ABSTRACT
Methods to access chiral sulfur(VI) pharmacophores are of interest in medicinal and synthetic chemistry. We report the desymmetrization of unprotected sulfonimidamides via asymmetric acylation with a cinchona-phosphinate catalyst. The desired products are formed in excellent yield and enantioselectivity with no observed bis-acylation. A data-science-driven approach to substrate scope evaluation was coupled to high throughput experimentation (HTE) to facilitate statistical modeling in order to inform mechanistic studies. Reaction kinetics, catalyst structural studies, and density functional theory (DFT) transition state analysis elucidated the turnover-limiting step to be the collapse of the tetrahedral intermediate and provided key insights into the catalyst-substrate structure-activity relationships responsible for the origin of the enantioselectivity. This study offers a reliable method for accessing enantioenriched sulfonimidamides to propel their application as pharmacophores and serves as an example of the mechanistic insight that can be gleaned from integrating data science and traditional physical organic techniques.
Subject(s)
Cinchona Alkaloids , Data Science , Molecular Structure , Stereoisomerism , Cinchona Alkaloids/chemistry , Catalysis , AcylationABSTRACT
Graphyne has attracted considerable interest and attention since its successful synthesis, due to its enormous potential for applications in the fields of electronics, energy, catalysis, information technology, etc. Although various methods for synthesizing graphyne have been explored, single-layer graphynes have not been successfully developed. Hexaethynylbenzene (HEB) is considered an ideal precursor molecule because it can undergo Glaser coupling reactions between molecules to synthesize single layer graphdiyne on single crystal metal surfaces via on-surface reactions. Unfortunately, this method fails to achieve the expected results, and the underlying mechanism is not clear. In this work, we employed a combination of ab initio molecular dynamics (AIMD) and quantum mechanics (QM) methods to investigate the initial reaction mechanism of HEB molecules on a Au(111) surface. We revealed that HEB molecules undergo both intermolecular coupling and intramolecular cyclization on the Au(111) surface. The favorable pathways of these two types of reactions were then distinguished, confirming that the distance between the terminal carbon atoms of the ethynyl groups plays an important role in C-C coupling. The insights revealed from this work could facilitate the rational design of precursor molecules and deepen the understanding of the reaction processes.
ABSTRACT
Stored products are constantly infested by insects, so finding eco-friendly bioinsecticides for insect management is important. The work aimed to assess the insecticidal and repellent activity of essential oil (EO) from Hedychium glabrum S. Q. Tong, Hedychium coronarium Koen., and Hedychium yunnanense Gagnep. against Tribolium castaneum, Lasioderma serricorne, and Liposcelis bostrychophila. Results showed that 88 chemical components were identified in the extracted Hedychium EOs, indicating that they exhibited diversity in components. According to principal component analysis (PCA), the composition of the EO from the H. yunnanense stem and leaf (EOHYSL) was significantly different from other EOs due to the different organs and species. The biological activity also varied continuously with plant species and organs. Only the EO of H. yunnanense (EOHY) showed strong fumigant toxicity. While in the contact tests, EOHGR showed the strongest toxicity effect on L. bostrychophila, with a LC50 value of 71.76â µg/cm2, which was closest to the positive control (Pyrethrin). All EOs had remarkable repellent activities against the three target insects, and repellency increased with concentration. According to the results of the comprehensive score, EOHY had the highest potential, which ranged from 0.7999 to 0.8689. Thus, Hedychium EOs possess potential biorational traits to be biological insecticides.
Subject(s)
Coleoptera , Insect Repellents , Insecticides , Oils, Volatile , Tribolium , Zingiberaceae , Animals , Oils, Volatile/toxicity , Oils, Volatile/chemistry , Insecta , Insecticides/chemistry , Insect Repellents/pharmacology , Insect Repellents/chemistryABSTRACT
Thermally-induced dehydrogenative coupling of polyphenylenes on metal surfaces is an important technique to synthesize ð-conjugated carbon nanostructures with atomic precision. However, this protocol has rarely been utilized to fabricate structurally defined carbon nanosheets composed of sp- and sp2-hybridized carbon atoms. Here, we present the synthesis of butadiyne-linked hexabenzocoronenes (HBCs) on Au(111) surfaces as core-expanded graphdiynes. The reaction started from hexa(4-ethylphenyl)benzene, which undergoes dehydrogenation toward hexa(4-vinylphenyl)benzene, followed by planarization to hexabenzocoronene, coupling between the vinyl groups, and further dehydrogenation. In addition to butadiyne linkages, benzene groups were also found as another type of linker. The reaction sequences were monitored by scanning tunneling microscopy and bond-resolved non-contact atomic force microscopy, which disclose the structures of intermediates and final products. In combination with density functional theory simulations, the key steps from ethyl substituents to butadiyne and benzene linkers were elucidated. This is a new on-surface synthesis of core-expanded graphdiynes with unprecedented electronic properties.
ABSTRACT
On-surface acetylenic homocoupling has been proposed to construct carbon nanostructures featuring sp hybridization. However, the efficiency of linear acetylenic coupling is far from satisfactory, often resulting in undesired enyne products or cyclotrimerization products due to the lack of strategies to enhance chemical selectivity. Herein, we inspect the acetylenic homocoupling reaction of polarized terminal alkynes (TAs) on Au(111) with bond-resolved scanning probe microscopy. The replacement of benzene with pyridine moieties significantly prohibits the cyclotrimerization pathway and facilitates the linear coupling to produce well-aligned N-doped graphdiyne nanowires. Combined with density functional theory calculations, we reveal that the pyridinic nitrogen modification substantially differentiates the coupling motifs at the initial C-C coupling stage (head-to-head vs head-to-tail), which is decisive for the preference of linear coupling over cyclotrimerization.
ABSTRACT
New methods for the general asymmetric synthesis of sulfonimidamides are of great interest due to their applications in medicinal chemistry, agrochemical discovery, and academic research. We report a palladium-catalyzed cross-coupling method for the enantioselective aryl-carbonylation of sulfonimidamides. Using data science techniques, a virtual library of calculated bisphosphine ligand descriptors was used to guide reaction optimization by effectively sampling the catalyst chemical space. The optimized conditions identified using this approach provided the desired product in excellent yield and enantioselectivity. As the next step, a data science-driven strategy was also used to explore a diverse set of aryl and heteroaryl iodides, providing key information about the scope and limitations of the method. Furthermore, we tested a range of racemic sulfonimidamides for compatibility of this coupling partner. The developed method offers a general and efficient strategy for accessing enantioenriched sulfonimidamides, which should facilitate their application in industrial and academic settings.
ABSTRACT
Acellular extracellular matrices (aECM) are commonly utilized, both experimentally and clinically, in the regenerative medicine field. However, some disadvantages such as rapid degradation, poor mechanical properties, chronic inflammatory reactions and low antioxidant activity have limited their further application. In this study the feasibility of caffeic acid as a crosslinking agent in fixing small intestinal submucosa (SIS) was evaluated. The ninhydrin assay, swelling ratio and FTIR spectra indicated that caffeic acid can efficiently react with free amino groups to crosslink SIS and the highest crosslinking index reached 21.60 ± 1.37%. Moreover, the shrinkage temperature of SIS remarkably increased from 59 °C to about 80 °C and the degradation rate of CA-SIS was all lower than 6%, demonstrating their improved biostability and hydrothermal stability. Importantly, the antioxidant activity of CA-SIS ranged from 55% to 90%, statistically higher than that of native SIS (37.33 ± 2.94%). Additionally the cytotoxicity test presented that the cytotoxicity grade of CA-SIS was 1 or 0, whilst large numbers of living HUVECs were attached to the surface of the material and exhibited high cell viability. These results indicated their excellent cytocompatibility. The data of subcutaneous implant displayed that the number of inflammatory cells in 2%- and 2.5%CA-SIS groups remained at a low level (below 100 cells/field) while that of the native SIS group continued increasing, finally reaching 142.33 ± 30.92 cells/field. In conclusion, caffeic acid is a promising candidate for modifying aECM and may play a vital role in the design and fabrication of tissue engineering scaffolds.
Subject(s)
Antioxidants , Caffeic Acids , Antioxidants/pharmacology , Feasibility Studies , Caffeic Acids/pharmacology , Extracellular MatrixABSTRACT
In this study, ultra-performance liquid chromatography-quadrupole-time-of-flight tandem mass spectrometry(UPLC-Q-TOF-MS~E) was used to analyze the plasma components of Danzhi Xiaoyao Formula after oral administration. Forty-nine plasma components were found in the serum of rats by comparing the compound extract, drug-containing serum, and blank serum. Components, such as 6-hydroxycoumarin, poricoic acid F, deoxoglabrolide, 30-norhederagenin, kanzonol R, 3',6'-di-O-galloylpaeoniflorin, 16α-hydroxytrametenolic acid, 16-deoxyporicoic acid B, 3-O-acetyl-16α-hydroxytrametenolic acid, and 16α,25-dihydroxydehydroeburiconic acid, were first found in rat serum. Behavioral tests, including the tail suspension test, novel object recognition test, and novelty-suppressed feeding test, were conducted for behavioral analysis. It was confirmed that this formula had therapeutic effects on perimenopausal depression. Furthermore, in combination with the network pharmacology method, 53 core targets including MAPK1, HRAS, AKT1, EGFR, and ESR1 were screened, and these targets participated in 165 signaling pathways, including PI3K-AKT, AMPK, VEGFA, MAPK, and HIF-1. In summary, the potential effects of Danzhi Xiaoyao Formula in treating perimenopausal depression are associated with mechanisms in accelerating inflammation repair, improving neuroplasticity, affecting neurotransmitters, regulating estrogen levels, and promoting new blood vessel formation.
Subject(s)
Depression , Drugs, Chinese Herbal , Animals , Rats , Chromatography, High Pressure Liquid , Depression/drug therapy , Network Pharmacology , Perimenopause , Phosphatidylinositol 3-Kinases , Drugs, Chinese Herbal/pharmacology , Molecular Docking SimulationABSTRACT
The atropselective iodination of 2-amino-6-arylpyridines catalyzed by chiral disulfonimides (DSIs) is described. Key to the development of this transformation was the use of a chemoinformatically guided workflow for the curation of a structurally diverse training set of DSI catalysts. Utilization of this catalyst training set in the atropselective iodination across a variety 2-aminopyridine substrates allowed for the recommendation of statistically higher-performing DSIs for this reaction. Data Fusion techniques were implemented to successfully predict the performance of catalysts when classical linear regression analysis failed to provide suitable models. This effort identified a privileged class of 3,3'-alkynyl-DSI catalysts which were effective in catalyzing the iodination of a variety of 2-amino-6-arylpyridines with high stereoselectivity and generality. Subsequent preparative-scale demonstrations highlighted the utility of this reaction by providing iodinated pyridines >90:10 er and in good chemical yield.
Subject(s)
Halogenation , CatalysisABSTRACT
Assembly of semiconducting organic molecules with multiple aryl-metal covalent bonds into stable one- and two-dimensional (1D and 2D) metal-organic frameworks represents a promising route to the integration of single-molecule electronics in terms of structural robustness and charge transport efficiency. Although various metastable organometallic frameworks have been constructed by the extensive use of single aryl-metal bonds, it remains a great challenge to embed multiple aryl-metal bonds into these structures due to inadequate knowledge of harnessing such complex bonding motifs. Here, we demonstrate the substrate-modulated synthesis of 1D and 2D metal-organic hybrids (MOHs) with the organic building blocks (perylene) interlinked solely with multiple aryl-metal bonds via the stepwise thermal dehalogenation of 3,4,9,10-tetrabromo-1,6,7,12-tetrachloroperylene and subsequent metal-organic connection on metal surfaces. More importantly, the conversion from 1D to 2D MOHs is completely impeded on Au(111) but dominant on Ag(111). We comprehensively study the distinct reaction pathways on the two surfaces by visually tracking the structural evolution of the MOHs with high-resolution scanning tunneling and noncontact atomic force microscopy, supported by first-principles density functional theory calculations. The substrate-dependent structural control of the MOHs is attributed to the variation of the M-X (M = Au, Ag; X = C, Cl) bond strength regulated by the nature of the metal species.
ABSTRACT
An efficient asymmetric synthesis of a potent KRAS G12C covalent inhibitor, GDC-6036 (1), is reported. The synthesis features a highly atroposelective Negishi coupling to construct the key C-C bond between two highly functionalized pyridine and quinazoline moieties by employing a Pd/Walphos catalytic system. Statistical modeling by comparing computational descriptors of a range of Walphos chiral bisphosphine ligands to a training set of experimental results was used to inform the selection of the best ligand, W057-2, which afforded the desired Negishi coupling product (Ra)-3 in excellent selectivity. A subsequent telescoped reaction sequence of alkoxylation, global deprotection, and acrylamide formation, followed by a final adipate salt formation, furnished GDC-6036 (1) in 40% overall yield from starting materials pyridine 5 and quinazoline 6.
Subject(s)
Antineoplastic Agents , Proto-Oncogene Proteins p21(ras) , Linear Models , Antineoplastic Agents/pharmacology , Quinazolines/chemistry , PyridinesABSTRACT
The aim is to explore the impact of the Kasai procedure (KP) and the length of native liver survival time (NLST) on outcomes of liver transplantation (LT). Patients with biliary atresia (BA), who underwent LT in Beijing Friendship Hospital from January 2017 to December 2019, were enrolled and divided into non-KP (N-KP) and post-KP (P-KP) groups. The patients in the P-KP group were further divided into early failure (KP-EF) defined by NLST <1 year, medium failure (KP-MF, NLST 1-5 years), and late failure (KP-LF, NLST >5 years) subgroups. Clinical data at baseline and during follow-up were collected. The inverse probability of treatment weighting method was used to evaluate the independent effect of KP and the length of NLST on clinical outcomes. Among 197 patients with BA, the N-KP group accounted for 43 (21.8%), KP-EF 71 (46.1%), KP-MF 59 (38.3%), and KP-LF 24 (15.6%) cases, respectively. The N-KP and KP-EF groups had significantly longer hospitalization and intensive care unit stays after LT. Graft and overall survival rates were 93.0% in the N-KP group and 97.4% in P-KP group, respectively. The mortality rate in the P-KP group were significantly lower compared with that of the N-KP group with a hazard ratio (HR) of 0.2 (P = 0.02). The risks of biliary and vascular complications and cytomegalovirus (CMV) infection after LT were significantly higher in KP-EF group than those in the KP-MF and KP-LF groups (HRs = 0.09, 0.2, and 0.3, respectively; all P < 0.001). The KP significantly improved after LT overall survival. Patients with early native liver failure after KP have significantly higher risks for biliary and vascular complications and CMV infection.
Subject(s)
Biliary Atresia , Liver Failure , Liver Transplantation , Biliary Atresia/surgery , Humans , Infant , Liver Failure/etiology , Liver Transplantation/methods , Portoenterostomy, Hepatic/adverse effects , Retrospective Studies , Treatment OutcomeABSTRACT
BACKGROUND: ESAT6-CFP10 (EC) skin test has been reported accurate and safe in identifying tuberculosis infection. We aimed to demonstrate the safety of EC skin test compared with tuberculin skin test (TST) in university freshmen. METHODS: We conducted a double-blind, randomized, controlled clinical study in a university freshmen population with 16,680 participates in China, and finally 14,579 completed the study. About a half received an EC skin test and the others received TST. Adverse reactions were evaluated. RESULTS: Out of the 14,579 participants, 48.2% (7029/14,579) were males. The average age was 18.1 ± 0.8 years and the average BMI was 20.9 ± 3.1 kg/m2. 50.4% (7351/14,579) participants received EC skin test and 49.6% (7228/14,579) received TST. The EC group had significantly less adverse reactions compared with the TST group (21.3%, 1565/7351 vs. 34.6%, 2499/7228, P = 0.000). The most common adverse reactions for EC were bleeding (5.63%, 414), dermatodyschroia (4.27%, 314), induration (3.90%, 287), swelling (2.49%, 183), pain (1.59%, 117) and pruritus (1.48%, 109). Bleeding, dermatodyschroia, swelling and erythema were significantly less in EC group (P < 0.05), while others were similar to those of TST. CONCLUSION: the EC skin test was safe in our cohort. And its incidence of total adverse drug reactions (ADRs) is less than that of TST. Most adverse reactions were mild or moderate, lasting less than 48 h and self-limiting. Considering the satisfactory diagnostic accuracy in identifying tuberculosis infection, the cost and safety, the EC skin test might be a potential candidate for replacing TST in high burden countries or those with routine BCG vaccination. CLINICAL TRIALS REGISTRATION: ChiCTR2000038622, Safety of the EC skin test to screen tuberculosis infection in two universities, compared with the tuberculin skin test: a double-blind, randomized, controlled trial. registered on 26/09/2020 at http://www.chictr.org.cn .
Subject(s)
Latent Tuberculosis , Tuberculosis , Adolescent , BCG Vaccine , Double-Blind Method , Female , Humans , Male , Tuberculin Test , Tuberculosis/diagnosis , VaccinationABSTRACT
Amide bond formation is one of the most important reactions in biochemistry, notably being of crucial importance for the origin of life. Herein, we combine scanning tunneling microscopy and X-ray photoelectron spectroscopy studies to provide evidence for thermally activated abiotic formation of amide bonds between adsorbed precursors through direct carboxyl-amine coupling under ultrahigh-vacuum conditions by means of on-surface synthesis. Complementary insights from temperature-programmed desorption measurements and density functional theory calculations reveal the competition between cross-coupling amide formation and decarboxylation reactions on the Au(111) surface. Furthermore, we demonstrate the critical influence of the employed metal support: whereas on Au(111) the coupling readily occurs, different reaction scenarios prevail on Ag(111) and Cu(111). The systematic experiments signal that archetypical bio-related molecules can be abiotically synthesized in clean environments without water or oxygen.
ABSTRACT
We describe the on-surface dehalogenative homocoupling of benzylic bromides, namely bis-bromomethyl- and bis-gem-(dibromomethyl) naphthalene as a potential route to either hydrocarbon dimers or conjugated polymers on Au(111). While bis-gem-(dibromomethyl) naphthalene affords different dimers with naphthocyclobutadiene as the key intermediate, bis-bromomethyl naphthalene furnishes a poly(o-naphthylene vinylidene) as a non-conjugated polymer which undergoes dehydrogenation toward its conjugated derivative poly(o-naphthylene vinylene) upon mild annealing. A combination of scanning tunneling microscopy, non-contact atomic force microscopy and density functional theory calculations provides deep insights into the prevailing mechanisms.
ABSTRACT
We report the development of a method to diastereoselectively access tetrasubstituted alkenes via nickel-catalyzed Suzuki-Miyaura cross-couplings of enol tosylates and boronic acid esters. Either diastereomeric product was selectively accessed from a mixture of enol tosylate starting material diastereomers in a convergent reaction by judicious choice of the ligand and reaction conditions. A similar protocol also enabled a divergent synthesis of each product isomer from diastereomerically pure enol tosylates. Notably, high-throughput optimization of the monophosphine ligands was guided by chemical space analysis of the kraken library to ensure a diverse selection of ligands was examined. Stereoelectronic analysis of the results provided insight into the requirements for reactive and selective ligands in this transformation. The synthetic utility of the optimized catalytic system was then probed in the stereoselective synthesis of various tetrasubstituted alkenes, with yields up to 94% and diastereomeric ratios up to 99:1 Z/E and 93:7 E/Z observed. Moreover, a detailed computational analysis and experimental mechanistic studies provided key insights into the nature of the underlying isomerization process impacting selectivity in the cross-coupling.
ABSTRACT
The first total synthesis of marine anti-cancer meroterpenoids dysideanoneâ B and dysiherbolâ A have been accomplished in a divergent way. The synthetic route features: 1)â a site and stereoselective α-position alkylation of a Wieland-Miescher ketone derivative with a bulky benzyl bromide to join the terpene and aromatic moieties together and set the stage for subsequent cyclization reactions; 2)â an intramolecular radical cyclization to construct the 6/6/6/6-tetracycle of dysideanoneâ B and an intramolecular Heck reaction to forge the 6/6/5/6-fused core structure of dysiherbolâ A. A late-stage introduction of the ethoxy group in dysideanoneâ B reveals that this group might come from the solvent ethanol. The structure of dysiherbolâ A has been revised based on our chemical total synthesis.
Subject(s)
Antineoplastic Agents, Phytogenic/chemical synthesis , Quinones/chemical synthesis , Sesquiterpenes/chemical synthesis , Antineoplastic Agents, Phytogenic/chemistry , Molecular Structure , Quinones/chemistry , Sesquiterpenes/chemistry , StereoisomerismABSTRACT
A dual experimental/theoretical investigation of the Ireland-Claisen rearrangement of tetrasubstituted α-phthalimido ester enolates to afford α-tetrasubstituted, ß-trisubstituted α-amino acids (generally >20:1 dr) is described. For trans allylic olefins, the Z- and E-enol ethers proceed through chair and boat transition states, respectively. For cis allylic olefins, the trend is reversed. As a result, the diastereochemical outcome of the reaction is preserved regardless of the geometry of the enolate or the accompanying allylic olefin. We term this unique convergence of all possible olefin isomers global diastereoconvergence. This reaction manifold circumvents limitations in present-day technologies for the stereoselective enolization of α,α-disubstituted allyl esters. Density functional theory paired with state-of-the-art local coupled-cluster theory (DLPNO-CCSD(T)) was employed for the accurate determination of quantum mechanical energies.
Subject(s)
Amino Acids/chemistry , Amino Acids/chemical synthesis , Alkenes/chemistry , Chemistry Techniques, Synthetic , Density Functional Theory , Ketones/chemistry , Models, Molecular , Molecular Conformation , StereoisomerismABSTRACT
While surface-confined Ullmann-type coupling has been widely investigated for its potential to produce π-conjugated polymers with unique properties, the pathway of this reaction in the presence of adsorbed oxygen has yet to be explored. Here, the effect of oxygen adsorption between different steps of the polymerization reaction is studied, revealing an unexpected transformation of the 1D organometallic (OM) chains to 2D OM networks by annealing, rather than the 1D polymer obtained on pristine surfaces. Characterization by scanning tunneling microscopy and X-ray photoelectron spectroscopy indicates that the networks consist of OM segments stabilized by chemisorbed oxygen at the vertices of the segments, as supported by density functional theory calculations. Hexagonal 2D OM networks with different sizes on Cu(111) can be created using precursors with different length, either 4,4â³-dibromo-p-terphenyl or 1,4-dibromobenzene (dBB), and square networks are obtained from dBB on Cu(100). The control over size and symmetry illustrates a versatile surface patterning technique, with potential applications in confined reactions and host-guest chemistry.
ABSTRACT
We demonstrate an enhancement of cyclization against polymerization for the on-surface debrominative coupling reaction, by using the metal-organic Cu-N coordination template to direct the reaction pathways. Experiments performed by using ultrahigh-vacuum scanning tunneling microscopy (UHV-STM), with the substitution of metal-coordination centers, metallic substrates and functional organic ligands, corroborate the template effect of the Cu-N coordination.