Computational Assessment and Understanding of C6 Product Selectivity for Chromium Phosphinoamidine Catalyzed Ethylene Trimerization

One approach to selectively generate 1-hexene is through ethylene trimerization using highly active Cr N-phosphinoamidine catalysts ((P,N)Cr). Depending on the ligand, (P,N)Cr catalysts can either generate nearly pure 1-hexene or form 1-hexene with significant mixtures of other C6 mass products, for example methylenecyclopentane. Here we report DFT transition state modeling examining 1-hexene catalysis pathways as well as pathways that lead to alternative C6 mass products. This provided qualitative and semi-quantitative modeling of the experimental 1-hexene purity values for several (P,N)Cr catalysts. Consistent with previous computational studies, the key 1-hexene purity-determining transition states were determined to be β-hydrogen transfer structures from the metallacycloheptane intermediate. The origin of selectivity for these (P,N)Cr catalysts can be attributed to steric effects in the transition-state structure with coordinated ethylene that leads to C6 impurities.

Elucidating the anti-cancer mechanisms for transition-state structure inhibitors of nucleoside phosphorylases methylthioadenosine-DADMe-immucillin A and forodesine

<p>Transition-state structure analogues are among the most powerful chemical inhibitors discovered to date with picomolar efficacy for enzymes. The nucleoside analogue methylthioadenosine-DADMe-immucillin A (MTDIA) is an inhibitor of the enzyme methylthioadenosine phosphorylase (MTAP) in polyamine biosynthesis. The recently approved forodesine (Mundesine®) is an inhibitor of purine nucleoside phosphorylase (PNP) and purine synthesis. Although the targets of these drugs were known at the time of drug design, it is important to know the compendium of cellular perturbations resulting from use of these inhibitors. Several suspected mechanisms of MTDIA and forodesine in progression of apoptotic cell death have been identified but the underlying mechanisms initiating apoptosis remain elusive. We hypothesize that numerous cellular processes are affected in MTDIA and forodesine treatments given the importance of polyamine and purine synthesis in cancer cells. To elucidate the unsuspected mechanisms mediating anti-cancer activity, unbiased genomic analyses were employed using Saccharomyces cerevisiae. First, gene-gene interactions with MEU1 (the MTAP orthologue in yeast) were determined using Synthetic Genetic Array methodology followed by assessment of drug-gene interactions with MTDIA treatment under a MEU1 essential condition with MTA as the sole source of sulphur. Disruptions to suspected mechanisms of amino acid metabolism, carbohydrate metabolism, response to starvation, vesicle-mediated transport, vacuole fusion, lipid homeostasis, chromatin organisation, transcription, and translation were implicated well as unsuspected mechanisms of NAD+ dependent cellular processes, multi-vesicular body formation, endosomal transport, ion homeostasis, mitochondrion organisation, and cell cycle progression. Induction of autophagy was subsequently confirmed with MTDIA to validate the disruptions to vesicle-mediated transport, response to starvation, multi-vesicular body formation and vacuolar fusion. Reduction in ergosterol levels and disruptions to ergosterol biosynthetic proteins were confirmed with MTDIA and meu1Δ to validate disruptions to lipid homeostasis. To complement the genetic analyses, the abundance and localisation of proteins were evaluated in response to MTDIA or MEU1-deficiency. Disruptions to proteins implicated in carbohydrate metabolism, methionine salvage, transcription, translation, transmembrane transport, lipid homeostasis, cell cycle and DNA repair were identified with meu1Δ and MTDIA. Key findings from the analysis of protein abundance and localization were the relocalisation of plasma membrane proteins and disruptions to vesicle mediated transport proteins consistent with the induction of autophagy and disruptions to proteins in homeostasis of all major lipid classes, further corroborating the findings of screening gene deletion mutants for elucidating drug mechanisms. To investigate the mechanisms of forodesine toxicity, genetic interactions with PNP1 (the PNP orthologue in yeast) were determined using Synthetic Genetic Array methodology. Disruptions to amino acid metabolism, starvation responsive genes, vacuolar organisation and vesicle mediated transport, carbohydrate metabolism, lipid homeostasis, chromatin organisation, chromosome segregation, transcription, and translation were identified in response to PNP1-deficency. Despite the introduction of several human genes and supplementation of metabolites required for forodesine bioactivity in humans, forodesine was not sufficiently bioactive in yeast to evaluate sensitivity of gene deletion mutants to forodesine. Overall, chemical genomic analyses in yeast with transition-state structure analogues MTDIA and forodesine effectively highlight the vast number of cellular processes affected by inhibition of a single target. Moreover, genome-wide pre-screening should be carried out in yeast to identify side-effects and secondary effects from drug target inhibition prior to assessing desired and undesired outcomes of highly specific drugs in human cells.</p>

Elucidating the anti-cancer mechanisms for transition-state structure inhibitors of nucleoside phosphorylases methylthioadenosine-DADMe-immucillin A and forodesine

<p>Transition-state structure analogues are among the most powerful chemical inhibitors discovered to date with picomolar efficacy for enzymes. The nucleoside analogue methylthioadenosine-DADMe-immucillin A (MTDIA) is an inhibitor of the enzyme methylthioadenosine phosphorylase (MTAP) in polyamine biosynthesis. The recently approved forodesine (Mundesine®) is an inhibitor of purine nucleoside phosphorylase (PNP) and purine synthesis. Although the targets of these drugs were known at the time of drug design, it is important to know the compendium of cellular perturbations resulting from use of these inhibitors. Several suspected mechanisms of MTDIA and forodesine in progression of apoptotic cell death have been identified but the underlying mechanisms initiating apoptosis remain elusive. We hypothesize that numerous cellular processes are affected in MTDIA and forodesine treatments given the importance of polyamine and purine synthesis in cancer cells. To elucidate the unsuspected mechanisms mediating anti-cancer activity, unbiased genomic analyses were employed using Saccharomyces cerevisiae. First, gene-gene interactions with MEU1 (the MTAP orthologue in yeast) were determined using Synthetic Genetic Array methodology followed by assessment of drug-gene interactions with MTDIA treatment under a MEU1 essential condition with MTA as the sole source of sulphur. Disruptions to suspected mechanisms of amino acid metabolism, carbohydrate metabolism, response to starvation, vesicle-mediated transport, vacuole fusion, lipid homeostasis, chromatin organisation, transcription, and translation were implicated well as unsuspected mechanisms of NAD+ dependent cellular processes, multi-vesicular body formation, endosomal transport, ion homeostasis, mitochondrion organisation, and cell cycle progression. Induction of autophagy was subsequently confirmed with MTDIA to validate the disruptions to vesicle-mediated transport, response to starvation, multi-vesicular body formation and vacuolar fusion. Reduction in ergosterol levels and disruptions to ergosterol biosynthetic proteins were confirmed with MTDIA and meu1Δ to validate disruptions to lipid homeostasis. To complement the genetic analyses, the abundance and localisation of proteins were evaluated in response to MTDIA or MEU1-deficiency. Disruptions to proteins implicated in carbohydrate metabolism, methionine salvage, transcription, translation, transmembrane transport, lipid homeostasis, cell cycle and DNA repair were identified with meu1Δ and MTDIA. Key findings from the analysis of protein abundance and localization were the relocalisation of plasma membrane proteins and disruptions to vesicle mediated transport proteins consistent with the induction of autophagy and disruptions to proteins in homeostasis of all major lipid classes, further corroborating the findings of screening gene deletion mutants for elucidating drug mechanisms. To investigate the mechanisms of forodesine toxicity, genetic interactions with PNP1 (the PNP orthologue in yeast) were determined using Synthetic Genetic Array methodology. Disruptions to amino acid metabolism, starvation responsive genes, vacuolar organisation and vesicle mediated transport, carbohydrate metabolism, lipid homeostasis, chromatin organisation, chromosome segregation, transcription, and translation were identified in response to PNP1-deficency. Despite the introduction of several human genes and supplementation of metabolites required for forodesine bioactivity in humans, forodesine was not sufficiently bioactive in yeast to evaluate sensitivity of gene deletion mutants to forodesine. Overall, chemical genomic analyses in yeast with transition-state structure analogues MTDIA and forodesine effectively highlight the vast number of cellular processes affected by inhibition of a single target. Moreover, genome-wide pre-screening should be carried out in yeast to identify side-effects and secondary effects from drug target inhibition prior to assessing desired and undesired outcomes of highly specific drugs in human cells.</p>

Morita-Baylis-Hillman Reaction. A Caveat

It is an oversight to consider that a Lewis base such as a trialkylamine adds to an activated alkene in conjugate fashion to generate an enolate as a 1,5-zwitterion, which next reacts in aldol fashion with an electrophile such as an aldehyde to move on further through other events to the Morita-Baylis-Hillman product. It is demonstrated from computational investigations that the union of trialkylamine and activated alkene leads possibly to a very low level charge-transfer entity, wherein the p-electron density of the alkene has little perturbed to call it an enolate in the conventional sense. It is suggested to consider the aldol reaction as the first step of the Morita-Baylis-Hillman reaction and arrive at the corresponding transition state structure directly from the three entities.

Morita-Baylis-Hillman Reaction. A Caveat

It is an oversight to consider that a Lewis base such as a trialkylamine adds to an activated alkene in conjugate fashion to generate an enolate as a 1,5-zwitterion, which next reacts in aldol fashion with an electrophile such as an aldehyde to move on further through other events to the Morita-Baylis-Hillman product. It is demonstrated from computational investigations that the union of trialkylamine and activated alkene leads possibly to a very low level charge-transfer entity, wherein the p-electron density of the alkene has little perturbed to call it an enolate in the conventional sense. It is suggested to consider the aldol reaction as the first step of the Morita-Baylis-Hillman reaction and arrive at the corresponding transition state structure directly from the three entities.

Ni/Photoredox-Catalyzed Enantioselective Cross-Electrophile Coupling of Styrene Oxides with Aryl Iodides

A Ni/photoredox-catalyzed enantioselective reductive coupling of styrene oxides and aryl iodides is reported. This reaction affords access to enantioenriched 2,2-diarylalcohols from racemic epoxides via a stereoconvergent mechanism. Multivariate linear regression (MVLR) analysis with 29 bioxazoline (BiOx) and biimidazoline (BiIm) ligands revealed that enantioselectivity correlates with electronic properties of the ligands, with more electron-donating ligands affording higher ee’s. Mechanistic studies were conducted, lending support to the hypothesis that the electronic character of the ligands influences the enantioselectivity by altering the position of the transition state structure along the reaction coordinate. This study demonstrates the benefits of utilizing statistical modeling as a platform for mechanistic understanding and provides new insight into an emerging class of chiral ligands for stereoconvergent Ni and Ni/photoredox cross-coupling.

Ni/Photoredox-Catalyzed Enantioselective Cross-Electrophile Coupling of Styrene Oxides with Aryl Iodides

A Ni/photoredox-catalyzed enantioselective reductive coupling of styrene oxides and aryl iodides is reported. This reaction affords access to enantioenriched 2,2-diarylalcohols from racemic epoxides via a stereoconvergent mechanism. Multivariate linear regression (MVLR) analysis with 29 bioxazoline (BiOx) and biimidazoline (BiIm) ligands revealed that enantioselectivity correlates with electronic properties of the ligands, with more electron-donating ligands affording higher ee’s. Mechanistic studies were conducted, lending support to the hypothesis that the electronic character of the ligands influences the enantioselectivity by altering the position of the transition state structure along the reaction coordinate. This study demonstrates the benefits of utilizing statistical modeling as a platform for mechanistic understanding and provides new insight into an emerging class of chiral ligands for stereoconvergent Ni and Ni/photoredox cross-coupling.

The significance of long-range correction to the hydroperoxyl radical-scavenging reaction of trans-resveratrol and gnetin C

Density functional theory has been gaining popularity for studying the radical scavenging activity of antioxidants. However, only a few studies investigate the importance of calculation methods on the radical-scavenging reactions. In this study, we examined the significance of (i) the long-range correction on the coulombic interaction and (ii) the London dispersion correction to the hydroperoxyl radical-scavenging reaction of trans-resveratrol and gnetin C. We employed B3LYP, CAM-B3LYP, M06-2X exchange-correlation functionals and B3LYP with the D3 version of Grimme’s dispersion in the calculations. The results showed that long-range correction on the coulombic interaction had a significant effect on the increase of reaction and activation energies. The increase was in line with the change of hydroperoxyl radical’s orientation in the transition state structure. Meanwhile, the London dispersion correction only had a minor effect on the transition state structure, reaction energy and activation energy. Overall, long-range correction on the coulombic interaction had a significant impact on the radical-scavenging reaction.

Reactions of aryl dimethylphosphinothioate esters with anionic oxygen nucleophiles: transition state structure in 70% water–30% ethanol

Solvent stabilization of initial state (along x, y axis) leads to looser TS (vector z).

Anion-Accelerated Aromatic Oxy-Cope Rearrangement in Geranylation/Nerylation of Xanthone: Stereochemical Insights and Synthesis of Fuscaxanthone F

An efficient installation of a 3,7-dimethylocta-2,6-dien-1-yl (geranyl or neryl) side chain at the C(1) position of a xanthone core by utilizing an anion-accelerated aromatic oxy-Cope rearrangement is described. Experiments revealed that this uncommon rearrangement takes place in a stereospecific manner through a chair-like transition-state structure. An application to the syntheses of the natural xanthone fuscaxanthone F, possessing a geranyl side chain, and its neryl analogue is also described.