With new advances in theoretical methods and increased computational power, applications of computational chemistry are becoming practical and routine in many fields of chemistry. In organic ...chemistry, computational chemistry plays an indispensable role in elucidating reaction mechanisms and the origins of various selectivities, such as chemo-, regio-, and stereoselectivities. Consequently, mechanistic understanding improves synthesis and assists in the rational design of new catalysts. In this Account, we present some of our recent works to illustrate how computational chemistry provides new mechanistic insights for improvement of the selectivities of several organic reactions. These examples include not only explanations for the existing experimental observations, but also predictions which were subsequently verified experimentally. This Account consists of three sections discuss three different kinds of selectivities. The first section discusses the regio- and stereoselectivities of hydrosilylations of alkynes, mainly catalyzed by Cp*Ru(MeCN)3+ or CpRu(MeCN)3+. Calculations suggest a new mechanism that involves a key ruthenacyclopropene intermediate. This mechanism not only explains the unusual Markovnikov regio-selectivity and anti-addition stereoselectivity observed by Trost and co-workers, but also motivated further experimental investigations. New intriguing experimental observations and further theoretical studies led to an extension of the reaction mechanism. The second section includes three cases of meta-selective C–H activation of aryl compounds. In the case of Cu-catalyzed selective meta-C–H activation of aniline, a new mechanism that involves a Cu(III)-Ar-mediated Heck-like transition state, in which the Ar group acts as an electrophile, was proposed. This mechanism predicted a higher reactivity for more electron-deficient Ar groups, which was supported by experiments. For two template-mediated, meta-selective C–H bond activations catalyzed by Pd(II), different mechanisms were derived for the two templates. One involves a dimeric Pd–Pd or Pd–Ag active catalyst, and the other involves a monomeric Pd catalyst, in which a monoprotected amino acid coordinates in a bidentate fashion and serves as an internal base for C–H activation. The third section discusses a desymmetry strategy in asymmetric synthesis. The construction of rigid skeletons is critical for these catalysts to distinguish two prochiral groups. Overall, fruitful collaborations between computational and experimental chemists have provided new and comprehensive mechanistic understanding and insights into these useful reactions.
Bisborylalkanes play important roles in organic synthesis as versatile bifunctional reagents. The two boron moieties in these compounds can be selectively converted into other functional groups ...through cross‐coupling, oxidation or radical reactions. Thus, the development of efficient methods for synthesizing bisborylalkanes is highly demanded. Herein we report a new strategy to access bisborylalkanes through the reaction of N‐trisylhydrazones with diboronate, in which the bis(boryl) methane is transformed into 1,2‐bis(boronates) via formal carbene insertion. Since the N‐trisylhydrazones can be readily derived from the corresponding aldehydes, this strategy represents a practical synthesis of 1,2‐diboronates with broad substrate scope. Mechanistic studies reveal an unusual neighboring group effect of 1,1‐bis(boronates), which accounts for the observed regioselectivity when unsymmetric 1,1‐diboronates are applied.
Intermolecular reaction of N‐trisylhydrazones with bis (boryl) methane led to the transformation of 1,1‐diboronate into 1,2‐bis(boronates) via 1,2‐borylmethyl migration. With unsymmetric diboronates with two different boryl moieties, the reaction proceeded with excellent regioselectivity. DFT studies reveal an unusual neighbouring boryl group effect that accounts for the observed regioselectivity.
A hybrid palladium catalyst assembled from a chiral phosphoric acid (CPA) and thioamide enables a highly efficient and enantioselective β‐C(sp3)−H functionalization of thioamides (up to 99 % yield, ...97 % ee). A kinetic resolution of unsymmetrical thioamides by intermolecular C(sp3)−H arylation can be achieved with high s‐factors. Mechanistic investigations have revealed that stereocontrol is achieved by embedding the substrate in a robust chiral cavity defined by the bulky CPA and a neutral thioamide ligand.
Bulk up: A Pd‐catalyzed enantioselective β‐C(sp3)−H functionalization of thioamides has been developed using a chiral phosphoric acid (CPA) as the chiral auxiliary. Mass spectrometry studies and DFT analysis elucidate the role of the bulky CPA and the assistance of the thioamide ligand, which define a robust chiral cavity for achieving a high level of stereocontrol.
An important pathological feature of Alzheimer's disease (AD) is the presence of extracellular senile plaques in the brain. Senile plaques are composed of aggregations of small peptides called ...β-amyloid (Aβ). Multiple lines of evidence demonstrate that overproduction/aggregation of Aβ in the brain is a primary cause of AD and inhibition of Aβ generation has become a hot topic in AD research. Aβ is generated from β-amyloid precursor protein (APP) through sequential cleavages first by β-secretase and then by γ-secretase complex. Alternatively, APP can be cleaved by α-secretase within the Aβ domain to release soluble APPα and preclude Aβ generation. Cleavage of APP by caspases may also contribute to AD pathologies. Therefore, understanding the metabolism/processing of APP is crucial for AD therapeutics. Here we review current knowledge of APP processing regulation as well as the patho/physiological functions of APP and its metabolites.
Understanding the mechanisms of chemical reactions, especially catalysis, has been an important and active area of computational organic chemistry, and close collaborations between experimentalists ...and theorists represent a growing trend. This Perspective provides examples of such productive collaborations. The understanding of various reaction mechanisms and the insight gained from these studies are emphasized. The applications of various experimental techniques in elucidation of reaction details as well as the development of various computational techniques to meet the demand of emerging synthetic methods, e.g., C–H activation, organocatalysis, and single electron transfer, are presented along with some conventional developments of mechanistic aspects. Examples of applications are selected to demonstrate the advantages and limitations of these techniques. Some challenges in the mechanistic studies and predictions of reactions are also analyzed.
Autism spectrum disorder (ASD) is a highly heterogeneous neurodevelopmental disorder with onset in childhood. The molecular mechanisms underlying ASD have not yet been elucidated completely. Evidence ...has emerged to support a link between microglial dysfunction and the etiology of ASD. This review summarizes current research on microglial dysfunction in neuroinflammation and synaptic pruning, which are associated with altered transcriptomes and autophagy in ASD. Dysbiosis of gut microbiota in ASD and its correlation with microglial dysfunction are also addressed.
The addition of a precisely positioned chiral center in the tether of a constrained peptide is reported, yielding two separable peptide diastereomers with significantly different helicity, as ...supported by circular dichroism (CD) and NMR spectroscopy. Single crystal X‐ray diffraction analysis suggests that the absolute configuration of the in‐tether chiral center in helical form is R, which is in agreement with theoretical simulations. The relationship between the secondary structure of the short peptides and their biochemical/biophysical properties remains elusive, largely because of the lack of proper controls. The present strategy provides the only method for investigating the influence of solely conformational differences upon the biochemical/biophysical properties of peptides. The significant differences in permeability and target binding affinity between the peptide diastereomers demonstrate the importance of helical conformation.
Chirality induced helicity: A precisely positioned in‐tether carbon chiral center was able to modulate the helicity, cell permeability, and target binding affinity of a peptide. This study provides an excellent method for studying the relationship between the conformation and biochemical/biophysical properties of peptides.
Cardiovascular disease (CVD), including heart attack, stroke, heart failure, arrhythmia, and other congenital heart diseases remain the leading cause of morbidity and mortality worldwide. The leading ...cause of deaths in CVD is attributed to myocardial infarction due to the rupture of atherosclerotic plaque. Atherosclerosis refers a condition when restricted or even blockage of blood flow occurs due to the narrowing of blood vessels as a result of the buildup of plaques composed of oxidized lipids. It is well-established that free radical oxidation of polyunsaturated fatty acids (PUFAs) in lipoproteins or cell membranes, termed lipid peroxidation (LPO), plays a significant role in atherosclerosis. LPO products are involved in immune responses and cell deaths in this process, in which previous evidence supports the role of programmed cell death (apoptosis) and necrosis. Ferroptosis is a newly identified form of regulated cell death characterized by the iron-dependent accumulation of lipid hydroperoxides to lethal levels, which exhibits distinct features from apoptosis, necrosis and autophagy in morphology, biochemistry and genetics. Emerging evidence appears to demonstrate that ferroptosis is also involved in CVD. In this review, we summarize the recent progress on ferroptosis in CVD and atherosclerosis, highlighting the role of free radical LPO. The evidence underlying the ferroptosis and challenges in the field will also be critically discussed.
Aucubin (Au), an iridoid glycoside from natural plants, has antioxidative and anti-inflammatory bioactivities; however, its effects on a traumatic brain injury (TBI) model remain unknown. We explored ...the potential role of Au in an H
O
-induced oxidant damage in primary cortical neurons and weight-drop induced-TBI in a mouse model.
In vitro experiments, the various concentrations of Au (50 μg/ml, 100 μg/ml, or 200 μg/ml) were added in culture medium at 0 h and 6 h after neurons stimulated by H
O
(100 μM). After exposed for 12 h, neurons were collected for western blot (WB), immunofluorescence, and M29,79-dichlorodihydrofluorescein diacetate (DCFH-DA) staining. In vivo experiments, Au (20 mg/kg or 40 mg/kg) was administrated intraperitoneally at 30 min, 12 h, 24 h, and 48 h after modeling. Brain water content, neurological deficits, and cognitive functions were measured at specific time, respectively. Cortical tissue around focal trauma was collected for WB, TdT-mediated dUTP Nick-End Labeling (TUNEL) staining, Nissl staining, quantitative real time polymerase chain reaction (q-PCR), immunofluorescence/immunohistochemistry, and enzyme linked immunosorbent assay (ELISA) at 72 h after TBI. RNA interference experiments were performed to determine the effects of nuclear factor erythroid-2 related factor 2 (Nrf2) on TBI mice with Au (40 mg/kg) treatment. Mice were intracerebroventricularly administrated with lentivirus at 72 h before TBI establishment. The cortex was obtained at 72 h after TBI and used for WB and q-PCR.
Au enhanced the translocation of Nrf2 into the nucleus, activated antioxidant enzymes, suppressed excessive generation of reactive oxygen species (ROS), and reduced cell apoptosis both in vitro and vivo experiments. In the mice model of TBI, Au markedly attenuated brain edema, histological damages, and improved neurological and cognitive deficits. Au significantly suppressed high mobility group box 1 (HMGB1)-mediated aseptic inflammation. Nrf2 knockdown in TBI mice blunted the antioxidant and anti-inflammatory neuroprotective effects of the Au.
Taken together, our data suggest that Au provides a neuroprotective effect in TBI mice model by inhibiting oxidative stress and inflammatory responses; the mechanisms involve triggering Nrf2-induced antioxidant system.
Tactile sensors capable of perceiving biophysical signals such as force, pressure, or strain have attracted extensive interest for versatile applications in electronic skin, noninvasive healthcare, ...and biomimetic prostheses. Despite these great achievements, they are still incapable of detecting bio/chemical signals that provide even more meaningful and precise health information due to the lack of efficient transduction principles. Herein, a tactile chemomechanical transduction strategy that enables the tactile sensor to perceive bio/chemical signals is proposed. In this methodology, pyramidal tactile sensors are linked with biomarker‐induced gas‐producing reactions, which transduce biomarker signals to electrical signals in real time. The method is advantageous as it enhances electrical signals by more than tenfold based on a triple‐step signal amplification strategy, as compared to traditional electrical biosensors. It also constitutes a portable and general platform capable of quantifying a wide spectrum of targets including carcinoembryonic antigen, interferon‐γ, and adenosine. Such tactile chemomechanical transduction would greatly broaden the application of tactile sensors toward bio/chemical signals perception which can be used in ultrasensitive portable biosensors and chemical‐responsive chemomechanical systems.
Tactile chemomechanical transduction is proposed, which allows tactile sensors to perceive bio/chemical signals. Based on an elastic pyramidal array, tactile sensors transduce chemical signals from biomarker‐induced gas‐producing reactions to electrical signals. This concept broadens the application domain of tactile sensors and also provides a general and ultrasensitive transduction principle for portable biosensors.
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