Challenging Task of Ni-Catalyzed Highly Regio-/Enantioselective Semihydrogenation of Racemic Tetrasubstituted Allenes via a Kinetic Resolution Process.

The first earth-abundant transition metal Ni-catalyzed highly regio- and enantioselective semihydrogenation of racemic tetrasubstituted allenes via a kinetic resolution process as a challenging task was well established. This protocol furnishes expedient access to a diversity of structurally important enantioenriched tetrasubstituted allenes and chiral allylic molecules with high regio-, enantio-, and Z/E-selectivity. Remarkably, this semihydrogenation proceeded with one carbon-carbon double bond of allenes, which was regioselective complementary to the Rh-catalyzed asymmetric version. Deuterium labeling experiments and density functional theory (DFT) calculations were carried out to reveal the reasonable reaction mechanism and explain the regio-/stereoselectivity.

Copper/Ruthenium Relay Catalysis for Stereodivergent Access to δ-Hydroxy α-Amino Acids and Small Peptides.

An atom- and step-economical and redox-neutral cascade reaction enabled by asymmetric bimetallic relay catalysis by merging a ruthenium-catalyzed asymmetric borrowing-hydrogen reaction with copper-catalyzed asymmetric Michael addition has been realized. A variety of highly functionalized 2-amino-5-hydroxyvaleric acid esters or peptides bearing 1,4-non-adjacent stereogenic centers have been prepared in high yields with excellent enantio- and diastereoselectivity. Judicious selection and rational modification of the Ru catalysts with careful tuning of the reaction conditions played a pivotal role in stereoselectivity control as well as attenuating undesired α-epimerization, thus enabling a full complement of all four stereoisomers that were otherwise inaccessible in previous work. Concise asymmetric stereodivergent synthesis of the key intermediates for biologically important chiral molecules further showcases the synthetic utility of this methodology.

Studies on the [4 + 2] cycloaddition and allylic substitution of indole-fused zwitterionic π-allylpalladium.

The zwitterionic π-allylpalladium species, also known as dipoles, are important synthons widely used in various reactions including cycloaddition and allylic substitution. This study reported the development of a new indole-fused zwitterionic π-allylpalladium precursor compound and its application in [4 + 2] cycloaddition and allylic substitution reactions. As a result, the synthesis of pyrrolo[3,2,1-ij]quinazolin-3-one and 7-vinyl indole compounds was achieved with moderate to good yields. Notably, the allylic substitution reaction exhibited excellent regio- and stereoselectivity.

A randomized, double-blind, placebo-controlled phase II study to evaluate the efficacy and safety of ivarmacitinib (SHR0302) in adult patients with moderate-to-severe alopecia areata.

BACKGROUND: Alopecia areata (AA) is a CD8+ T cell-mediated autoimmune disease characterized by nonscarring hair loss. Ivarmacitinib, which is a selective oral Janus kinase 1 inhibitor, may interrupt certain cytokine signaling implicated in the pathogenesis of AA. OBJECTIVE: To evaluate the efficacy and safety of ivarmacitinib in adult patients with AA who have ≥25% scalp hair loss. METHODS: Eligible patients were randomized 1:1:1:1 to receive ivarmacitinib 2, 4, or 8 mg once daily or placebo for 24 weeks. The primary end point was the percentage change from baseline in the Severity of Alopecia Tool score at week 24. RESULTS: A total of 94 patients were randomized. At week 24, the least squares mean difference in the percentage change from baseline in the Severity of Alopecia Tool score for ivarmacitinib 2, 4, and 8 mg and placebo groups were -30.51% (90% CI, -45.25, -15.76), -56.11% (90% CI, -70.28, -41.95), -51.01% (90% CI, -65.20, -36.82), and -19.87% (90% CI, -33.99, -5.75), respectively. Two serious adverse events-follicular lymphoma and COVID-19 pneumonia-were reported. LIMITATIONS: A small sample size limits the generalizability of the results. CONCLUSION: Treatment with ivarmacitinib 4 and 8 mg doses in patients with moderate and severe AA for 24 weeks was efficacious and generally tolerated.

Al distribution and structural stability of H-BEA zeolites at different Si/Al ratios and temperatures: a first-principles study.

Beta zeolites have been widely used in acid-catalyzed reactions because of their excellent properties. An in-depth study of the position, quantity, and distribution of beta zeolites substituted by Al is significant to understand the catalytic performance of the active site of zeolite catalysts. The distribution of Al in H-BEA and the structure of silanol nests in dealuminated BEA at different Si/Al ratios and synthesis temperatures were studied by the DFT method. T1, T2, T7, and T9 sites were chosen to be simulated. The synthesis temperature can change the distribution of Al and the proportion of T sites at different Si/Al ratios. The proportion of T7 and T9 is more than 70% at different Si/Al ratios of H-BEA and decreases with the synthesis temperature. T1 and T2 sites begin to appear when Si/Al < 20 and the proportion of T1 and T2 sites is less than 20%. When Si/Al < 8, the substitution energy of the AlSiAl structure, which has Si(2Al, 2Si) species, is obviously lower than that of the normal structure, which indicates that the Al-O-Si-O-Al species will appear in H-BEA. The Al(T7)Si(T5)Al(T9)Si(T5)Al(T7) and Al(T1)Si(T1)Al(T9) groups can not only stabilize H-BEA but also play an essential role in the formation of Si(2Al, 2Si) species. For dealuminated BEA zeolites, the silanol nest forms four hydrogen bonds through four silanols. The orientation of silanol groups in the silanol nest formed after dealumination at different T sites is different. The T7 and T9 sites in H-BEA are more likely to undergo dealumination. By contrast, the dealumination of the T1 and T2 sites is a challenge.

Iridium-Catalyzed Asymmetric Cascade Allylation/Retro-Claisen Reaction.

An enantiomerically enriched 3-hydroxymethyl pentenal unit is one of the key structural cores in plenty of natural products and drug candidates with significant biological activities. However, very few synthetic methodologies for the facile construction of the related skeletons have been reported to date. Herein, an elegant iridium-catalyzed asymmetric cascade allylation/retro-Claisen reaction of readily available ß-diketones with VEC was successfully developed, and a wide range of functionalized chiral 3-hydroxymethyl pentenal derivatives could be prepared in good yields with excellent enantioselectivities. Various 1,3-diketones and functionalized ketones containing different electron-withdrawing groups on the ß-position were well tolerated as outstanding partners with high reactivity and excellent regio-/chemo-/enantioselectivity. The synthetic utility of product chiral 3-hydroxymethyl pentenal derivatives was well shown through gram-scale transformation, hydrogenation, cyclopropanation, hydroboration, and olefin metathesis. Moreover, this elegant protocol demonstrated synthetic applications in the concise synthesis of synthetically useful chiral building block (S)-Taniguchi lactone and the formal synthesis of natural product cytisine. A rational reaction pathway was proposed based on the experimental results and control experiments.

Insights into the mechanism of carbon chain growth on zeolite-based Fischer-Tropsch Co/Y catalysts.

In a zeolite-based Fischer-Tropsch bifunctional catalyst, zeolites, as the support of the active metal, can interact with the metal cluster to affect the electronic properties and structural effect of the catalyst, thus affecting the Fischer-Tropsch synthesis reaction. In this work, the Fischer-Tropsch synthesis process using a Co catalyst supported by Y-zeolite was simulated by the DFT method from the microscopic point of view. The reaction network was designed to investigate the reaction mechanism in terms of four parts consisting of H-assisted CO dissociation, C1 hydrogenation, CHx-CHx coupling, and C2-C4 growth. It was found that the introduction of Y-zeolite enhanced the adsorption capacity of the catalyst for most species. Moreover, the catalytic mechanism of the Co/Y catalyst was clarified, and we found that the introduction of the Y-zeolite mainly reduced the reaction energy barriers of the CH-CH coupling and C2-C4 carbon chain growth process, which also explained the high proportion of long carbon chain hydrocarbons in the Fischer-Tropsch synthesis products after Y-zeolite was introduced.

Stem Cells from Human Exfoliated Deciduous Teeth Attenuate Atopic Dermatitis Symptoms in Mice through Modulating Immune Balance and Skin Barrier Function.

Atopic dermatitis (AD) is a chronic skin inflammatory disease associated with immune abnormalities and disrupted skin barrier function. Mesenchymal stem cells (MSCs) have been suggested as an alternative therapeutic option in AD. Stem cells from human exfoliated deciduous teeth (SHEDs) are a unique postnatal stem cell population with high immunomodulatory properties. The aim of this study was to explore the effects of SHEDs on AD in the BALB/c mouse model induced by 2,4-dinitrochlorobenzene (DNCB). SHEDs were administrated intravenously or subcutaneously, and clinical severity, histopathological findings, skin barrier function, and organ indexes were evaluated. Skin tissue cytokine mRNA levels and serum cytokine protein levels were further analysed. SHED administration significantly alleviated AD clinical severity, including dermatitis scores, ear thickness, scratching behaviour, and infiltration of mast cells. In addition, disrupted skin barrier function and enlarged spleens were restored by SHED administration. Further, SHED treatment reduced the levels of IgE, IgG1, and thymic stromal lymphopoietin (TSLP) in the serum and the modulated expression of Th1-, Th2-, and Th17-associated cytokines in skin lesions. In conclusion, SHEDs attenuated AD-like skin lesions in mice by modulating the immune balance and skin barrier function. SHEDs could be a potential new treatment agent for AD.

Noncovalent Interaction-Assisted Ferrocenyl Phosphine Ligands in Asymmetric Catalysis.

Noncovalent interactions are ubiquitous in nature and are responsible for the precision control in enzyme catalysis via the cooperation of multiple active sites. Inspired by this principle, noncovalent interaction-assisted transition metal catalysis has emerged recently as a powerful tool and has attracted intense interest. However, it is still highly desirable to develop efficient and operationally convenient ligands along this line with new structural motifs. Based on the specific nature of hydrogen bonding and ion pairing interactions, we developed a series of noncovalent interaction-assisted chiral ferrocenyl phosphine ligands, including Zhaophos, Wudaphos, and miscellaneous SPO-Wudaphos. Due to the assistance of noncovalent interactions, this catalytic mode is capable of achieving transition metal catalyzed asymmetric hydrogenation and other transformations with remarkable improvement of reactivity and selectivity. In some specific challenging cases, this probably represents one of the most productive methods. Moreover, these ligands are easily prepared, air stable, and highly tunable, meeting the requirements of industrial application.In this Account, we give a concise review of recent advances in asymmetric catalysis. By means of hydrogen bonding interactions, Rh- and Ir-Zhaophos complexes exhibited excellent activities and enantioselectivities in asymmetric hydrogenation of a wide range of substrates: C═C bonds of substituted conjugate alkenes with neutral hydrogen bond acceptors, including nitro groups, carbonyl groups (ketones, esters, amides, maleinimides, and anhydrides), ethers, and sulfones; C═N bonds of substituted iminium salts with chloride as an anionic hydrogen bond acceptor, including N-H imines and cyclic imines; N-heteroaromatic compounds with HCl as an additive, including unprotected quinolines, isoquinolines, and indoles; carbocation of substituted oxocarbenium ions. By means of ion pairing interactions, Rh-Wudaphos complexes enabled the catalytic asymmetric hydrogenation of α-substituted unsaturated carboxylic acids, carboxy-directed α,α-disubstituted terminal olefins, and sodium α-arylethenylsulfonates. Rh-SPO-Wudaphos utilized both hydrogen bonding and ion pairing interactions in asymmetric hydrogenation of α-substituted unsaturated carboxylic acids and phosphonic acids. In addition, Zhaophos has achieved highly selective intramolecular reductive amination and inter- and intramolecular asymmetric decarboxylative allylation. Investigations into mechanism implied that noncovalent interactions were involved in the catalytic cycle and played a critical role for both high reactivity and selectivity. Notably, a rare ionic hydrogenation pathway has been proposed in some cases. Furthermore, these catalytic systems have been used in the gram-scale synthesis of natural products and pharmaceuticals.

Efficient synthesis of chiral ß-hydroxy sulfones via iridium-catalyzed hydrogenation.

A highly efficient Ir/f-Amphol-catalyzed asymmetric hydrogenation of prochiral ß-keto sulfones was successfully developed to prepare a series of chiral ß-hydroxy sulfones with good to excellent results (62%->99% conversions, 35%-99% yields and 86%->99% ee). Our Ir/f-Amphol L4 catalytic system exhibited very high activity; the gram-scale asymmetric hydrogenation was performed well with just 0.005 mol% catalyst loading (S/C = 20 000) to afford the desired product 2a with >99% conversion, 99% yield and 93% ee.

Synthesis of chiral seven-membered ß-substituted lactams via Rh-catalyzed asymmetric hydrogenation.

Rh/bisphosphine-thiourea ligand (ZhaoPhos)-catalyzed asymmetric hydrogenation of seven-membered ß-substituted α,ß-unsaturated lactams was successfully developed to prepare various chiral seven-membered ß-substituted lactams with good to excellent results (up to >99% conversion, 99% yield, and >99% ee).

A DFT study on Zr-SBA-15 catalyzed conversion of ethanol to 1,3-butadiene.

Density functional theory (DFT) calculations have been used to elucidate the influence of the surface properties of Zr-SBA-15 on the conversion of ethanol to 1,3-butadiene at the molecular level. To identify the critical reactive intermediates of ethanol catalysis to catalytically form 1,3-butadiene on the Zr-SBA-15 surface, the model of Zr-SBA-15 was first built. The overall enthalpy energy surface was explored for the highly-debated reaction mechanisms, including Toussaint's aldol condensation mechanism and Fripiat's Prins mechanism. It was found that ethanol dehydration to form ethylene possessed a lower energy barrier than dehydrogenation to yield acetaldehyde, which means they are competing reactive pathways. C-C bond coupling to form acetaldol (3-hydroxybutanal) proceeds with a 2.15 eV forward reaction barrier. Direct reaction of ethylene and acetaldehyde proceeds with a free energy barrier of 2.90 eV suggesting that Prins condensation hardly occurs. The results here provide a first glimpse into the overall mechanism of 1,3-butadiene formation on Zr-SBA-15 reactive sites in light of the variety of proposed mechanistic pathways mostly based on conventional homogenous organic chemistry reactions.

NHC-Catalyzed Electrophilic Trifluoromethylation: Efficient Synthesis of γ-Trifluoromethyl α,ß-Unsaturated Esters.

Described herein is a highly regioselective and efficient N-heterocyclic-carbene-catalyzed γ-trifluoromethylation of vinylogous enolates. Control experiments and DFT calculations provided important insight into the reaction mechanism.

Readily Accessible and Highly Efficient Ferrocene-Based Amino-Phosphine-Alcohol (f-Amphol) Ligands for Iridium-Catalyzed Asymmetric Hydrogenation of Simple Ketones.

We have successfully developed a series of novel and modular ferrorence-based amino-phosphine-alcohol (f-Amphol) ligands, and applied them to iridium-catalyzed asymmetric hydrogenation of various simple ketones to afford the corresponding chiral alcohols with excellent enantioselectivities and conversions (98-99.9 % ee, >99 % conversion, turnover number up to 200 000). Control experiments and density functional theory (DFT) calculations have shown that the hydroxyl group of our f-Amphol ligands played a key role in this asymmetric hydrogenation.

A DFT study on the aldol condensation reaction on MgO in the process of ethanol to 1,3-butadiene: understanding the structure-activity relationship.

Using periodic density functional theory calculations, the aldol condensation of acetaldehyde to 3-hydroxybutanal over dehydroxylated MgO surfaces with and without structure defects was investigated. Compared with the C-C coupling step, the enolization step via proton transfer of the α-hydrogen of acetaldehyde to the MgO surface or the proton back-transfer step to form the desired 3-hydroxybutanal has a higher energy barrier, indicating that the proton transfer process is the key step for the aldol condensation on MgO. To highlight the effect of water, we also calculated the proton transfer steps in the presence of water and studied the reaction pathways over the partially hydroxylated MgO surface. The results show that water can participate in the proton back-transfer step by donating a proton to the alkoxide anion to form the 3-hydroxybutanal, thus reducing the activation energy; the surface OH groups induce a lowering of the activation energy barriers for the overall reaction. The results of the electronic structure analysis indicate that a strong Lewis acid-weak/medium base pair may have the best performance for aldol condensation, such as Mg3C-O4C-D produced by divacancy defects and Mg4C-O2CH produced by the dissociative adsorption of water. A strong Lewis acid generated by low-coordinated Mg2+ can adsorb and stabilize the acetaldehyde molecule near the catalyst surface which is beneficial for the abstraction of an α-proton from an acetaldehyde molecule, and a medium or weak Brønsted base is favorable for the proton back-transfer step.

Enzyme-Inspired Chiral Secondary-Phosphine-Oxide Ligand with Dual Noncovalent Interactions for Asymmetric Hydrogenation.

Inspired by the unique character of enzymes, we developed novel chiral SPO (secondary-phosphine-oxide) ligand (SPO-Wudaphos) which can enter into both ion pair and H-bond noncovalent interactions. The novel chiral SPO-Wudaphos exhibited excellent results in the asymmetric hydrogenation of α-methylene-γ-keto carboxylic acids, affording the chiral γ-keto acids with up to over 99 % ee. A series of control experiments and DFT calculations were conducted to illustrate the critical roles of both the ion pair and H-bond noncovalent interactions.

Rhodium/Yanphos-Catalyzed Asymmetric Interrupted Intramolecular Hydroaminomethylation of trans-1,2-Disubstituted Alkenes.

The first interrupted asymmetric hydroaminomethylation reaction was developed. The challenging trans-1,2-disubstituted olefins were employed as substrates, and a series of valuable chiral pyrrolidinones and pyrrolidines were obtained in high yields with high regioselectivities and excellent enantioselectivities. Several synthetic transformations were conducted, demonstrating the high synthetic utility of our method. A creative route for the synthesis of vernakalant and Enablex was also developed.

Chiral Ligands for Rhodium-Catalyzed Asymmetric Hydroformylation: A Personal Account.

Asymmetric hydroformylation represents one of the most efficient routes for the preparation of chiral aldehydes from alkenes in the presence of syngas in a perfect atom-economic way. During the past few decades, a variety of chiral ligands have been developed for the asymmetric hydroformylation. However, only a few ligands exhibit good performance in terms of the regio- and enantioselectivities. Additionally, for the chiral ligands developed up to now, only limited substrates were tolerated and no examples have led to the application of the asymmetric hydroformylation reaction on a commercial scale due to several technical challenges. This account provides a brief introduction of the current efficient chiral ligands for asymmetric hydroformylation and the ongoing efforts we have made in this field.

Rhodium-catalyzed asymmetric hydrogenation of unprotected ß-enamine phosphonates.

We have successfully developed a strategy for the first time for the enantioselective Rh-TaniaPhos catalyzed asymmetric hydrogenation of unprotected ß-enamine phosphonates to free ß-amino phosphonates directly with good enantioselectivities (80%-86% ee) and high conversions (>99% conversion). The resulting chiral free ß-amino phosphonates and their derivatives are important intermediates in biochemistry and pharmaceuticals.

Investigation on the conversion of ethylene to ethylidyne on Pt(100) and Pd(100) using density functional theory.

The comprehensive formation network of ethylidyne (CH3C) from ethylene (CH2CH2) is investigated on Pt(100) and Pd(100) using the density functional theory method. The structural and energetic features of all intermediate products were considered. We found that the trend of the activation barriers in each pathway on Pt(100) and Pd(100) are the same, whereas the barriers on Pt(100) are higher than that on Pd(100). The activation barriers of 1,2-H shift reactions are relatively high compared with the other reactions. We screened three possible pathways and selected the optimal route as CH2CH2(ethylene) → CH2CH(vinyl) → CH2C(vinylidene) → CH3C(ethylidyne).