependent methyltransferases. Among these, Hma (MmaA4) is responsible for the introduction of oxygenated modifications.

Origin of the enantioselectivity in organocatalytic Michael additions of β-ketoamides to α,β-unsaturated carbonyls: a combined experimental, spectroscopic and theoretical study.

The organocatalytic enantioselective conjugate addition of secondary β-ketoamides to α,β-unsaturated carbonyl compounds is reported. Use of bifunctional Takemoto's thiourea catalyst allows enantiocontrol of the reaction leading either to simple Michael adducts or spirocyclic aminals in up to 99 % ee. The origin of the enantioselectivity has been rationalised based on combined DFT calculations and kinetic analysis.

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-Hodgkin's lymphoma. Enantiopure samples of BrHPP in gram scale are required for further studies on structure-bioactivity relationship.

Synthesis of chiral ionic liquids by ion cross-metathesis: en route to enantioselective water-ionic liquid extraction (EWILE), an eco-friendly variant of the ELLE process.

From two initial ILs two other ILs are obtained by simultaneous ion exchange. The hydrophobic ions unite in the hydrophobic layer, whereas the hydrophilic ions gather in water. This protocol is explored as a variant of the ELLE process, in which an enantiomer of a racemic mixture is preferentially extracted with water.

A cooperative participation of the amido group in the organocatalytic construction of all-carbon quaternary stereocenters by Michael addition with β-ketoamides.

The secondary amido group of α-substituted β-ketoamides plays a crucial role in the control of the reactivity and spatial arrangement (selectivity) in the organocatalyzed Michael addition to unsaturated carbonyls. This results in an unprecedented activation mode of substrates through H-bonding interactions allowing the construction of enantiomerically enriched functionalized all-carbon quaternary centers and spiroaminals of high synthetic potential.

Multicomponent reactions and ionic liquids: a perfect synergy for eco-compatible heterocyclic synthesis.

The efficiency of a chemical synthesis can be nowadays measured, not only by parameters like selectivity and overall yield, but also by its raw material, time, human resources and energy requirements, as well as the toxicity and hazard of the chemicals and the protocols involved. The development of multicomponent reactions (MCRs) in the presence of task-specific ionic liquids (ILs), used not only as environmentally benign reaction media, but also as catalysts, is a new approach that meet with the requirements of sustainable chemistry. The aim of this tutorial review is to highlight the synergistic effect of the combined use of MCRs and ILs for the development of new eco-compatible methodologies for heterocyclic chemistry.

Thiazolinium and imidazolium chiral ionic liquids derived from natural amino acid derivatives.

Starting from commercially available amino acid derivatives, two novel families of chiral ionic liquids having either a thiazolinium or an imidazolium cation were prepared by simple and straightforward procedures in good overall yields. The properties of these new salts can be finely tuned by careful selection of the anion and the cation.

Is the optical rotation sign/absolute configuration relationship still a problem? Examples taken from unnatural quaternary aminoacids.

The optical rotation sign/absolute configuration relationships of several alpha-methyl-alpha-arylglycines have been reinvestigated by crystallographic methods, as they have been found to be inconsistent in recent literature. Assignments previously made by enzymatic resolution, by analogy with natural tertiary aminoacids were found to be erroneous in the case of these quaternary aminoacids.

Cinchona alkaloid-based polymer-bound phase-transfer catalysts: efficient enantioselective alkylation of benzophenone imine of glycine esters.

Cross-linked polystyrene-bound and poly(ethylene glycol)-bound phase-transfer catalysts as well as homopolymers of cinchona alkaloid derivatives have been synthesised. Both soluble and insoluble polymers have been investigated. The enantioselective alkylation of N-diphenyl methylene glycine t-butyl ester has been successfully carried out in heterogeneous and homogeneous systems.

Enantioselective synthesis of BMS-204352 (MaxiPost) using N-fluoroammonium salts of cinchona alkaloids (F-CA-BF4).

The enantioselective synthesis of a potent Maxi-K potassium channel opener (BMS-204352) mediated by N-fluoroammonium salts of cinchona alkaloids is described. Two synthetic pathways were evaluated. An ee as high as 88% was achieved (>99% after a single recrystallisation).

Strategies for access to enantiomerically pure ecadotril, dexecadotril and fasidotril: a review.

Ecadotril and dexecadotril are powerful and selective inhibitors of neprilysin (NEP, EC 3.4.24.

New insights in the search for chiral Brønsted bases.

The concept of using chiral bases in asymmetric synthesis appeared with the emergence of the chemistry of chiral lithium amides. In recent years, new classes of chiral bases, such as chiral magnesium bisamides and chiral alkali alkoxides have proven to be highly efficient and easy to handle. This paper highlights recent advances and new concepts in the chemistry of this second generation of chiral bases.

Electrophilic Fluorination Mediated by Cinchona Alkaloids: Highly Enantioselective Synthesis of α-Fluoro-α-phenylglycine Derivatives.

A decisive step forward: A one-step fluorination on modified cinchona alkaloids produced a new range of enantiopure fluorinating agents that display high enantioselectivities in electrophilic fluorination. The first enantioselective synthesis of N-protected α-fluorophenylglycine derivatives was achieved with an enantiomeric excess up to 94 % [Eq. (a); R=Et, CN; HMDS=hexamethyldisilazanide].

Design, synthesis, and evaluation of a novel class of enantioselective electrophilic fluorinating agents: N-fluoro ammonium salts of cinchona alkaloids (F-CA-BF(4)).

The first enantiopure N-fluoro quaternary ammonium salts of cinchona alkaloids as enantioselective fluorinating agents are reported. A one-step transfer-fluorination on the naturally occurring cinchona alkaloids gave the fluorinating agents F-CA-BF(4). This new generation of fluorinating agents exhibited asymmetric induction up to 61% on fluorination of enolates and silyl enol ethers of 2-methyl-1-tetralone.

Enantioselective synthesis of both enantiomers of methyl dihydrojasmonate using solid-liquid asymmetric phase-transfer catalysis.

Both enantiomers of methyl dihydrojasmonate (-)-1 and (+)-1 were obtained by a short route using asymmetric Michael addition of dimethyl malonate onto pentyl enone 3, followed by nonracemizing demethoxycarbonylation. The key enantioselective step involves a new system of asymmetric solid-liquid phase-transfer catalysis using solvent-free conditions. Enantiomeric excess as high as 90% (91% yield) was achieved.

Frog diazepam-binding inhibitor: peptide sequence, cDNA cloning, and expression in the brain.

Three peptides derived from diazepam-binding inhibitor (DBI) were isolated in pure form from the brain of the frog Rana ridibunda. The primary structures of these peptides showed that they correspond to mammalian DBI-(1-39), DBI-(58-87), and DBI-(70-87). A set of degenerate primers, whose design was based on the amino acid sequence data, was used to screen a frog brain cDNA library.

Mixed inhibitors of angiotensin-converting enzyme (EC 3.4.15.1) and enkephalinase (EC 3.4.24.11): rational design, properties, and potential cardiovascular applications of glycopril and alatriopril.

Angiotensin-converting enzyme (ACE) and enkephalinase, two cell surface metallopeptidases, are responsible for angiotensin II formation and atrial natriuretic factor (ANF) degradation, respectively, and thereby play a critical role in the metabolism of hormonal peptides exerting essentially opposite actions in cardiovascular regulations. To affect simultaneously both hormonal systems by a single molecular structure, we have designed glycoprilat and alatrioprilat [(S)-N-[3-(3,4-methylene-dioxyphenyl)-2-(mercaptomethyl)-1-oxoprop yl] glycine and -alanine, respectively]. In vitro the two compounds inhibit both ACE and enkephalinase activities with similar, nanomolar potencies, and in vivo, glycopril and alatriopril, the corresponding diester prodrugs, occupy the two enzyme molecules in lung at similar low dosages (0.

Enantiomers of thiorphan and acetorphan: correlation between enkephalinase inhibition, protection of endogenous enkephalins and behavioral effects.

The relationships between various properties of inhibitors of enkephalinase (membrane metalloendopeptidase, EC 3.4.24.