Mechanistic investigation of Rh(i)-catalysed asymmetric Suzuki–Miyaura coupling with racemic allyl halides

Understanding how catalytic asymmetric reactions with racemic starting materials can operate would enable new enantioselective cross-coupling reactions that give chiral products. Here we propose a catalytic cycle for the highly enantioselective Rh(I)-catalysed Suzuki–Miyaura coupling of boronic acids and racemic allyl halides. Natural abundance 13C kinetic isotope effects provide quantitative information about the transition-state structures of two key elementary steps in the catalytic cycle, transmetallation and oxidative addition. Experiments with configurationally stable, deuterium-labelled substrates revealed that oxidative addition can happen via syn- or anti-pathways, which control diastereoselectivity. Density functional theory calculations attribute the extremely high enantioselectivity to reductive elimination from a common Rh complex formed from both allyl halide enantiomers. Our conclusions are supported by analysis of the reaction kinetics. These insights into the sequence of bond-forming steps and their transition-state structures will contribute to our understanding of asymmetric Rh–allyl chemistry and enable the discovery and application of asymmetric reactions with racemic substrates

The efficacy of the quercetin analogue LY294002 in immortalized cancer cell lines is related to the oxygenic and metabolic status of cells

Purpose: LY294002, a promising drug for chemotherapy, suppresses the activity of Phosphatidylinositol 3-Kinase (PI3K) which is pivotal to a number of processes such as proliferation, metabolism, and apoptosis. The compound has, however, been seen to have very variable efficacy in vivo.Methods: Proliferation and viability of two immortalized cells with divergent bioenergetic profiles was determined using crystal violet staining, and the 3-(4, 5-dimethylthiazol-2yl)-2, 5-diphenyl tetrazolium bromide (MTT) assay. Oxygen consumption rates were determined using MitoXpress-Xtra probes, and lactate generation was assessed with pH-Xtra probe and BM-lactate strips. Immunoblotting was performed with phospho-Akt-Ser 473 and Akt-pan primary antibodies.Results: U87 cells were shown to have a glycolytic metabolism, whereas RD cells exhibited a more aerobic metabolism. In both lines, hypoxia was shown to increase lactate production, and LY294002 reduced lactate production. The drug decreased cell proliferation and viability under all conditions, but the effect was greatest in U87 cells under normoxic conditions.Conclusion: Metabolic analysis showed a link between a glycolytic cell status and LY294002 induced cell death. However, in both cell lines the drug was also less effective under hypoxic conditions, as would be found in a tumour in vivo. Furthermore, in the presence of LY294002 the phosphorylation status of Akt, a target of PI3K, was found to be related to both the mechanism of cell respiration, and the oxygenic status of the cells

Insights into transition metal catalysed asymmetric transformations

A crucial element in successfully developing efficient asymmetric catalytic reactions is finding a suitable chiral catalyst. Ligand discovery/development is not always easy to achieve. The most common practice often relies on trial and error. To move away from this, we have adopted a systematic approach that integrates traditional experimental screening approaches with statistical models (QSSR) and DFT calculations. Our aim is to increase useful information drawn from the experimental results, rather than just relying on chemical intuition alone. We have applied this approach to two copper catalysed conjugate addition reactions and an iridium catalysed hydrogenation, all of which involved chiral phosphoramidite ligands. The QSSR models are shown to be both predictive and informative. This approach is not limited to only transition metal catalysed reaction or only with phosphoramidite-type ligands. In theory, it is applicable to any asymmetric transformation of interest involving any type of ligand.</p

Mechanistic Investigation of Rh(I)-Catalyzed Asymmetric Suzuki-Miyaura Coupling with Racemic Allyl Halides

A mechanism for Rh(I)-catalyzed asymmetric Suzuki-Miyaura coupling with racemic allyl halides is proposed based on a combination of experimental studies and quantum chemical calculations. <br /

Enantioselective Conjugate Addition Catalyzed by a Copper Phosphoramidite Complex: Computational and Experimental Exploration of Asymmetric Induction

The stereochemical role of the phosphoramidite ligand in the asymmetric conjugate addition of alkylzirconium species to cyclic enones has been established through experimental and computational studies. Systematic, synthetic variation of the modular ligand established that the configuration of the binaphthol backbone is responsible for absolute stereocontrol, whereas modulation of the amido substituents leads to dramatic variations in the level of asymmetric induction. Chiral amido substituents are not required for enantioselectivity, leading to the discovery of a new family of easily synthesized phosphoramidites based on achiral amines that deliver equal levels of selectivity to Feringa’s ligand. A linear correlation between the length of the aromatic amido groups and experimentally determined enantioselectivity was uncovered for this class of ligand, which, following an optimization, led to highly selective ligands (up to 94% ee) with naphthyl rather than phenyl groups. An electronic effect of sterically similar aromatic substituents was investigated through NMR and DFT studies, showing that electron-rich aryl groups allow better Cu coordination. An interaction between the metal center and an aromatic group is responsible for this enhanced affinity and leads to a more tightly coordinated transition structure, leading to the major enantiomer. These studies illustrate the use of parametric quantitative structure–selectivity relationships to generate mechanistic models for asymmetric induction and catalyst structures that may be further probed by experiment and computation. This integrated approach leads to the rational modification of chiral ligands to achieve enhanced levels of selectivity