The Development of a Sulfamate-Tethered Aza-Michael Cyclization Allows for the Preparation of (-)-Negamycin tert-Butyl Ester.

We present the first examples of intramolecular aza-Michael cyclizations of sulfamates and sulfamides onto pendant α,ß-unsaturated esters, thioesters, amides, and nitriles. Stirring the substrate with catalytic quantities of the appropriate base delivers the product in good yield and excellent diastereoselectivity. The reactions are operationally simple, can be performed open to air, and are tolerant of a variety of important functional groups. We highlight the utility of this technology by using it in the preparation of a (-)-negamycin derivative.

Anion Binding to Ammonium and Guanidinium Hosts: Implications for the Reverse Hofmeister Effects Induced by Lysine and Arginine Residues.

Anions have a profound effect on the properties of soluble proteins. Such Hofmeister effects have implications in biologics stability, protein aggregation, amyloidogenesis, and crystallization. However, the interplay between the important noncovalent interactions (NCIs) responsible for Hofmeister effects is poorly understood. To contribute to improving this state of affairs, we report on the NCIs between anions and ammonium and guanidinium hosts 1 and 2, and the consequences of these. Specifically, we investigate the properties of cavitands designed to mimic two prime residues for anion-protein NCIs─lysines and arginines─and the solubility consequences of complex formation. Thus, we report NMR and ITC affinity studies, X-ray analysis, MD simulations, and anion-induced critical precipitation concentrations. Our findings emphasize the multitude of NCIs that guanidiniums can form and how this repertoire qualitatively surpasses that of ammoniums. Additionally, our studies demonstrate the ease by which anions can dispense with a fraction of their hydration-shell waters, rearrange those that remain, and form direct NCIs with the hosts. This raises many questions concerning how solvent shell plasticity varies as a function of anion, how the energetics of this impact the different NCIs between anions and ammoniums/guanidiniums, and how this affects the aggregation of solutes at high anion concentrations.

Anticancer Drug Extraction from Plasma Samples Using Three-Dimensional Polyoxometalate-Based Supramolecular Frameworks as Sorbents.

Four self-assembled inorganic-organic hybrid materials, namely, H{Na(H2O)3[Gd(PDA)(H2O)2]3[BW12O40]}·4H2O (1), H{Na(H2O)3[Tb(PDA)(H2O)2]3[BW12O40]}·3H2O (2), H{Na(H2O)3[Er(PDA)(H2O)3]3[BW12O40]}·H2O (3) (PDA = 1,10-phenanthroline-2,9-dicarboxylate), and [Pr3(H2O)13(pydc-OH)2][BW12O40]·12H2O (4) (pydc-OH = 4-hydroxy-2,6-pyridinedicarboxylate), were hydrothermally synthesized and structurally characterized. Hybrids 1-3 are isostructural and contain a Keggin unit, which is linked to lanthanoids to produce distinct trinuclear lanthanoid building blocks. The fragments are connected by anion-π and hydrogen bonding interactions to create 3D networks. In hybrid 4, a trimeric Pr-organic species bearing a Keggin unit forms a 2D coordination polymer, and then hydrogen bonding interactions between 2D layers lead to the formation of a 3D structure. These polyoxometalate-based frameworks were used as sorbents for the dispersive microsolid-phase extraction (D-µSPE) of two anticancer drugs (doxorubicin and epirubicin) in human plasma samples. Analytes were quantified and separated using high-performance liquid chromatography with fluorescence detection (HPLC-FLD). The method's linearity was between 0.8-500 ng mL-1 and 1.0-500 ng mL-1 for the antineoplastic drugs doxorubicin and epirubicin, respectively. The limits of detection (S/N = 3) were in the range of 0.2-0.3 ng mL-1, while the precision was in the range of 3.5-4.3%. Finally, human plasma samples from patients treated with doxorubicin or epirubicin were analyzed by using the D-µSPE-HPLC-FLD method.

Asymmetric by Design: Heteroleptic Coordination Compounds with Redox-Active Dithiolene and 1,2,4,5-Tetrakis(isopropylthio)benzene Ligands.

The 1,2,4,5-tetrakis(alkylthio)benzenes are redox-active organosulfur molecules that support oxidation to a stable radical cation. Their utility as ligands for the assembly of multimetal complexes with tailored functionality/property is unexamined. Here, 1,2,4,5-tetrakis(isopropylthio)benzene (tptbz, 1) is shown to bind PdCl2 at either one end, leaving the other open, or at both ends to form centrosymmetric [Cl2Pd(tptbz)PdCl2], 4. Ligand metathesis between Na2[(N≡C)2C2S2] (Na2mnt) and [Cl2M(tptbz)] (M = Pd, 2; M = Pt, 3) yields [(mnt)M(tptbz)] (M = Pd, 5; M = Pt, 6), but an alternative route involving transmetalation with [(mnt)SnMe2] delivers substantially greater yield. The mixed dithiolene-dithioether compound [(Ph2C2S2)Pt(tptbz)] (8) is formed by a similar transmetalation protocol using [(Ph2C2S2)SnnBu2]. Compounds 5, 6, and 8 are the first such heteroleptic complexes prepared by deliberate synthesis. The cyclic voltammetry of 8 reveals anodic waves at +0.14 and +0.97 V vs Fc+/Fc, which are attributed to successive dithiolene oxidation processes. While oxidized at +0.73 V as a free ligand, the redox-active MO of tptbz is pushed to a higher potential upon coordination to Pt2+ and is inaccessible. Calculations of the structures of [8]+ and of [((Cl2-3,5-C6H3)2C2S2)Pt(tptbz)]+ show that, in the latter, the dithiolene MOs are drawn down in energy into proximity with the tptbz MOs.

CuII Pyrazolyl-Benzimidazole Dinuclear Complexes with Remarkable Antioxidant Activity.

Three dinuclear coordination complexes generated from 1-n-butyl-2-((5-methyl-1H-pyrazole-3-yl)methyl)-1H-benzimidazole (L), have been synthesized and characterized spectroscopically and structurally by single crystal X-ray diffraction analysis. Reaction with iron(II) chloride and then copper(II) nitrate led to a co-crystal containing 78 % of [Cu(NO3 )(µ-Cl)(L')]2 (C1 ) and 22 % of [Cu(NO3 )(µ-NO3 )(L')]2 (C2 ), where L was oxidized to a new ligand L' . A mechanism is provided. Reaction with copper chloride led to the dinuclear complex [Cu(Cl)(µ-Cl)(L)]2 (C3 ). The presence of N-H⋅⋅⋅O and C-H⋅⋅⋅O intermolecular interactions in the crystal structure of C1 and C2 , and C-H⋅⋅⋅N and C-H⋅⋅⋅Cl hydrogen bonding in the crystal structure of C3 led to supramolecular structures that were confirmed by Hirshfeld surface analysis. The ligands and their complexes were tested for free radical scavenging activity and ferric reducing antioxidant power. The complex C1 /C2 shows remarkable antioxidant activities as compared to the ligand L and reference compounds.

Sulfamate-Tethered Aza-Wacker Cyclization Strategy for the Syntheses of 2-Amino-2-deoxyhexoses: Preparation of Orthogonally Protected d-Galactosamines.

We present a new strategy for the assembly of protected d-galactosamine synthons. Our route uses a sulfamate-tethered aza-Wacker cyclization as a key step and commences from d-erythrono-1,4-lactone. This stands in contrast to most literature syntheses of 2-amino-2-deoxyhexose derivatives, as these generally employ glycals or hexoses as starting materials. This strategy may serve as a template for the assembly of many other 2-amino-2-deoxyhexoses with protection patterns difficult to access by conventional methods.

Ring Opening of Aziridines by Pendant Silanols Allows for Stereospecific Preparations of 1'-Amino-tetrahydrofurans.

We have developed a highly stereospecific cyclization of aziridine silanols into 1'-amino-tetrahydrofurans. Our protocol of stirring a substrate with 10 mol % Sc (OTf)3 and 1 equivalent of NaHCO3 in CH2Cl2 is mild and compatible with a range of activating aziridine N-substituents (including tosylates, mesylates, and carbamates) and functional groups on the alkyl chains (including substituted aryl rings, alkyl bromides, and alkyl ethers). In all cases examined, trans di-substituted aziridine silanols give products with an erythro configuration; conversely, cis di-substituted aziridine silanols give products with a threo configuration. While literature syntheses of 1'-amino-tetrahydrofurans exist, only one example, contemporaneous with our work, uses a similar cyclization for their construction. Control experiments demonstrate that, for this transformation, the silanol is not particularly privileged, and a variety of protecting groups on the alcohol (including other silicon protecting groups, benzyl ethers, and MOM ethers) are compatible with product formation.

Ring Opening of Aziridines by Pendant Sulfamates Allows for Regioselective and Stereospecific Preparation of Vicinal Diamines.

The ring opening of aziridines by pendant sulfamates is a viable strategy for the rapid preparation of vicinal diamines. Our reaction is compatible with both disubstituted cis- and trans-aziridines; unsubstituted, N-alkyl, and N-aryl sulfamates engage effectively. In all cases examined, the cyclization reaction is perfectly regioselective and stereospecific. Once activated, the product oxathiazinane heterocycles can be ring opened with a diverse range of nucleophiles.

Opioid Drug Detection in Hair Samples Using Polyoxometalate-Based Frameworks.

A series of two-dimensional (2D) polyoxometalate-based frameworks, [Ln3(PDA)3(H2O)6(PMo12O40)]·xH2O (Ln = La (1); Ce (2); Pr (3); Nd (4); PDA = 1,10-phenanthroline-2,9-dicarboxylate), have been synthesized and structurally characterized by various analytical techniques. Single-crystal X-ray diffraction reveals that 1-4 have a unique 2D layer structure in which Keggin anions have coordinated upward and downward the plane, and this feature makes them suitable candidates for surface binding of common drugs via supramolecular and electrostatic interactions. Also, the ability of 1-4 (as the first polyoxomolybdate-containing frameworks) as sorbents for the extraction and quantitative determination of opioid drugs (morphine, methadone, and pethidine) was investigated by using dispersive micro-solid-phase extraction (D-µSPE) and high-performance liquid chromatography (HPLC). The method showed wide linear ranges in the range of 0.3 to 300 ng mg-1 and low limits of detection (LODs) ranged from 0.1 to 0.2 ng mg-1 of hair.

Fully Reduced and Mixed-Valent Multi-Copper Aggregates Supported by Tetradentate Diamino Bis(thiolate) Ligands.

Tetradentate diamino bis(thiolate) ligands (l-N2S2(2-)) with saturated linkages between heteroatoms support fully reduced [(Cu(l-N2S2))2Cu2] complexes that bear relevance as an entry point toward molecules featuring the Cu2ICu2II(µ4-S) core composition of nitrous oxide reductase (N2OR). Tetracopper [(Cu(l-N2(SMe2)2))2Cu2] (l-N2(SMe2H)2 = N1,N2-bis(2-methyl-2-mercaptopropane)-N1,N2-dimethylethane-1,2-diamine) does not support clean S atom oxidative addition but undergoes Cl atom transfer from PhICl2 or Ph3CCl to afford [(Cu(l-N2(SMe2)2))3(CuCl)5], 14. When introduced to Cu(I) sources, the l-N2(SArH)2 ligand (l-N2(SArH)2 = N1,N2-bis(2-mercaptophenyl)-N1,N2-dimethylethane-1,2-diamine), made by a newly devised route from N1,N2-bis(2-fluorophenyl)-N1,N2-dimethylethane-1,2-diamine, ultimately yields the mixed-valent pentacopper [(Cu(l-N2SAr2))3Cu2] (19), which has 3-fold rotational symmetry (D3) around a Cu2 axis. The single CuII ion of 19 is ensconced within an equatorial l-N2(SAr)2(2-) ligand, as shown by 14N coupling in its EPR spectrum. Formation of 19 proceeds from an initial, fully reduced product, [(Cu(l-N2SAr2))3Cu2(Cu(MeCN))] (17), which is C2 symmetric and exceedingly air-sensitive. While unreactive toward chalcogen donors, 19 supports reversible reduction to the all-cuprous state; generation of [19]1- and treatment with S atom donors only return 19 because structural adjustments necessary for oxidative addition are noncompetitive with outer-sphere electron transfer. Oxidation of 19 is marked by intense darkening, consistent with greater mixed valency, and by dimerization in the crystalline state to a decacopper species ([20]2+) of S4 symmetry.

How great is the stabilization of crowded polyphenylbiphenyls by London dispersion?

Decaphenylbiphenyl (1) and 2,2',4,4',6,6'-hexaphenylbiphenyl (2) are bulky molecules expected to be greatly destabilized by steric crowding. Herein, through a combined experimental and computational approach, we evaluate the molecular energetics of crowded biphenyls. This is complemented by the study of phase equilibria for 1 and 2. Compound 1 shows a rich phase behavior, displaying an unusual interconversion between two polymorphs. Surprisingly, the polymorph with distorted molecules of C1 symmetry is found to have the highest melting point and to be the one that is preferentially formed. The thermodynamic results also indicate that the polymorph displaying the more regular D2 molecular geometry has larger heat capacity and is probably the more stable at lower temperatures. The melting and sublimation data clearly reveal the weakening of cohesive forces in crowded biphenyls due to the lower molecular surface area. The experimental quantification of the intramolecular interactions in 1 and 2 indicated, using homodesmotic reactions, a molecular stabilization of about 30 kJ mol-1. We attribute the origin of this stabilization in both compounds to the existence of two parallel-displaced π⋯π interactions between the ortho-phenyl substituents on each side of the central biphenyl. Computational calculations with dispersion-corrected DFT methods underestimate the stabilization in 1, unless the steric crowding is well balanced in a homodesmotic scheme. This work demonstrates that London dispersion forces are important in crowded aromatic systems, making these molecules considerably more stable than previously thought.

Ring-Opening Reactions of Phosphoramidate Heterocycles.

We present protocols for the conversion of phosphoramidate heterocycles into 1,3-chloroamines and 1,3-aminoalcohols. For the formation of chloroamines, our optimized protocol involves heating the phosphoramidate starting material with 4 equivalents of HCl in a dioxane/toluene solvent mixture. The substituents on the phosphoramidate starting material have a profound influence on product formation. Phosphoramidates with a variety of aza-heterocyclic substituents engage, but those containing a 5-chloro-8-quinolinol arm are most competent for 1,3-chloroamine formation. Furthermore, only the phosphoramidate cis diastereomers allow for 1,3-chloroamine formation. X-ray crystallography studies coupled with DFT analysis provide a basis for the stark difference in reactivity between the cis and trans diastereomers. Amino-alcohol products form by heating phosphoramidate heterocycles with aqueous HF in toluene. Here, there is no diastereomeric preference or a requirement for an aza-heterocyclic arm. Based on a substrate survey, both reactions tolerate a broad range of substitution patterns and functional groups. This work establishes that phosphoramidates are competent synthons for interesting amine products and further increases the prominence of tethered aza-Wacker technology.

Synthesis, X-ray Crystal Structure, Anticancer, Hirshfeld Surface Analysis, DFT, TD-DFT, ADMET, and Molecular Docking of 3-Phenyl-1,2,4-triazolo[3,4-h]-13,4-thiaza-11-crown-4.

In this work, we describe the synthesis of new macrocycles derived from 3-phenyl-1,2,4-triazole-5-thione 1 in a heterogeneous medium using liquid-solid phase transfer catalysis (PTC) conditions. The structures of the two compounds (3 and 4) isolated were elucidated based on spectral data (1H-NMR, 13C-NMR) and confirmed in the case of 3-phenyl-1,2,4-triazolo [3,4-h]-13,4--thiaza-11-crown-4 (3) by a single-crystal X-ray diffraction analysis. Furthermore, the experimental spectral and the X-ray geometrical parameters were compared with their corresponding predicted ones obtained at the B3LYP/6-311++G(d,p) level of theory. The intercontacts between crystal units were investigated through Hirshfeld surface analysis. The drug-like macrocycles were predicted using ADMET and drug-likeness properties, which showed that 3 may act as an inhibitor of DNA-dependent protein kinase (DNA-PK). This assumption was confirmed by the well-binding fitting of 3 into the binding site of DNA-PK and the formation of a stable 3-DNA-PK complex with a binding energy of -7 kcal-mol-1. Finally, the anticancer activity of 3 was assessed by an MTT assay against A549 cells, which showed that 3 has moderate anticancer activity compared to that of the doxorubicin reference drug.

Exploring the Efficacy of Benzimidazolone Derivative as Corrosion Inhibitors for Copper in a 3.5 wt.% NaCl Solution: A Comprehensive Experimental and Theoretical Investigation.

This study focuses on the synthesis, theoretical analysis, and application of the corrosion inhibitor known as benzimidazolone, specifically 1-(cyclohex-1-enyl)-1,3-dihydro-2H-benzimiazol-2-one (CHBI). The structure of CHBI was determined by X-ray diffraction (XRD). The inhibitory properties of CHBI were investigated in a 3.5 wt.% NaCl solution on pure copper using various electrochemical techniques such as potentiodynamic polarization curves (PDPs) and electrochemical impedance spectroscopy (EIS), as well as scanning electron microscopy with energy dispersive X-ray spectroscopy (SEM-EDX), UV-visible spectroscopy, and theoretical calculations. The obtained results indicate that CHBI is an excellent inhibitor, exhibiting remarkable effectiveness with an inhibition rate of 86.49% at 10-3 M. To further confirm the extent of adsorption of the inhibitory molecule on the copper surface, density functional theory (DFT) and Monte Carlo (MC) simulation studies were conducted. The results of this study demonstrate the synthesis and characterization of CHBI as a corrosion inhibitor. The experimental and theoretical analyses provide valuable insights into the inhibitory performance of CHBI, indicating its strong adsorption on the copper surface.

The Pursuit of Perphenylterphenyls.

Tetradecaphenyl-p-terphenyl (2) was synthesized from 2,3,5,6-tetraphenyl-1,4-diiodobenzene (11) by two methods. Ullmann coupling of 11 with pentaphenyliodobenzene (9) gave compound 2 in 1.7 % yield, and Sonogashira coupling of 11 with phenylacetylene, followed by a double Diels-Alder reaction of the product diyne 12 with tetracyclone (6), gave 2 in 1.5 % overall yield. The latter reaction also gave the monoaddition product 4-(phenylethynyl)-2,2',3,3',4',5,5',6,6'-nonaphenylbiphenyl (13) in 4 % overall yield. The X-ray structures of compounds 2 and 13 show them to possess core aromatic rings distorted into shallow boat conformations. Density functional calculations indicate that these unusual structures are not the lowest energy conformations in the gas phase and may be the result of packing forces in the crystal. In addition, while uncorrected DFT calculations indicate that the strain energy in compound 2 is approximately 50 kcal/mol, dispersion-corrected DFT calculations suggest that it is essentially unstrained, due to compensating, favorable, intramolecular interactions of its many phenyl rings. An attempted synthesis of tetradecaphenyl-o-terphenyl (4) by reaction of diphenylhexatriyne (14) with three equivalents of tetracyclone at 350 °C gave only the diadduct 2-(phenylethynyl)-2',3,3',4,4',5,5',6,6'-nonaphenylbiphenyl (15) in 17 % yield. Even higher temperatures failed to produce 4 and lowered the yield of 15, perhaps due to rapid decomposition of the starting materials. Ullmann coupling of 3,4,5,6-tetraphenyl-1,2-diiodobenzene (16) and compound 9 also failed to give compound 4.

Highly Stereospecific Cyclizations of Homoallylic Silanols.

We demonstrate that di-tert-butylsilanols are competent nucleophiles for the intramolecular interception of palladium π-allyl species. In these reactions, allyl ethyl carbonates are the best precursors for the formation of palladium π-allyl intermediates, and [(Cinnamyl)PdCl]2/BINAP is superior to other Pd salt/ligand framework combinations. Our optimized protocol is compatible with a variety of silanol substrates. Importantly, the cyclization is perfectly stereospecific, proceeding via an anti-syn mechanism, which stands in contrast to reported analogous reactions of alcohols and phenols, known to proceed via an anti-anti mechanism. The alkenes in the product dioxasilinanes serve as blank slates for further functionalization.

Heterotrimetallic Assemblies with 1,2,4,5-Tetrakis(diphenylphosphino)benzene Bridges: Constructs for Controlling the Separation and Spatial Orientation of Redox-Active Metallodithiolene Groups.

Metallodithiolene complexes of the type [(R2C2S2)M(η2-tpbz)] [R = CN, Ph, or p-anisyl; M = Ni2+, Pd2+, or Pt2+; tpbz = 1,2,4,5-tetrakis(diphenylphosphino)benzene] chelate transition metals ions to form trimetallic arrays [[(R2C2S2)M(tpbz)]2M']n+, where M' is square planar Pt2+, tetrahedral Cu+, Ag+, or Au+, or octahedral {ReBr(CO)}/{Re(CO)2}+. Forcing conditions (190 °C reflux in decalin, 72 h) are demanded for the Re+ compounds. With third-row metals at the nexus, the compounds are stable to air. Twelve members of the set have been characterized by X-ray diffraction and reveal dithiolene centroid-centroid distances ranging from 22.4 to 24.0 Å. Folding around each tpbz intrachelate P···P axis such that the MP2/M'P2 planes meet the tpbz P2C6P2 mean plane at non-zero values gives rise to core topologies that appear "S-like" or herringbone-like for M' = Pt2+ or {ReBr(CO)}/{Re(CO)2}+. Calculations reveal that departure from idealized D2h/D2d/C2v symmetries is induced by steric crowding between Ph groups and that dynamic, fluxional behavior is pertinent to the solution phase because multiple, lower-symmetry minima of comparable energy exist. Spectroscopically, the formation of the trimetallic arrays is marked by a shift of the open end 31P nuclear magnetic resonance signal from approximately -14.5 ppm to approximately +41, approximately +20.5, and approximately +28.5 ppm for M' = Pt2+, Au+, and {ReBr(CO)}/{Re(CO)2}+, respectively. Electrochemically, dithiolene-based oxidations are observed for the R = Ph and M' = Pt2+ or Au+ compounds but at potentials that are anodically shifted relative to charge-neutral [[(R2C2S2)M]2(µ-tpbz)]. The compounds reported clarify the possibilities for the synthesis of assemblies in which weakly coupled spins may be created in their modular (R2C2S2)M and M' parts.

Synthesis, crystal structure investigation and computational approach to discover potential hydrazide derivatives as a potent inhibitor of cyclooxygenase-2 enzyme.

This study reports the synthesis of two new hydrazide derivatives, namely, (E)-N'-(4- bromobenzylidene)-2-(4-isobutylphenyl)propanehydrazide (4a) and (E)-N'-benzylidene-2-(4-isobutylphenyl)propanehydrazide (4b), respectively. The compounds were synthesized by the reaction of benzaldehyde with Ibuprofen acid hydrazide. Their structures were confirmed by X-ray crystallography. To try to do a more detailed investigation, computational studies including Hirshfeld surface analyses, energy frameworks, density functional theory (DFT) optimizations, frontier orbital analyses, molecular electrostatic potential analyses, and natural bond orbital analyses of the studied compounds are performed. Moreover, molecular docking and dynamics simulations of complexes of the compounds with the cyclooxygenase-2 (COX-2) enzyme were performed to determine the anti-inflammatory potential of the compounds. These analyses predicted the compounds to show maximum chemical interactions and be dynamically stable during simulation time. Furthermore, estimation of binding free energies confirmed the high binding affinity of the compounds for the COX-2 enzyme.

Progress towards the syntheses of Bactobolin A and C4-epi-Bactobolin A using a sulfamate-tethered aza-Wacker cyclization strategy.

We present a progress report towards Bactobolin A and C4-epi-Bactobolin A. Sulfamate-tethered aza-Wacker cyclization followed by a Tsuji-Wacker ketone synthesis furnishes a key tricyclic intermediate which we hypothesize can be elaborated into C4-epi-Bactobolin A. Epimerization of one of the stereocenters of this compound furnishes an intermediate which we hypothesize can be elaborated into Bactobolin A.

An efficient diastereoselective synthesis of novel fused 5H-furo[2,3-d]thiazolo[3,2-a]pyrimidin-5-ones via one-pot three-component reaction.

Herein, a convenient and efficient synthesis of 7-benzoyl-6-(aryl)-6,7-dihydro-5H-furo[2,3-d]thiazolo[3,2-a]pyrimidin-5-one derivatives was achieved from the reaction of isoquinolinium N-ylides, aromatic aldehydes, and heterocyclic 1,3-dicarbonyl compounds via one-pot three-component diastereoselective domino reaction in good-to-excellent yields. The advantages of this protocol are easily available starting materials, operational simplicity, and avoidance of hazardous organic solvents and catalyst. The synthesized products were characterized by IR, 1H NMR, 13C NMR and mass spectra. Additionally, the conclusive structure of target compounds was confirmed by X-Ray diffraction analysis.