Propargylic Dialkyl Effect for Cyclobutene Formation through Ir(III)-Catalyzed Cycloisomerization of 1,6-Enynes.

The propargylic dialkyl effect (PDAE) has a significant impact on the cyclization reaction of enynes, partly reflected in changing the types of products. Herein, we described the influence of the propargylic dialkyl effect on the Ir(III)-catalyzed cycloisomerization of 1,6-enynes to provide strained cyclobutenes. A series of substituted 1,6-enynes were proved to be excellent substrate candidates in the presence of [Cp*IrCl2]2 in toluene. Mechanistic investigation, based on deuterium labeling experiments and control experiments, indicated that the propargylic dialkyl effect might boost C(sp)-H activation by preventing the coordination of active iridium species to the C(sp)≡C(sp) bond of enynes. This finding contributes to the fundamental understanding of enyne cyclization reactions and offers valuable insight into the propargylic dialkyl effect.

Reshaping aromatic frameworks: expansion of aromatic system drives metallabenzenoids to metallapentalenes.

Reshaping an aromatic framework to generate other skeletons is a challenging issue due to the stabilization energy of aromaticity. Such reconfigurations of aromatics commonly generate non-aromatic products and hardly ever reshape to a different aromatic framework. Herein, we present the transformation of metallaindenols to metallapentalenes and metallaindenes in divergent pathways, converting one aromatic framework to another with an extension of the conjugation framework. The mechanistic study of this transformation shows that phosphorus ligands play different roles in the divergent processes. Further theoretical studies indicate that the expansion of the aromatic system is the driving force promoting this skeletal rearrangement. Our findings offer a new concept and strategy to reshape and construct aromatic compounds.

Aromatic chloroosmacyclopentatrienes.

Aromatic metallacycles are of considerable current interest. Reported aromatic metallacycles are mainly those with carbon, nitrogen, oxygen and sulfur. In this work, we report the synthesis and characterization of aromatic chloroosmacyclopentatrienes, which represent the first structurally confirmed metallaaromatic with a chlorine atom in its framework. Single-crystal X-ray diffraction studies show that these planar chloroosmacyclopentatrienes possess a very short Os-ClC distance suggesting M=ClC bond character.

Synthesis and Characterization of a Rhenanaphthalene Isomer.

Exploration of organometallic metallacycles has led to the development of various polycyclic compounds with fascinating structures, which could be used as functional materials. In this work, a new rhenanaphthalene isomer was isolated from the reaction of ReH5 (PMe2 Ph)3 with o-ethynylphenyl alkyne in the presence of excess HCl. Its structure was then identified using the single-crystal X-ray diffraction and NMR spectroscopy. DFT studies suggest that its formation involves two protonation reactions and two migration reactions. This new rhenanaphthalene isomer enriches the family of metallacycles.

Isolation, Reactivity, and Tunable Properties of a Strained Antiaromatic Osmacycle.

Strain and antiaromaticity in compounds are recognized as two substantial destabilizing features, and consequently, realization of dual destabilizing features in a single molecule is challenging and far more difficult in a single ring. Moreover, transformation of an antiaromatic framework to different antiaromatic or aromatic species is a significant subject in antiaromatic chemistry and has attracted increasing interest. In this work, we isolated a highly strained antiaromatic metallacycle in which a cyclic metal vinylidene unit is embedded. Computational studies revealed its ring strain energies and antiaromatic character and showed that the metal incorporation and the phosphonium substituents play a crucial role in its stabilization. The mechanism of its formation has been illustrated by density functional theory (DFT) calculations and the isolation of a key intermediate. We further discovered diverse reactivities and structural reshuffling of this unusual strained antiaromatic complex according to its two destabilizing characters. We obtained two isomers of metallaindenes fused with oxiranes from the direct oxidation of the metal vinylidene or by nucleophilic addition to an isolated metallacyclocumulene formed by the reaction of metal vinylidene with hydroxide ion, achieving a reconfiguration of the antiaromatic framework. Transformations of the antiaromatic metallacycle by electrophiles to various aromatic metallaindynes have been achieved, and that a condensed Fukui function was employed to confirm the regioselectivity of the electrophilic additions, and the acid/base-induced aromaticity switch along with tunable photophysical properties were investigated. These interesting transformations not only enrich the chemistry of metal vinylidenes and antiaromatics and could also perform potentially as switchable optical materials.

Hetero-carbolong chemistry: experimental and theoretical studies of diaza-metallapentalenes.

Four diaza-osmapentalenes were prepared by two-step reactions, through the treatment of an alkyne-coordinated osmium complex with azo compounds, followed by the addition of AgSbF6/CO. Their aromaticity was confirmed by crystal parameters, NMR spectra and theoretical calculations. These complexes are the first diaza-metallapentalenes representing a new class of metallaaromatics.

Experimental and theoretical evidences for the formation of transition metal complexes with five coplanar metal-carbon σ bonds.

The σ bond is an important concept in chemistry, and the metal-carbon (M-C) σ bond in particular is a central feature in organometallic chemistry. Synthesis of stable complexes with five coplanar M-C σ bonds is challenging. Here, we describe the synthesis of two different types of stable complexes with five coplanar M-C σ bonds, and examine the stability of such complexes which use rigid conjugated carbon chains to chelate with the metal center. Density functional theory (DFT) calculations show that the M-C σ bonds in these complexes have primarily a covalent character. Besides the σ nature, there are also a π conjugation component among the metal center and carbons, which causes delocalization. This work expanded the coplanar M-C σ bonds to five.

Bidentate Ru(II)-NC Complex as a Catalyst for Semihydrogenation of Azoarenes to Hydrazoarenes with Ethanol.

The transfer hydrogenation of azoarenes to hydrazoarenes using ethanol as a hydrogen source by a bidentate Ru(II)-NC complex is developed. A weak base is crucial for this semihydrogenation that can efficiently avoid hydrazoarene dehydrogenation under strongly basic conditions. Control experiments and density functional theory calculations demonstrate the mechanism via a Meerwein-Ponndorf-Verley mechanism, and the only byproduct is ethyl acetate. This study offers a new and simple approach for the synthesis of hydrazoarenes.

Anchoring Vertical Dipole to Enable Efficient Charge Extraction for High-Performance Perovskite Solar Cells.

Perovskite solar cells (PSCs) via two-step sequential method have received great attention in recent years due to their high reproducibility and low processing costs. However, the relatively high trap-state density and poor charge carrier extraction efficiency pose challenges. Herein, highly efficient and stable PSCs via a two-step sequential method are fabricated using organic-inorganic (OI) complexes as multifunctional interlayers. In addition to reduce the under-coordinated Pb2+ ions related trap states by forming interactions with the functional groups, the complexes interlayer tends to form dipole moment which can enhance the built-in electric field, thus facilitating charge carrier extraction. Consequently, with rational molecular design, the resulting devices with a vertical dipole moment that parallels with the built-in electric field yield a champion efficiency of 23.55% with negligible hysteresis. More importantly, the hydrophobicity of the (OI) complexes contributes to an excellent ambient stability of the resulting device with 91% of initial efficiency maintained after 3000 h storage.

Selective Difunctionalization of Unactivated Aliphatic Alkenes Enabled by a Metal-Metallaaromatic Catalytic System.

The design of organometallic catalysts is crucial in the development of catalytic reactions. Herein, we describe a heterometallic [Os-Cu] complex with the characteristics of bimetallics, metallaaromatics, and pincer complexes. This complex serves as a highly effective catalyst for selective amino- and oxyselenation of unactivated alkenes. More than 80 examples including challenging substrates of unsymmetric aliphatic alkenes and amine-based nucleophiles in such reactions are provided. These reactions produce 1,2-difunctionalized products with good yields and high levels of chemo-, regio-, and stereoselectivity. Our studies revealed the following: (i) The usually inert osmium center activates the N- or O-centered nucleophiles. (ii) The copper-osmium bonding and its cooperative effects play essential roles in control the selectivity by bringing the reaction components into close proximity. (iii) The metallaaromatic moiety helps to stabilize the intermediate. These findings provide a versatile platform for catalyst design based on metal-metallaaromatic cooperative effects that have not been attained previously with bimetallic complexes.

Synthesis of (Thio)Furan-Fused Phospholes via Phosphonation Cyclization and a Base-Promoted Phospha-Friedel-Crafts Reaction.

Herein, we developed a novel strategy for synthesizing ladder (thio)furan-fused phospholes via intermolecular phosphonation cyclization and a base-promoted phospha-Friedel-Crafts reaction under mild conditions. The starting substrates are readily available phosphinic acids and easy-to-handle alkynes. The details of the reaction mechanism were further rationalized using theoretical calculations. This protocol can be widely applied to synthesize furan- and thiofuran-fused phospholes as well as the corresponding large π-extended derivatives, which are of great interest in the domain of organic functional materials.

Electrophilic aromatic substitution reactions of compounds with Craig-Möbius aromaticity.

Electrophilic aromatic substitution (EAS) reactions are widely regarded as characteristic reactions of aromatic species, but no comparable reaction has been reported for molecules with Craig-Möbius aromaticity. Here, we demonstrate successful EAS reactions of Craig-Möbius aromatics, osmapentalenes, and fused osmapentalenes. The highly reactive nature of osmapentalene makes it susceptible to electrophilic attack by halogens, thus osmapentalene, osmafuran-fused osmapentalene, and osmabenzene-fused osmapentalene can undergo typical EAS reactions. In addition, the selective formation of a series of halogen substituted metalla-aromatics via EAS reactions has revealed an unprecedented approach to otherwise elusive compounds such as the unsaturated cyclic chlorirenium ions. Density functional theory calculations were conducted to study the electronic effect on the regioselectivity of the EAS reactions.

Carbolong chemistry: nucleophilic aromatic substitution of a triflate functionalized iridapentalene.

The reactivity of the triflate functionalized iridapentalene 1, [Ir{[double bond, length as m-dash]CHC(CH2C(CO2Me)2CH2)[double bond, length as m-dash]CC[double bond, length as m-dash]CHC(OTf)[double bond, length as m-dash]CH}(CO)(PPh3)2]OTf, with C-, N-, O- and S-centered neutral nucleophiles was studied, leading to the isolation of a wide array of irida-carbolong derivatives. As an extension, a polycyclic complex with a rare six-fused-ring structure was constructed. This strategy provides a new route for the construction of functionalized metallaaromatic complexes, and the resulting iridacycles exhibit broad spectral absorption ranges, making them potential photoelectric materials.

Total Synthesis and Assignment of the Absolute Configuration of (+)-Omphalic Acid.

Omphalane diterpenoids usually contain a cyclohexane-fused bicyclo[3.2.1]octane scaffold embedded with two continuous quaternary carbon centers, which pose considerable challenges to synthetic chemists. Herein, we reported the first total synthesis of omphalic acid with high stereochemical control, featuring an intermolecular Diels-Alder cycloaddition, ring reorganization through Criegee oxidative cleavage and programmed aldol condensations, conformationally controlled hydrogenation, and Pd-catalyzed carboxylation. The absolute configuration of omphalic acid was defined for the first time via the asymmetric total synthesis facilitated by a derivatization resolution protocol.

Epigenetic regulation of intestinal peptide transporter PEPT1 as a potential strategy for colorectal cancer sensitization.

Human intestinal peptide transporter PEPT1 is commonly repressed in human colorectal cancer (CRC), yet its relationship with sensitivity to the common CRC treatment ubenimex has not previously been elucidated. In this study, we confirmed PEPT1 suppression in CRC using real-time quantitative polymerase chain reaction and western blotting and then investigated the underlying epigenetic pathways involved using bisulfite sequencing, chromatin immunoprecipitation, siRNA knockdown, and reporter gene assays. We found that PEPT1 transcriptional repression was due to both DNMT1-mediated DNA methylation of the proximal promoter region and HDAC1-mediated histone deacetylation, which blocked P300-mediated H3K18/27Ac at the PEPT1 distal promoter. Finally, the effects of the epigenetic activation of PEPT1 on the CRC response to ubenimex were evaluated using sequential combination therapy of decitabine and ubenimex both in vitro and in xenografts. In conclusion, epigenetic silencing of PEPT1 due to increased DNMT1 and HDAC1 expression plays a vital role in the poor response of CRC to ubenimex.

Tuning an Electrode Work Function Using Organometallic Complexes in Inverted Perovskite Solar Cells.

Low-work-function (WF) metals (including silver (Ag), aluminum (Al), and copper (Cu)) used as external cathodes in inverted perovskite solar cells (PSCs) encounter oxidation caused by air exposure and halogen-diffusion-induced corrosion, which threaten the long-term stability of the device. The cathode interlayer (CIL) has shown promise in reducing the metal WF and thus boosting the device power conversion efficiency (PCE). However, it remains a challenge for current CIL materials to enable high-WF metals (e.g., Au) to be used as cathodes to achieve PSCs with a superior PCE and long-term stability. Here, we use a series of synthesized (carbolong-derived) organometallic complexes as CILs to tune the electrode WF in inverted PSCs. Density functional theory calculations and surface characterizations show that the organometallic complexes that contain anions and cations are prone to form anion-cation dipoles on the metal surface, hence drastically reducing the metal's WF. Photovoltaic devices based on a Ag cathode, which was modified with these organometallic complexes, received a boosted PCE up to 21.29% and a remarkable fill factor that reached 83.52%, which are attributed to the dipole-enhanced carrier transport. The environmental stability of PSCs was further improved after employing Au as a cathode with these organometallic complexes, and the modified devices exhibited no efficiency loss after 4080 h storage measurements.

Site-Specific Photochemical Desaturation Enables Divergent Syntheses of Illicium Sesquiterpenes.

Desaturation of unactivated alkanes remains a challenging yet desirable strategy to make olefins. The Illicium sesquiterpenes usually possess highly oxygenated cage-like architectures, and some of them exhibit prominent neurotrophic effects. Here, we disclose a unique photochemical desaturation strategy for the efficient, highly stereocontrolled total syntheses of five Illicium sesquiterpenes from inexpensive (R)-pulegone, featuring a 13-step gram-scale synthesis of (-)-merrilactone A. The efficiency of the syntheses derives from an expedient construction of a tetracyclic framework via two annulations, a site-specific photoinduced single-step desaturation in a complex hydrocarbon system, and diverse oxygenation manipulations around the resultant olefin intermediate. This work highlights how late-stage desaturation can dramatically streamline the synthesis of complex terpenes and diverse non-natural analogues for establishing the structure-activity relationship and elucidating their molecular mechanisms of bioactivity.

CYP2C9 inhibits the invasion and migration of esophageal squamous cell carcinoma via downregulation of HDAC.

Cytochrome P450 2C9 (CYP2C9) is involved in the metabolism of cancer drugs and exogenous carcinogens. In our study, CYP2C9 was downregulated in multiple cohorts of human esophageal squamous cell carcinoma (ESCC). Until now, its role and epigenetic regulation of CYP2C9 repression in ESCC remain poorly understood. CYP2C9 repression in collected ESCC patient tumor tissues was demonstrated by RT-qPCR and Western blot. The histone acetylation level was carried out by the treatment of histone deacetylase inhibitor TSA and RNA interference. Epigenetic analysis revealed that the increased expression of CYP2C9 in KYSE-150 and TE1 cells was characterized by inhibition of HDAC8 and HDAC1, respectively. TSA decreased the levels of HDAC occupancy around CYP2C9 promoter region greatly. Overexpression of CYP2C9 reduced the invasion and migration of ESCC cells.

Metallaaromatic Chemistry: History and Development.

Since the prediction of the existence of metallabenzenes in 1979, metallaaromatic chemistry has developed rapidly, due to its importance in both experimental and theoretical fields. Now six major types of metallaromatic compounds, metallabenzenes, metallabenzynes, heterometallaaromatics, dianion metalloles, metallapentalenes and metallapentalynes (also termed carbolongs), and spiro metalloles, have been reported and extensively studied. Their parent organic analogues may be aromatic, non-aromatic, or even anti-aromatic. These unique systems not only enrich the large family of aromatics, but they also broaden our understanding and extend the concept of aromaticity. This review provides a comprehensive overview of metallaaromatic chemistry. We have focused on not only the six major classes of metallaaromatics, including the main-group-metal-based metallaaromatics, but also other types, such as metallacyclobutadienes and metallacyclopropenes. The structures, synthetic methods, and reactivities are described, their applications are covered, and the challenges and future prospects of the area are discussed. The criteria commonly used to judge the aromaticity of metallaaromatics are presented.

Icotinib With Concurrent Radiotherapy vs Radiotherapy Alone in Older Adults With Unresectable Esophageal Squamous Cell Carcinoma: A Phase II Randomized Clinical Trial.

Importance: Palliative radiotherapy (RT) is generally recommended for older patients with esophageal squamous cell carcinoma (ESCC) with poor prognosis. A new combination treatment is therefore needed. Objective: To assess the efficacy and toxicity of RT plus icotinib vs RT alone in older patients with ESCC. Design, Setting, and Participants: This randomized, multicenter, open-label, phase II clinical trial was conducted in China, with enrollment between January 1, 2015, and October 31, 2016. Patients aged 70 years or older with clinical stage T2 to T4, N0/1, M0/1a unresectable (because of comorbidities, T4 disease, unresectable lymph node, or refused surgery) ESCC were randomized 1:1 to receive RT plus icotinib or RT alone. Radiation was prescribed at 60 Gy in 30 fractions in both groups, and icotinib was administered at a dosage of 125 mg 3 times a day in the RT plus icotinib group. The last follow-up was completed on June 30, 2019, and data were analyzed from July 1 to September 30, 2019. Interventions: Patients were randomized to either RT plus icotinib or RT alone. Main Outcomes and Measures: The primary end point was overall survival (OS). Treatment-related toxic effects were evaluated. Immunohistochemistry was performed to analyze epidermal growth factor receptor (EGFR) expression if available. Results: A total of 127 patients (median age, 76 years [range, 70-91 years]; 76 men [59.8%]) were enrolled and were eligible for survival analysis. Median OS was 24.0 (95% CI, 22.2-25.8) months in the RT plus icotinib group vs 16.3 (95% CI, 13.8-18.8) months in the RT group (hazard ratio, 0.53; 95% CI, 0.33-0.87; P = .008). No difference was observed in grades 3 or 4 adverse events. Patients with EGFR overexpression had a significantly better median overall survival (not reached vs 16.3 months [range, 2.6-45.1 months]; P = .03) in the RT plus icotinib group. Conclusions and Relevance: In this randomized clinical trial, icotinib plus RT was well tolerated and improved OS in older patients with ESCC relative to RT alone. Patients with EGFR overexpression benefitted more from icotinib with RT. Trial Registration: ClinicalTrials.gov Identifier: NCT02375581.