Design and Optimization of Catalysts Based on Mechanistic Insights Derived from Quantum Chemical Reaction Modeling

© 2019 American Chemical Society.Until recently, computational tools were mainly used to explain chemical reactions after experimental results were obtained. With the rapid development of software and hardware technologies to make computational modeling tools more reliable, they can now provide valuable insights and even become predictive. In this review, we highlighted several studies involving computational predictions of unexpected reactivities or providing mechanistic insights for organic and organometallic reactions that led to improved experimental results. Key to these successful applications is an integration between theory and experiment that allows for incorporation of empirical knowledge with precise computed values. Computer modeling of chemical reactions is already a standard tool that is being embraced by an ever increasing group of researchers, and it is clear that its utility in predictive reaction design will increase further in the near futur

Scorpionate Catalysts for Coupling CO2 and Epoxides to Cyclic Carbonates: A Rational Design Approach for Organocatalysts

Novel scorpionate-type organocatalysts capable of effectively coupling carbon dioxide and epoxides under mild conditions to afford cyclic propylene carbonates were developed. On the basis of a combined experimental and computational study, a precise mechanistic proposal was developed and rational optimization strategies were identified. The epoxide ring-opening, which requires an iodide as a nucleophile, was enhanced by utilizing an immonium functionality that can form an ion pair with iodide, making the ring opening process intramolecular. The CO2 activation and cyclic carbonate formation were catalyzed by the concerted action of two hydrogen bonds originating from two phenolic groups placed at the claw positions of the scorpionate scaffold. Electronic tuning of the hydrogen bond donors allowed to identify a new catalyst that can deliver >90% yield for a variety of epoxide substrates within 7 h at room temperature under a CO2 pressure of only 10 bar, and is highly recyclable © 2018 American Chemical Societ

Excited-State Intramolecular Hydrogen Transfer of Compact Molecules Controls Amyloid Aggregation Profiles

© 2022 The Authors. Published by American Chemical Society.Developing chemical methodologies to directly modify harmful biomolecules affords the mitigation of their toxicity by persistent changes in their properties and structures. Here we report compact photosensitizers composed of the anthraquinone (AQ) backbone that undergo excited-state intramolecular hydrogen transfer, effectively oxidize amyloidogenic peptides, and, subsequently, alter their aggregation pathways. Density functional theory calculations showed that the appropriate position of the hydroxyl groups in the AQ backbone and the consequent intramolecular hydrogen transfer can facilitate the energy transfer to triplet oxygen. Biochemical and biophysical investigations confirmed that these photoactive chemical reagents can oxidatively vary both metal-free amyloid-β (Aβ) and metal-bound Aβ, thereby redirecting their on-pathway aggregation into off-pathway as well as disassembling their preformed aggregates. Moreover, the in vivo histochemical analysis of Aβ species produced upon photoactivation of the most promising candidate demonstrated that they do not aggregate into oligomeric or fibrillar aggregates in the brain. Overall, our combined computational and experimental studies validate a light-based approach for designing small molecules, with minimum structural complexity, as chemical reagents targeting and controlling amyloidogenic peptides associated with neurodegenerative disorders.11Nsciescopu

Excited-State Intramolecular Hydrogen Transfer of Compact Molecules Controls Amyloid Aggregation Profiles

Designing new chromophores by tuning their molecular structures and optimizing their photophysical properties leads to suitable photochromic features. Herein, we report a series of anthraquinone (AQ)-based photosensitizers that undergoes excited-state intramolecular hydrogen transfer and effectively oxidizes amyloidogenic peptides, which significantly affects the subsequent aggregation pathways. DFT calculations showed that the appropriate position of the hydroxyl groups in the AQ backbone and the consequent intramolecular hydrogen transfer can facilitate the energy transfer to triplet oxygen. Biochemical and biophysical investigations confirmed that these photoactive chemical reagents are able to oxidatively modify both metal-free amyloid-β (Aβ) and metal-bound Aβ, thereby redirecting their on-pathway aggregation into off-pathway as well as disassembling their pre-formed aggregates. Moreover, the in vivo histochemical analysis of Aβ species produced upon photoactivation of the most promising candidate demonstrated that they do not aggregate into toxic oligomeric or fibrillar aggregates in the brain. Overall, our combined computational and experimental studies validate a light-based approach for designing small molecules as chemical reagents targeting and controlling amyloidogenic peptides associated with neurodegenerative disorders

Strategies for developing flavonoids with multiple reactivities against pathological features in Alzheimer’s disease

The etiology of Alzheimer’s disease (AD) is still unknown because of its complicated nature associated with various pathological components, including free radicals, acetylcholinesterase, and metal-free and metal-bound amyloid-beta. Thus, chemical reagents with modulating reactivities against multiple pathogenic factors are necessary for advancing our understanding of the complex pathogenesis. Here we report rational strategies for developing flavonoids that can control multiple pathological elements found in the brains of AD patients. Our investigations employing a series of flavonoids illuminated structural features critical for regulatory reactivities against desired targets. Moreover, the most promising flavonoid with multiple functions was developed based on our complete structure–activity relationship. Mechanistic studies confirmed that such versatile reactivities of the flavonoid are achieved by its redox potential and direct interactions with pathogenic factors. Overall, our studies demonstrate the feasibility of devising small molecules as multifunctional chemical reagents against pathological features found in AD

Designing multi-target-directed flavonoids: a strategic approach to Alzheimer's disease

The underlying causes of Alzheimer's disease (AD) remain a mystery, with multiple pathological components, including oxidative stress, acetylcholinesterase, amyloid-b, and metal ions, all playing a role. Here we report a strategic approach to designing flavonoids that can effectively tackle multiple pathological elements involved in AD. Our systematic investigations revealed key structural features for flavonoids to simultaneously target and regulate pathogenic targets. Our findings led to the development of a highly promising flavonoid that exhibits a range of functions, based on a complete structure–activity relationship analysis. Furthermore, our mechanistic studies confirmed that this flavonoid's versatile reactivities are driven by its redox potential and direct interactions with pathogenic factors. This work highlights the potential of multi-target-directed flavonoids as a novel solution in the fight against AD

Scorpionate Catalysts for Coupling CO₂ and Epoxides to Cyclic Carbonates: A Rational Design Approach for Organocatalysts

Novel scorpionate-type organocatalysts capable of effectively coupling carbon dioxide and epoxides under mild conditions to afford cyclic propylene carbonates were developed. On the basis of a combined experimental and computational study, a precise mechanistic proposal was developed and rational optimization strategies were identified. The epoxide ring-opening, which requires an iodide as a nucleophile, was enhanced by utilizing an immonium functionality that can form an ion pair with iodide, making the ring-opening process intramolecular. The CO₂ activation and cyclic carbonate formation were catalyzed by the concerted action of two hydrogen bonds originating from two phenolic groups placed at the claw positions of the scorpionate scaffold. Electronic tuning of the hydrogen bond donors allowed to identify a new catalyst that can deliver >90% yield for a variety of epoxide substrates within 7 h at room temperature under a CO₂ pressure of only 10 bar, and is highly recyclable

Understanding the Origin of the Regioselectivity in Cyclopolymerizations of Diynes and How to Completely Switch It

Grubbs-type olefin metathesis catalysts are known to cyclopolymerize 1,6-heptadiynes to afford conjugated polyenes containing five- or six-membered carbocycles. Although high levels of regioselectivity up to >99:1 were observed previously for the formation of five-membered rings, it was neither possible to deliberately obtain six-membered rings at similar levels of selectivity nor understood why certain catalysts showed this selectively. Combining experimental and computational methods, a novel and general theory for what controls the regiochemistry of these cyclopolymerizations is presented. The electronic demands of the ruthenium-based Fischer carbenes are found to innately prefer to form five-membered rings. Reducing the electrophilicity of the carbene by enforcing a trigonal-bipyramidal structure for the ruthenium, where stronger π-backdonation increases the electron density on the carbene, is predicted to invert the regioselectivity. Subsequent experiments provide strong support for the new concept, and it is possible to completely switch the regioselectivity to a ratio of <1:99

Cytochrome c as a distinct modulator of amyloid-beta amyloidogenesis in a peroxide-dependent manner

Cytochrome c (Cyt c) is an important, multifunctional protein for controlling cell fate. Emerging evidence suggests a potential role of Cyt c in the amyloid pathology associated with Alzheimer’s disease (AD); however, the interaction between Cyt c and Abeta with the consequent impact on the aggregation and toxicity of Abeta is not known. Here we report the discovery that Cyt c can directly bind to Abeta and alter the aggregation and toxicity profiles of Abeta in a peroxide-dependent manner. Cyt c redirects Abeta peptides into less toxic, off-pathway amorphous aggregates in the presence of hydrogen peroxide (H2O2), whereas it accelerates Abeta fibrillization without H2O2. Such effects can be achieved by three possible mechanisms, including the complexation between Cyt c and Abeta, the oxidation of Abeta by Cyt c and H2O2, and the H2O2-mediated modification of Cyt c. Our studies demonstrate a new function of Cyt c as a modulator against Abeta amyloidogenesis

Scorpionate Catalysts for Coupling CO₂ and Epoxides to Cyclic Carbonates: A Rational Design Approach for Organocatalysts

Novel scorpionate-type organocatalysts capable of effectively coupling carbon dioxide and epoxides under mild conditions to afford cyclic propylene carbonates were developed. On the basis of a combined experimental and computational study, a precise mechanistic proposal was developed and rational optimization strategies were identified. The epoxide ring-opening, which requires an iodide as a nucleophile, was enhanced by utilizing an immonium functionality that can form an ion pair with iodide, making the ring-opening process intramolecular. The CO₂ activation and cyclic carbonate formation were catalyzed by the concerted action of two hydrogen bonds originating from two phenolic groups placed at the claw positions of the scorpionate scaffold. Electronic tuning of the hydrogen bond donors allowed to identify a new catalyst that can deliver >90% yield for a variety of epoxide substrates within 7 h at room temperature under a CO₂ pressure of only 10 bar, and is highly recyclable