Chiral Diphosphine Ligands and New Reactions of Organozinc Compounds

Using the [2,3]-sigmatropic rearrangement of chiral allylic diarylphosphinites, a number of new enantiopure 1,3-diphoshine ligands were prepared. Enzymatic kinetic rezolution of allylic alcohols was used for the preparation of enantiopure starting materials. Several new reactions of organozinc compounds, i. e. new thiolation method, Ni-catalyzed cross-coupling reactions and a method of preparation of alkylzinc bromides from the corresponding alkylbromides were developed

Direct Aminoalkylation of Arenes, Heteroarenes, and Alkenes via Ni-Catalyzed Negishi Cross-Coupling Reactions

A room-temperature Ni-catalyzed cross-coupling of aryl, heteroaryl, and alkenyl electrophiles with aminoalkylzinc bromides, readily available from the corresponding aminoalkyl chlorides via Grignard reagents, was developed. The reaction allows a convenient one-step preparation of various aminoalkyl products, including piperidine and tropane derivatives. Such functionalized amine moieties are widely present in various biologically active molecules. Aryl, heteroaryl, and alkenyl iodides, bromides, chlorides and triflates are suitable electrophiles. A short total synthesis of two natural products, (±)-galipinine and (±)-cusparine, is also reported

Synthesis and biological evaluation of novel non-racemic indole-containing allocolchicinoids

Two novel indole-containing allocolchicinoids were prepared from naturally occurring coichicine exploiting the Curtius rearrangement and tandem Sonogashira coupling/Pd-catalyzed cyclization as the key transformations. Their cytotoxic properties, apoptosis-inducing activity, tubulin assembly inhibition and short-time cytotoxic effects were investigated. Compound 7 demonstrated the most pronounced anti-cancer activity: IC50 < 1 nM, cell cycle arrest in the G2/M phase, 25% apoptosis induction, as well as lower destructive short-time effects on HT-29 cell line in comparison with colchicine. Docking studies for prepared indole-derived allocolchicine analogues were carried out. (C) 2017 Elsevier Masson SAS. All rights reserved

Discovery of dihydrofuranoallocolchicinoids - Highly potent antimitotic agents with low acute toxicity

International audienceTwo series of heterocyclic colchicinoids bearing β-methylenedihydrofuran or 2H-pyran-2-one fragments were synthesized by the intramolecular Heck reaction. Methylenedihydrofuran compounds 9a and 9h were found to be the most cytotoxic among currently known colchicinoids, exhibiting outstanding antiproliferative activity on tumor cell lines in picomolar (0.01-2.1 nM) range of concentrations. Compound 9a potently and substoichiometrically inhibits microtubule formation in vitro, being an order of magnitude more active in this assay than colchicine. Derivatives 9a and 9h revealed relatively low acute toxicity in mice (LD50 ≥ 10 mg/kg i.v.). The X-Ray structure of colchicinoid 9a bound to tubulin confirmed interaction of this compound with the colchicine binding site of tubulin

Stereoselective C-Glycosylation Reactions with Arylzinc Reagents

A general, transition-metal-free, highly stereoselective cross-coupling reaction between glycosyl bromides and various arylzinc reagents leading to β-arylated glycosides is reported. The stereoselectivity of the reaction is explained by invoking anchimeric assistance via a bicyclic intermediate. Stereochemical probes confirm the participation of the 2-pivaloyloxy group. Finally, this new method was applied to a short and efficient stereoselective synthesis of Dapagliflozin and Canagliflozin