Enantioselective De Novo Synthesis of α,α-Diaryl Ketones from Alkynes

Chiral α,α-diaryl ketones are structural motifs commonly present in bioactive molecules, and they are also valuable building blocks in synthetic organic chemistry. However, catalytic asymmetric synthesis of α,α-diaryl ketones bearing a tertiary stereogenic center remains largely unsolved. Herein, we report a catalytic de novo enantioselective synthesis of α,α-diaryl ketones from simple alkynes via chiral phosphoric acid (CPA) catalysis. A broad range of enolizable α,α-diaryl ketones are prepared in good yields and with excellent enantioselectivities. The described protocol also serves as an efficient deuteration method for the preparation of enantiomerically enriched deuterated α,α-diaryl ketones. Using the methodology reported, bioactive molecules, including one of the best-selling anti-breast cancer drugs, tamoxifen, are readily synthesized.     

Palladium-Catalyzed Skeletal Rearrangement of Substituted 2-Silylaryl Triflates via 1,5-C−Pd/C−Si Bond Exchange

A palladium-catalyzed skeletal rearrangement of 2-(2-allylarylsilyl)aryl triflates has been developed to give highly fused tetrahydrophenanthrosilole derivatives via unprecedented 1,5-C−Pd/C−Si bond exchange. The reaction pathways can be switched toward 4-membered ring-forming C(sp²)−H alkylation by tuning the reaction conditions to give completely different products, fused dihydrodibenzosilepin derivatives, from the same starting materials. The inspection of the reaction conditions revealed the importance of carboxylates in promoting the C−Pd/C−Si bond exchange.     

Efficient Visible-Light-Activated Ultra-Long Room-Temperature Phosphorescence Triggered by Multi-Esterification

The development of ultra-long room-temperature phosphorescence (UL-RTP) in processable amorphous organic materials is highly desirable for applications in flexible displays, anti-counterfeiting, and bio-imaging. However, achieving efficient UL-RTP from amorphous materials remains a challenging task, especially with activation by visible light and a bright afterglow. Here we report a general and rational molecular-design strategy to enable efficient visible-light-excited UL-RTP by multi-esterification of a rigid large-plane phosphorescence core. Notably, multi-esterification minimizes the aggregation-induced quenching and accomplishes a ′four birds with one stone′ possibility in the generation and radiation process of UL-RTP: i) shifting the excitation from ultraviolet light to blue-light through enhancing the transition dipole moment of low-lying singlet-states, ii) facilitating the intersystem crossing process through the incorporation of lone-pair electrons, iii) boosting the decay process of long-lived triplet excitons resulting from a significantly increased transition dipole moment, and iv) reducing the intrinsic triplet nonradiative decay by substitution of high-frequency vibrating hydrogen atoms. All these factors synergistically contribute to the most efficient and stable visible-light-stimulated UL-RTP (lifetime up to 2.01 s and efficiency up to 35.4 % upon excitation at 450 nm) in flexible films using multi-esterified coronene, which allows high-tech applications in single-component time-delayed white light-emitting diodes and information technology based on flashlight-activated afterglow encryption.     

In silico study of novel niclosamide derivatives,SARS-CoV-2 nonstructural proteins catalytic residue-targeting small molecules drug candidates

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-mediated coronavirus disease 2019 (COVID-19) infection remains a global pandemic and health emergency with overwhelming social and economic impacts throughout the world. Therapeutics for COVID-19 are limited to only remdesivir; therefore, there is a need for combined, multidisciplinary efforts to develop new therapeutic molecules and explore the effectiveness of existing drugs against SARS-CoV-2. In the present study, we reported eight (SCOV-L-02, SCOV-L-09, SCOV-L-10, SCOV-L-11, SCOV-L-15, SCOV-L-18, SCOV-L-22, and SCOV-L-23) novel structurally related small-molecule derivatives of niclosamide (SCOV-L series) for their targeting potential against angiotensin-converting enzyme-2 (ACE2), type II transmembrane serine protease (TMPRSS2), and SARS-COV-2 nonstructural proteins (NSPs) including NSP5 (3CLpro), NSP3 (PLpro), and RdRp. Our correlation analysis suggested that ACE2 and TMPRSS2 modulate host immune response via regulation of immune-infiltrating cells at the site of tissue/organs entries. In addition, we identified some TMPRSS2 and ACE2 microRNAs target regulatory networks in SARS-CoV-2 infection and thus open up a new window for microRNAs-based therapy for the treatment of SARS-CoV-2 infection. Our in vitro study revealed that with the exception of SCOV-L-11 and SCOV-L-23 which were non-active, the SCOV-L series exhibited strict antiproliferative activities and non-cytotoxic effects against ACE2- and TMPRSS2-expressing cells. Our molecular docking for the analysis of receptor-ligand interactions revealed that SCOV-L series demonstrated high ligand binding efficacies (at higher levels than clinical drugs) against the ACE2, TMPRSS2, and SARS-COV-2 NSPs. SCOV-L-18, SCOV-L-15, and SCOV-L-09 were particularly found to exhibit strong binding affinities with three key SARS-CoV-2’s proteins: 3CLpro, PLpro, and RdRp. These compounds bind to the several catalytic residues of the proteins, and satisfied the criteria of drug-like candidates, having good adsorption, distribution, metabolism, excretion, and toxicity (ADMET) pharmacokinetic profile. Altogether, the present study suggests the therapeutic potential of SCOV-L series for preventing and managing SARs-COV-2 infection and are currently under detailed investigation in our lab.     

Is DFT Accurate Enough to Calculate Regioselectivity? The Case of 1,3-Dipolar Cycloaddition of Azide to Alkynes and Alkenes

The importance of regioselectivity in 1,3-dipolar cycloadditions (DCs) makes it surprising that no benchmarking study on this problem has appeared. We investigated whether DFT calculations are an accurate tool to predict the regioselectivity of uncatalyzed thermal azide 1,3-DCs. We considered the reaction between HN₃ and 12 dipolarophiles, comprising ethynes HC≡C−R and ethenes H₂C=CH−R (R=F, OH, NH₂, Me, CN, CHO), which cover a broad range of electron demand and conjugation ability. We established benchmark data by the W3X protocol [complete-basis-set-extrapolated CCSD(T)-F12 energy with T-(T) and (Q) corrections and MP2-calculated core/valence and relativistic effects] and showed that core/valence effects and high-order excitations are important for accurate regioselectivity. Regioselectivities calculated using an extensive set of density functional approximations (DFAs) were compared with benchmark data. Range-separated and meta-GGA hybrids gave the best results. Good treatment of self-interaction and electron exchange are the key features for accurate regioselectivity. Dispersion correction slightly improves agreement with W3X results. The best DFAs provide the isomeric TS energy difference with an expected error ≈0.7 mh and errors ≈2 mh can occur. The isomer yield provided by the best DFA has an expected error of ±5 %, though errors up to 20 % are not rare. At present, an accuracy of 1–2 % is unfeasible but it seems that we are not far from achieving this goal.     

Stereo- and Regiochemical Effect of N,N-Dialkylamide Extractants on the Speciation of Pu Complexes

The relationship between extractant stereochemistry and their extraction performance has only poorly been established. In order to address a part of this concern, we investigated the Pu(IV) liquid-liquid extraction (LLE) by using the N,N-di-(2-ethylhexyl)butyramide (DEHBA), as well as those of its position isomers. DEHBA (ββ-isomer) and N-(2-ethylhexyl)-N-(oct-3-yl)butyramide (EHOBA or αβ-isomer) were synthesized as a mixture of stereoisomer or stereoenriched (R,S)- and (S,S)-diastereoisomers, and were all assessed for Pu^IV LLE. The results showed that both the position and the stereoisomerism of the aliphatic substituents affect Pu^IV complexation and extraction. We found that Pu extraction is lowered by factor 2 to 4 when the ethyl branching group is closer to the complexing site. UV-vis spectroscopy showed that this extraction decrease was affected by steric hindrance inducing a deprivation of Pu inner sphere complex. Effect of stereoisomerism is highlighted for branching closer to the complexing site (α-position). Enantiopure DEHBA stereoisomers provided similar Pu extraction, whereas a slight decrease could be noticed for the more cluttered stereoenriched (αβ)-isomers, which was also concomitant with a smaller population of inner sphere complex. In contrast, the stereoisomers mixture led to a strong decrease of Pu extraction because of an antagonistic association in the mixed complexes.     

Chiral-at-Molybdenum – A Computational Study on N-Substituted cis-MoO2(nacnac)2

Cis-MoO₂(nacnac)₂ (nacnac=β-diketiminate) can be a viable chiral-at-metal catalyst when its two β-diketiminate (nacnac) ligands are N-substituted to prevent Λ⇌Δ racemization. Even simple methyl groups raise the barriers for racemization significantly for the Bailar, Rây-Dutt, Conte-Hippler, and Dhimba-Muller-Lammertsma (DML) twists to a respectable 28.5, 37.8, 30.5, and 25.1 kcal/mol, respectively, at ωB97X-D/6-311+G(2d,p) (LANL2DZ for Mo) including acetonitrile solvation. The lowest energy DML barrier increases to ΔG^o=27.4 kcal/mol with N-substituted t-butyl groups. The nacnac ligands’ electronic and steric components to the racemization barriers are discussed.     

Diastereoselective Synthesis of Pyrazolo[1,2-a][1,2,4]triazine Derivatives via Cross-1,3-dipolar Cyclizations of Azaoxyallyl Cations with N,N′-Cyclic Azomethine Imines

A cross-1,3-dipolar cycloaddition reaction of α-halohydroxamates (in situ generated azaoxyallyl cations) with N,N′-cyclic azomethine imines was developed. The synthetic protocol provided facile and rapid access to pyrazolo[1,2-a][1,2,4]triazine derivatives in good yields and excellent diastereoselectivities under mild metal-free conditions.     

催化裂解-金汞齐富集-冷原子吸收光谱仪测定土壤样品中总汞含量

为建立采用催化裂解-金汞齐富集-冷原子吸收光谱仪即直接测汞仪测定土壤样品中汞含量的方法,本研究配制汞总量为0~2 ng、0~15 ng和25~1023 ng的三种不同汞浓度系列的标准工作曲线,选取9个土壤样品,3种国家土壤有证标准物质,同一样品分别进行6组平行测定,并抽取3个土壤样品进行3种不同浓度加标回收试验,以对其方法精密度和准确度进行论证。 结果显示：仪器信号值与Hg总量之间均呈良好的线性关系。根据仪器多次测定空白数据结果,按照称样量0.1 g计算,方法最小检出量为0.09 ng/g;平行测定结果相对标准偏差均小于10%,土壤标准物质测定值与标准物质标准参考值均相符,不同浓度的加标回收率范围为78.4%～92.7%。结果表明催化裂解-金汞齐富集-冷原子吸收光谱仪,可用于批量土壤样品中汞含量的快速测定分析,方法的精密度和准确度可满足测定分析要求,且实验过程中无需前处理消煮,操作方便、快速高效。     

Rapid synthesis of bovine serum albumin-conjugated gold nanoparticles using pulsed laser ablation and their anticancer activity on hela cells

Nanoscience research aims to produce nanoparticles without adverse effects for medical applications. The pulsed laser ablation (PLA) technique was utilized in this study to synthesize gold nanoparticles (AuNPs) using bovine serum albumin (BSA) in simulated body fluid (SBF) at the fundamental wavelength of the Nd: YAG laser (1064 nm). BSA acted as a stabilizer, reducing and capping agent to produce spherically shaped AuNPs (diameter 3–10 nm). The successful synthesis of AuNPs was confirmed through color changes and UV–vis spectroscopy. The agglomeration and precipitation of AuNPs are attributed to the presence of BSA in the solution, and electrostatic repulsion interactions between BSA and Au nanoclusters. The effect of salt concentration of SBF on BSA stability as well as the interaction of BSA conjugated AuNPs to form complexes was studied using molecular dynamic simulations. Our results show that the stability of AuNPs-BSA conjugates increase with the salt concentration of BSA. Moreover, the synthesized AuNPs exhibit low toxicity and high biocompatibility, supporting their application in drug delivery. Investigation of the cytotoxic effect of the synthesized AuNPs show that normal fibroblast cells (L929) remain intact after treatment whereas a dose-dependent inhibition effect on the growth of cervix cancer cells (HeLa) is observed. In general, this study presents an effective, environmentally-friendly, and facile approach to the synthesis of multifunctional AuNPs using the PLA technique, as a promising efficacious therapeutic treatment of cervical cancer.