Rapid and scalable synthesis of innovative unnatural α,β or γ-amino acids functionalized with tertiary amines on their side-chains.

We report a selective ruthenium catalyzed reduction of tertiary amides on the side chain of Fmoc-Gln-OtBu derivatives, leading to innovative unnatural α,β or γ-amino acids functionalized with tertiary amines. Rapid and scalable, this process allowed us to build a library of basic unnatural amino acids at the gram-scale and directly usable for liquid- or solid-phase peptide synthesis. The diversity of available tertiary amines allows us to modulate the physicochemical properties of the resulting amino acids, such as basicity or hydrophobicity.journal article2015 Jul 072015 06 01importe

POxAP Precatalysts and the Negishi Cross-Coupling Reaction

Recently developed for Fukuyama reaction, POxAP precatalysts are also very efficient to catalyze Negishi cross-coupling reaction between organohalides and organozinc reagents. Using very low catalyst loading, POxAPs shows similar catalytic activities than classical precatalysts such as XPhos Pd G4 or PEPPSI-IPr, with TON about 90,000. Easily prepared and stable to air and moisture, POxAPs tolerate a wide range of functional groups in the Negishi CCR, and complete advantageously the arsenal of organic chemists in terms of Pd precatalysts

N-acyl substituted 7-amino-4-chloroisocoumarin: a peptide degradation model via an imide mechanism.

During the coupling reaction between 3-alkoxy-7-amino-4-chloroisocoumarin and N-acyl alanine dipeptide, an unexpected deamidation reaction was observed. The proposed mechanism for this reaction involved the formation of an imide intermediate which after cleavage led to the release of amino acid moiety. The described deamidation reaction represents the first chemical model involving a non-peptidic moiety, which mimics biological and chemical deamidation processes occurring in proteins or peptides incorporating an asparagine or a glutamine residue.info:eu-repo/semantics/publishe

In Situ Formation of Cationic π-Allylpalladium Precatalysts in Alcoholic Solvents: Application to C–N Bond Formation

International audienceWe report an efficient Buchwald-Hartwig cross-coupling reaction in alcoholic solvents, in which low catalyst loading showed excellent performance for coupling aryl halides (I, Br, Cl) with a broad set of amines, amides, ureas, or carbamates under mild conditions. Mechanistically speaking, in protic and polar medium, extremely bulky biarylphosphine ligands interact with dimeric precatalyst [Pd(π-Rallyl)Cl]2 to form the corresponding cationic complexes [Pd(π-Rallyl)(L)]Cl in situ and spontaneously. The resulting precatalyst further evolves under basic conditions into the corresponding L-Pd(0) catalyst, which is commonly employed for cross-coupling reactions. This mechanistic study highlights the prominent role of alcoholic solvents for the formation of the active catalyst

Mitochondria modulatory effects of new TSPO ligands in a cellular model of tauopathies

Translocator protein 18 kDa (TSPO) is a mitochondrial protein located in the outer membrane and involved in cholesterol translocation, a prerequisite for steroid biosyn‐ thesis. TSPO modulation also appears to play a role in other mitochondrial functions, including mitochondrial respiration and cell survival. In the central nervous system, its expression is up‐regulated in neuropathology such as Alzheimer's disease (AD). Previously, we demonstrated that two new TSPO ligands, named 2a and 2b, stimu‐ lated pregnenolone synthesis and ATP production in a cellular model of AD overpro‐ ducing β‐amyloid peptide. The present study aimed to evaluate the impact of the new TSPO ligands on mitochondrial dysfunction in a cellular model of AD‐related tauopa‐ thy (human neuroblastoma cells SH‐SY5Y stably overexpressing the P301L‐mutant Tau) presenting mitochondrial impairments, including a decreased ATP synthesis and mitochondrial membrane potential, as well as a decrease in pregnenolone synthesis compared to control cells. The effects of our new ligands were compared with those of TSPO ligands described in the literature (XBD173, SSR‐180,575 and Ro5‐4864). The TSPO ligands 2a and 2b exerted beneficial mitochondrial modulatory effects by increasing ATP levels and mitochondrial membrane potential, paralleled by an increase of pregnenolone levels in mutant Tau cells, as well as in control cells. The compounds 2a and 2b showed effects on mitochondrial activity similar to those obtained with the TSPO ligands of reference. These findings indicate that the new TSPO ligands modulate the mitochondrial bioenergetic phenotype as well as the de novo synthesis of neurosteroids in a cellular model of AD‐related tauopathy, suggesting that these compounds could be potential new therapeutic tools for the treatment of AD