Ligand-to-Metal Charge Transfer (LMCT) Catalysis: Harnessing Simple Cerium Catalysts for Selective Functionalization of Inert C-H and C-C Bonds.

ConspectusChemists have long pursued harnessing light energy and photoexcitation processes for synthetic transformations. Ligand-to-metal charge transfer (LMCT) in high-valent metal complexes often triggers bond homolysis, generating oxidized ligand-centered radicals and reduced metal centers. While photoinduced oxidative activations can be enabled, this process, typically seen as photochemical decomposition, remains underexplored in catalytic applications. To mitigate decomposition during LMCT excitation, we developed a catalytic cycle integrating in situ coordination, LMCT, and ligand homolysis to activate ligated alcohols transiently into alkoxy radicals. This catalytic approach leverages Ce(IV) LMCT excitation and highly reactive alkoxy radical intermediates for selective functionalizations of C(sp3)-H and C(sp3)-C(sp3) bonds under mild conditions. In this Account, we discuss these advancements, highlighting the practical utility of cost-effective cerium salts as catalysts and their potential to develop innovative transformations, addressing long-standing synthetic challenges.Selective functionalization of chemically inert C(sp3)-H bonds has long posed a significant challenge. We first detail our research using LMCT-enabled alkoxy radical-mediated hydrogen atom transfer (HAT) processes for selective C(sp3)-H functionalizations. Using readily available CeCl3, we established a general protocol for employing free alcohols in the Barton reaction. By integrating LMCT and HAT catalysis, we introduced a selective photocatalytic strategy for functionalizing feedstock alkanes, converting gaseous hydrocarbons into valuable products. Employing simple cerium salts like Ce(OTf)3 and CeCl3, we achieved selective C-H amination of methane and ethane at ambient temperature, achieving turnover numbers of 2900 and 9700, respectively. This catalytic manifold has been further exploited to address the site-selectivity challenge in the C-H functionalization of linear alkanes. The use of methanol as a cocatalyst enabled preferential functionalization of the most electron-rich sites, achieving a high intrinsic selectivity over 12:1 of secondary vs primary sites in pentane and hexane.Next, we discuss the catalytic utilization of alkoxy-radical-mediated ß-scission, a frequently encountered side reaction in HAT transformations, for selective cleavage and functionalization of C-C bonds. The versatility of the LMCT catalytic platform facilitates the generation of alkoxy radicals from various free alcohols. In our initial demonstration of LMCT-enabled C(sp3)-C(sp3) bond activation, we developed a cerium-catalyzed ring-opening and amination of cycloalkanols, providing an effective protocol for cleaving unstrained C-C bonds. This strategy has been successfully applied to various radical cross-coupling processes, leading to innovative transformations such as ring expansions of cycloalkanols, dehydroxymethylative alkylation, amination, alkenylation, and ring expansions of cyclic ketones. These results highlight the synthetic potential of employing LMCT-mediated ß-scission and ubiquitous C-C bonds as unconventional functional handles for generating molecular complexity.Lastly, we delve into our mechanistic investigations. Beyond the catalytic application of Ce(IV) LMCT in various transformations, we have undertaken comprehensive mechanistic studies. These investigations encompass characterization of Ce(IV) alkoxide complexes to elucidate their structures, evaluation of their photoactivity and selectivity in radical generation, and elucidation of kinetic pathways associated with transient LMCT excited states. Our research has revealed ultrafast bond homolysis, back electron transfer, and the selectivity of heteroleptic complexes in homolysis, providing crucial insights for advancing LMCT catalysis.

Alkoxy Radicals See the Light: New Paradigms of Photochemical Synthesis.

Alkoxy radicals are highly reactive species that have long been recognized as versatile intermediates in organic synthesis. However, their development has long been impeded due to a lack of convenient methods for their generation. Thanks to advances in photoredox catalysis, enabling facile access to alkoxy radicals from bench-stable precursors and free alcohols under mild conditions, research interest in this field has been renewed. This review comprehensively summarizes the recent progress in alkoxy radical-mediated transformations under visible light irradiation. Elementary steps for alkoxy radical generation from either radical precursors or free alcohols are central to reaction development; thus, each section is categorized and discussed accordingly. Throughout this review, we have focused on the different mechanisms of alkoxy radical generation as well as their impact on synthetic utilizations. Notably, the catalytic generation of alkoxy radicals from abundant alcohols is still in the early stage, providing intriguing opportunities to exploit alkoxy radicals for diverse synthetic paradigms.

Research on predicting hematoma expansion in spontaneous intracerebral hemorrhage based on deep features of the VGG-19 network.

PURPOSE: To construct a clinical noncontrastive computed tomography (NCCT) deep learning joint model for predicting early hematoma expansion (HE) after cerebral hemorrhage (sICH) and evaluate its predictive performance. METHODS: All 254 patients with primary cerebral hemorrhage from January 2017 to December 2022 in the General Hospital of the Western Theater Command were included. According to the criteria of hematoma enlargement exceeding 33% or the volume exceeding 6 ml, the patients were divided into the HE group and the hematoma non-enlargement (NHE) group. Multiple models and the 10-fold cross-validation method were used to screen the most valuable features and model the probability of predicting HE. The area under the curve (AUC) was used to analyze the prediction efficiency of each model for HE. RESULTS: They were randomly divided into a training set of 204 cases in an 8:2 ratio and 50 cases of the test set. The clinical imaging deep feature joint model (22 features) predicted the area under the curve of HE as follows: clinical Navie Bayes model AUC 0.779, traditional radiology logistic regression (LR) model AUC 0.818, deep learning LR model AUC 0.873, and clinical NCCT deep learning multilayer perceptron model AUC 0.921. CONCLUSION: The combined clinical imaging deep learning model has a high predictive effect for early HE in sICH patients, which is helpful for clinical individualized assessment of the risk of early HE in sICH patients.

Identification of Alkoxy Radicals as Hydrogen Atom Transfer Agents in Ce-Catalyzed C-H Functionalization.

The intermediacy of alkoxy radicals in cerium-catalyzed C-H functionalization via H-atom abstraction has been unambiguously confirmed. Catalytically relevant Ce(IV)-alkoxide complexes have been synthesized and characterized by X-ray diffraction. Operando electron paramagnetic resonance and transient absorption spectroscopy experiments on isolated pentachloro Ce(IV) alkoxides identified alkoxy radicals as the sole heteroatom-centered radical species generated via ligand-to-metal charge transfer (LMCT) excitation. Alkoxy-radical-mediated hydrogen atom transfer (HAT) has been verified via kinetic analysis, density functional theory (DFT) calculations, and reactions under strictly chloride-free conditions. These experimental findings unambiguously establish the critical role of alkoxy radicals in Ce-LMCT catalysis and definitively preclude the involvement of chlorine radical. This study has also reinforced the necessity of a high relative ratio of alcohol vs Ce for the selective alkoxy-radical-mediated HAT, as seemingly trivial changes in the relative ratio of alcohol vs Ce can lead to drastically different mechanistic pathways. Importantly, the previously proposed chlorine radical-alcohol complex, postulated to explain alkoxy-radical-enabled selectivities in this system, has been examined under scrutiny and ruled out by regioselectivity studies, transient absorption experiments, and high-level calculations. Moreover, the peculiar selectivity of alkoxy radical generation in the LMCT homolysis of Ce(IV) heteroleptic complexes has been analyzed and back-electron transfer (BET) may have regulated the efficiency and selectivity for the formation of ligand-centered radicals.

Atrophy in subcortical gray matter in adult patients with moyamoya disease.

BACKGROUND: Acute cerebrovascular accidents, long-term hypoperfusion, and/or remote neuronal degeneration may lead to structural alterations in patients with moyamoya disease (MMD). This study sought to comprehensively investigate the distribution characteristics of subcortical gray matter volume and their correlations with angiographic changes in the intracranial artery in patients with MMD. METHOD: One hundred forty-two patients with MMD and 142 age- and sex-matched healthy controls underwent 3-dimensional high-resolution structural magnetic resonance imaging. Volumes of subcortical gray matter and subregions of the hippocampus and amygdala were calculated, and the degree of stenosis/occlusion of intracranial arteries in patients with MMD was evaluated on MR angiography. RESULTS: Volume reductions in the thalamus, caudate, putamen, hippocampus, amygdala, pallidum, and nucleus accumbens were found in patients with MMD. Hippocampal subfields and amygdala subnuclei in patients with MMD showed distinct vulnerability, and morphological alterations in specific subregions were more obvious than in the whole hippocampus/amygdala. Volume loss in several subcortical areas was related to disease duration and intracranial arterial changes. CONCLUSIONS: Our findings revealed structural alteration patterns of subcortical gray matter in MMD. The specific atrophy in subregions of the hippocampus and the amygdala suggested potential cognitive and affective impairments in MMD, which warrants further investigation. Chronic cerebral hemodynamic alterations in MMD may play a pivotal role in morphological changes in subcortical areas.

Photocatalytic Dehydroxymethylative Arylation by Synergistic Cerium and Nickel Catalysis.

Under mild reaction conditions with inexpensive cerium and nickel catalysts, easily accessible free alcohols can now be utilized as operationally simple and robust carbon pronucleophiles in selective C(sp3)-C(sp2) cross-couplings. Facilitated by automated high-throughput experimentation, sterically encumbered benzoate ligands have been identified for robust cerium complexes, enabling the synergistic cooperation of cerium catalysis in the emerging metallaphotoredox catalysis. A broad range of free alcohols and aromatic halides can be facilely employed in this transformation, representing a new paradigm for the C(sp3)-C(sp2) bond construction between free alcohols and aryl halides with the extrusion of formaldehyde. Moreover, mechanistic investigations have been conducted, leading to the identification of a tribenzoate cerium(III) complex as a viable intermediate.

Photocatalytic Aerobic Oxidative Ring Expansion of Cyclic Ketones to Macrolactones by Cerium and Cyanoanthracene Catalysis.

We describe a cerium-catalyzed aerobic oxidative ring expansion for the expedient construction of synthetically challenging macrolactones under visible-light conditions. Cyanoanthracene has been employed as co-catalyst to accelerate the turnover of the cerium cycle leading to a fast conversion within 20 min of irradiation. Taking advantage of the high efficiency and operationally simple conditions, a collection of over 100 macrolactones equipped with ring systems ranging from 9- to 19-membered macrocycles have been prepared from simple building blocks. Moreover, the enabling potential of this strategy to simplify the generation of molecular complexity has been demonstrated through the concise synthesis of sonnerlactone.

Cerium-Catalyzed C-H Functionalizations of Alkanes Utilizing Alcohols as Hydrogen Atom Transfer Agents.

Modern photoredox catalysis has traditionally relied upon metal-to-ligand charge-transfer (MLCT) excitation of metal polypyridyl complexes for the utilization of light energy for the activation of organic substrates. Here, we demonstrate the catalytic application of ligand-to-metal charge-transfer (LMCT) excitation of cerium alkoxide complexes for the facile activation of alkanes utilizing abundant and inexpensive cerium trichloride as the catalyst. As demonstrated by cerium-catalyzed C-H amination and the alkylation of hydrocarbons, this reaction manifold has enabled the facile use of abundant alcohols as practical and selective hydrogen atom transfer (HAT) agents via the direct access of energetically challenging alkoxy radicals. Furthermore, the LMCT excitation event has been investigated through a series of spectroscopic experiments, revealing a rapid bond homolysis process and an effective production of alkoxy radicals, collectively ruling out the LMCT/homolysis event as the rate-determining step of this C-H functionalization.

Dehydroxymethylation of Alcohols Enabled by Cerium Photocatalysis.

Dehydroxymethylation, the direct conversion of alcohol feedstocks as alkyl synthons containing one less carbon atom, is an unconventional and underexplored strategy to exploit the ubiquity and robustness of alcohol materials. Under mild and redox-neutral reaction conditions, utilizing inexpensive cerium catalyst, the photocatalytic dehydroxymethylation platform has been furnished. Enabled by ligand-to-metal charge transfer catalysis, an alcohol functionality has been reliably transferred into nucleophilic radicals with the loss of one molecule of formaldehyde. Intriguingly, we found that the dehydroxymethylation process can be significantly promoted by the cerium catalyst, and the stabilization effect of the fragmented radicals also plays a significant role. This operationally simple protocol has enabled the direct utilization of primary alcohols as unconventional alkyl nucleophiles for radical-mediated 1,4-conjugate additions with Michael acceptors. A broad range of alcohols, from simple ethanol to complex nucleosides and steroids, have been successfully applied to this fragment coupling transformation. Furthermore, the modularity of this catalytic system has been demonstrated in diversified radical-mediated transformations including hydrogenation, amination, alkenylation, and oxidation.

Blood Oxygen Level-Dependent Response Changes in the Ipsilateral Primary Somatosensory Cortex and Thalamus of Patients With Moyamoya Disease During Median Nerve Electrical Stimulation.

OBJECTIVE: The objective of this study was to investigate the changes in the blood oxygen level-dependent (BOLD) response in the ipsilateral primary somatosensory cortex (SI) and thalamus of patients with moyamoya disease (MMD) during sensory stimulation. METHODS: Sixty-four MMD patients, and 15 healthy volunteers were enrolled. Thirty-three MMD patients exhibited paroxysmal numbness or hypoesthesia in the unilateral limbs. Fifteen patients with acroparesthesia underwent unilateral encephaloduroarteriosynangiosis (EDAS). All volunteers underwent BOLD functional magnetic resonance imaging (BOLD-fMRI) under median nerve electrical stimulation (MNES). Blood oxygen level-dependent fMRI data were processed to obtain time-signal intensity curves in the activation areas of the bilateral SI and thalamus. Processed dynamic susceptibility contrast-enhanced magnetic resonance imaging data were used to measure the time to peak of the BOLD response in the regions of interest, including the bilateral SI, thalamus, and cerebellum. Changes in the time-signal intensity curve-related hemodynamic parameters in the ipsilateral SI and thalamus were examined between healthy controls, nonacroparesthesia patients, and asymptomatic and symptomatic sides of unilateral acroparesthesia patients during MNES. Changes in these parameters in MMD patients before and after EDAS were examined. RESULTS: Compared with healthy volunteers, 3 groups of MMD patients exhibited an increased peak of the positive BOLD response in the ipsilateral thalamus during MNES (0.65 ± 0.24 vs 0.79 ± 0.35, 0.94 ± 0.57, and 0.89 ± 0.50; P = 0.0335). The positive response peak in the ipsilateral SI markedly increased in MMD patients with acroparesthesia during MNES on the asymptomatic side (0.56 ± 0.37 vs 0.38 ± 0.27, P = 0.0243). The time to peak negative response in the ipsilateral SI was prolonged during MNES on the symptomatic side after EDAS (12.14 ± 8.90 seconds vs 18.86 ± 9.20 seconds, P = 0.0201). CONCLUSIONS: During sensory stimulation treatment, BOLD response changes occurred in the ipsilateral SI and thalamus of MMD patients. These changes enabled the contralateral hemisphere of the brain to better deal with sensory stimuli.

δ-Selective Functionalization of Alkanols Enabled by Visible-Light-Induced Ligand-to-Metal Charge Transfer.

We demonstrate the application of ligand-to-metal charge transfer (LMCT) excitation to the direct catalytic generation of energetically challenging alkoxy radicals from alcohols through a coordination-LMCT-homolysis process with an abundant and inexpensive cerium salt as the catalyst. This catalytic manifold provides a simple and efficient way to utilize the characteristic reactivity and selectivity of transient alkoxy radicals for δ-selective C-H bond functionalization. Under mild redox-neutral conditions without the need for prefunctionalization, this method provides a versatile platform to access molecular complexity from simple and abundant alcohols.

Cerium-Catalyzed Formal Cycloaddition of Cycloalkanols with Alkenes through Dual Photoexcitation.

We describe a synergistic utilization of cerium photocatalysis and photoinduced electron transfer catalysis that enables an atom- and step-economical ring expansion of readily available cycloalkanols. This operationally simple protocol provides rapid access to privileged and synthetically challenging bridged lactones. The mild catalytic manifold has been adapted to continuous flow for scale-up applications and employed for the concise synthesis of polycyclic core of nepalactones.

Changes in Hemodynamic Response Patterns in Motor Cortices Measured by Task-Based Functional Magnetic Resonance Imaging in Patients With Moyamoya Disease.

OBJECTIVE: We aimed to study the value of blood oxygen level-dependent functional magnetic resonance imaging (BOLD-fMRI) in assessing cerebral hemodynamic changes for moyamoya disease (MMD). METHODS: We recruited 15 healthy volunteers, 15 patients with MMD without dyskinesia, and 30 patients with MMD who experienced paroxysmal limb dyskinesia. The BOLD-fMRI scans were obtained during grasping motions of the left or right hand. Hemodynamic response curves in the primary motor cortices were generated. Six response parameters including negative response time (Tnr), maximum signal intensity of negative response, time to peak, maximum peak arrival time, maximum signal intensity of positive response, and positive response time were measured. RESULTS: The hemodynamic response curve in the primary motor cortices of MMD patients showed extended Tnr, prolonged positive response time, and delayed time to peak than those of the controls. The response curve showed longer Tnr and maximum peak arrival time in the primary motor cortices on the affected side of the dyskinesia group. CONCLUSIONS: Blood oxygen level-dependent fMRI is an effective technique to assess hemodynamic changes in patients with MMD.

Clinical assessment of cerebral hemodynamics in Moyamoya disease via multiple inversion time arterial spin labeling and dynamic susceptibility contrast-magnetic resonance imaging: A comparative study.

BACKGROUND AND PURPOSE: For Moyamoya disease (MMD) patients, accurate hemodynamic assessment is critical for treatment selection and efficacy assessment. This study aims to investigate the clinical value of mTI-ASL in assessing the cerebral hemodynamics of MMD patients before and after revascularization, relative to DSC-MRI. MATERIALS AND METHODS: Forty-one MMD patients underwent mTI-ASL and DSC-MRI during blood perfusion. Quantitative parameters for the bilateral supply vessels of middle and anterior cerebral arteries, including DSC-TTP, DSC-CBF, ASL-BAT, and ASL-CBF were measured. The correlations between DSC-ΔTTP (TTPhemisphere - TTPbrainstem) and ASL-ΔBAT (BAThemisphere - BATbrainstem) and between DSC-CBF and ASL-CBF were determined. The consistency between the two techniques in assessing the cerebral ischemic state before and after revascularization was analyzed. RESULTS: DSC-ΔTTP and ASL-ΔBAT (r=0.36, P<0.001) and DSC-CBF and ASL-CBF (r=0.32, P<0.001) exhibited significant correlation on 824 regions of interest (ROIs) and similar numbers of ischemic areas on 902 ROIs (κ=0.82, P<0.001). The ischemic scores were 3.17±3.02 and 2.98±2.81 by DSC-MRI and ASL-MRI, respectively (ICC=0.92). For 15 surgically treated patients, the scores for blood perfusion improvement on the operated side were 3.13±1.68 and 3.27±1.33 with DSC-TTP and ASL-BAT, respectively (ICC=0.94). CONCLUSION: Compared to DSC-MRI, mTI-ASL can assess the cerebral hemodynamics in MMD and evaluate ischemic state before revascularization and ischemia reduction after revascularization effectively. And mTI-ASL is more advantageous because it does not require contrast agents.

Enantioselective Decarboxylative Arylation of α-Amino Acids via the Merger of Photoredox and Nickel Catalysis.

An asymmetric decarboxylative Csp(3)-Csp(2) cross-coupling has been achieved via the synergistic merger of photoredox and nickel catalysis. This mild, operationally simple protocol transforms a wide variety of naturally abundant α-amino acids and readily available aryl halides into valuable chiral benzylic amines in high enantiomeric excess, thereby producing motifs found in pharmacologically active agents.

Intramolecular dearomative oxidative coupling of indoles: a unified strategy for the total synthesis of indoline alkaloids.

Indole alkaloids, one of the largest classes of alkaloids, serve as an important and rich source of pharmaceuticals and have inspired synthetic chemists to develop novel chemical transformations and synthetic strategies. Many biologically active natural products contain challenging indoline scaffolds, which feature a C3 all-carbon quaternary stereocenter that is often surrounded by a complicated polycyclic ring system. The creation of this quaternary stereocenter creates an inherent synthetic challenge because the substituents on the carbon center cause high steric repulsion. In addition, the presence of nitrogen atoms within the surrounding polycyclic rings can lead to synthetic difficulties. Oxidative coupling between two sp(3)-hybridized carbon anions provides a unique and powerful method for building C-C single bonds, especially for generating a C-C bond that joins one or two vicinal quaternary stereocenters. Although chemists have known of this transformation for a long time, they have only applied this reaction in total synthesis of complex natural products during the past decade. The progress of this class of reaction depends on the use of indole moieties as coupling partners. In this Account, we summarize our recent efforts to develop iodine-mediated intramolecular dearomative oxidative coupling (IDOC) reactions of indoles as part of a unified strategy for the total synthesis of three classes of indoline alkaloids. We categorized these IDOC reactions into three types based on their mode of connection to the indole moiety. In type I, the carboanion nucleophile was tethered to the indole at the C3 position. This reaction enabled the assembly of skeleton A, which features a spiro ring at the C3 position of the indole. We demonstrated the efficiency of this method by quickly assembling two classes of tetracyclic compounds and completing the total synthesis of (-)-communesins F, A, and B. For the type II IDOC reactions, the carboanion nucleophile residing at the C2 position of the indole formed a quaternary center at the C3 position of indole to produce skeleton B. We applied this IDOC reaction to synthesize two akuammiline alkaloids, vincorine and aspidophylline A. Type III IDOC reactions employed substrates with a preinstalled ring at the C2 and C3 positions of the indole. These transformations proceeded smoothly to afford polycyclic ring system C, which we used in the first enantioselective total synthesis of Kopsia alkaloid methyl N-decarbomethoxychanofruticosinate. These results further demonstrate how new chemical strategies and reactions facilitate both the first total syntheses of natural products and the discovery of more efficient synthetic routes.

Photocatalytic C-C Bond Cleavage and Amination of Cycloalkanols by Cerium(III) Chloride Complex.

A general strategy for the cleavage and amination of C-C bonds of cycloalkanols has been achieved through visible-light-induced photoredox catalysis utilizing a cerium(III) chloride complex. This operationally simple methodology has been successfully applied to a wide array of unstrained cyclic alcohols, and represents the first example of catalytic C-C bond cleavage and functionalization of unstrained secondary cycloalkanols.

Decarboxylative arylation of α-amino acids via photoredox catalysis: a one-step conversion of biomass to drug pharmacophore.

The direct decarboxylative arylation of α-amino acids has been achieved via visible light-mediated photoredox catalysis. This method offers rapid entry to prevalent benzylic amine architectures from an abundant biomass, specifically α-amino acid precursors. Significant substrate scope is observed with respect to both the amino acid and arene components.

Carboxylic acids as a traceless activation group for conjugate additions: a three-step synthesis of (±)-pregabalin.

The direct application of carboxylic acids as a traceless activation group for radical Michael additions has been accomplished via visible light-mediated photoredox catalysis. Photon-induced oxidation of a broad series of carboxylic acids, including hydrocarbon-substituted, α-oxy, and α-amino acids, provides a versatile CO2-extrusion platform to generate Michael donors without the requirement for organometallic activation or propagation. A diverse array of Michael acceptors is amenable to this new conjugate addition strategy. An application of this technology to a three-step synthesis of the medicinal agent pregabalin (commercialized by Pfizer under the trade name Lyrica) is also presented.

Short-term changes in chest CT images among individuals at low altitude after entering high-altitude environments.

Objective: To investigate the short-term changes in chest CT images of low-altitude populations after entering a high-altitude environment. Methods: Chest CT images of 3,587 people from low-altitude areas were obtained within one month of entering a high-altitude environment. Abnormal CT features and clinical symptoms were analyzed. Results: Besides acute high-altitude pulmonary edema, the incidence of soft tissue space pneumatosis was significantly higher than that in low-altitude areas. Pneumatosis was observed in the mediastinum, cervical muscle space, abdominal cavity, and spinal cord epidural space, especially the mediastinum. Conclusion: In addition to acute high-altitude pulmonary edema, spontaneous mediastinal emphysema often occurs when individuals in low-altitude areas adapt to the high-altitude environment of cold, low-pressure, and hypoxia. When the gas escapes to the abdominal cavity, it is easy to be misdiagnosed as gastrointestinal perforation. It is also not uncommon for gas accumulation to escape into the epidural space of the spinal cord. The phenomenon of gas diffusion into distant tissue space and the mechanism of gas escape needs to be further studied.