A Sterically Accessible Monomeric Stibine Oxide Activates Organotetrel(IV) Halides, Including C-F and Si-F Bonds.

Phosphine oxides and arsine oxides are common laboratory reagents with diverse applications that stem from the chemistry exhibited by these monomeric species. Stibine oxides are, in contrast, generally dimeric or oligomeric species because of the reactivity-quenching self-association of the highly polarized stiboryl (Sb=O/Sb+-O-) group. We recently isolated Dipp3SbO (Dipp = 2,6-diisopropylphenyl), the first example of a kinetically stabilized monomeric stibine oxide, which exists as a bench-stable solid and bears an unperturbed stiboryl group. Herein, we report the isolation of Mes3SbO (Mes = mesityl), in which the less bulky substituents maintain the monomeric nature of the compound but unlock access to a wider range of reactivity at the unperturbed stiboryl group relative to Dipp3SbO. Mes3SbO was found to be a potent Lewis base in the formation of adducts with the main-group Lewis acids PbMe3Cl and SnMe3Cl. The accessible Lewis acidity at the Sb atom results in a change in the reactivity with GeMe3Cl, SiMe3Cl, and CPh3Cl. With these species, Mes3SbO formally adds the E-Cl (E = Ge, Si, C) bond across the unsaturated stiboryl group to form a 5-coordinate stiborane. The biphilicity of Mes3SbO is sufficiently potent to activate even the C-F and Si-F bonds of C(p-MeOPh)3F and SiEt3F, respectively. These results mark a significant contribution to an increasingly rich literature on the reactivity of polar, unsaturated main-group motifs. Furthermore, these results highlight the utility of a kinetic stabilization approach to access unusual bonding motifs with unquenched reactivity that can be leveraged for small-molecule activation.

Synthesis and Functionalization of Challenging meso-Substituted Aryl Bis-pocket Porphyrins Accessed via Suzuki-Miyaura Cross-Coupling.

Herein we report an investigation into the synthesis, metalation, and functionalization of bis-pocket porphyrins using the Suzuki-Miyaura cross-coupling reaction. Steric limitations to accessing bis-pocket porphyrins were overcome by using this Pd-catalyzed C-C-bond-forming strategy to introduce steric bulk after macrocyclization: 2,6-dibromo-4-trimethylsilybenzaldehyde was condensed with pyrrole, and a variety of boronic acids were coupled to the resulting porphyrin in up to 95% yield. Furthermore, we show that these porphyrins can be metalated with a variety of metals and sulfonated to create water-soluble bis-pocket porphyrins.

Selective Chromium(VI) Trapping by an Acetate-Releasing Coordination Polymer.

We report the high-capacity and selective uptake of Cr(VI) from water using the coordination polymer silver bipyridine acetate (SBA, [Ag(4,4'-bipy)][CH3CO2]·3H2O). Cr capture involves the release of acetate, and we have structurally characterized two of the product phases that form: silver bipyridine chromate (SBC, SLUG-56, [Ag(4,4'-bipy)][CrO4]0.5·3.5H2O) and silver bipyridine dichromate (SBDC, SLUG-57, [Ag(4,4'-bipy)][Cr2O7]0.5·H2O). SBA maintains a high Cr uptake capacity over a wide range of pH values (2-10), reaching a maximum of 143 mg Cr/g at pH 4. This Cr uptake capacity is one of the highest among coordination polymers. SBA offers the additional benefits of a one-step, room temperature, aqueous synthesis and its release of a non-toxic anion following Cr(VI) capture, acetate. Furthermore, SBA capture of Cr(VI) remains >97% in the presence of a 50-fold molar excess of sulfate, nitrate, or carbonate. We also investigated the Cr(VI) sequestration abilities of silver 1,2-bis(4-pyridyl)ethane nitrate (SEN, [Ag(4,4'-bpe)][NO3]) and structurally characterized the silver 1,2-bis(4-pyridyl)ethane chromate (SEC, SLUG-58, [Ag(4,4'-bpe)][CrO4]0.5) product. SEN was, however, a less effective Cr(VI) sequestering material than SBA.

Biomimetic Total Synthesis and Investigation of the Non-Enzymatic Chemistry of Oxazinin A.

We report the first total synthesis of an antimycobacterial natural product oxazinin A that takes advantage of a multi-component cascade reaction of anthranilic acid and a precursor polyketide containing an aldehyde. The route utilized for the synthesis of the pseudodimeric oxazinin A validates a previously proposed biosynthetic mechanism, invoking a non-enzymatic pathway to the complex molecule. We found a 76 : 10 : 9 : 5 ratio of oxazinin diastereomers from the synthetic cascade, which is an identical match to that found in the fermentation media from the fungus Eurotiomycetes 110162. Further investigation of the non-enzymatic formation of oxazinin A using 1 H-15 N HMBC NMR spectroscopy allowed for a plausible determination of the stepwise mechanism. The developed route is highly amenable for the synthesis of diverse sets of analogs around the oxazinin scaffold to study structure-activity relationships (SAR).

H-Atom Assignment and Sb-O Bonding of [Mes3SbOH][O3SPh] Confirmed by Neutron Diffraction, Multipole Modeling, and Hirshfeld Atom Refinement.

Neutron wavelength-resolved Laue diffraction experiments permit accurate refinement of the H-atom positions and anisotropic displacement parameters of [Mes3SbOH][O3SPh]. A multipole-based charge density refinement and a topological analysis of the refined electron density were also performed. Hirshfeld atom refinement (HAR) recovers the neutron-determined H-atom parameters, and the quantum-mechanical electron density used in HAR recovers the electron density topology from the refined multipole model. These results confirm that [Mes3SbOH][O3SPh] does indeed feature a hydroxystibonium cation with a nominal Sb-O single bond and not a stibine oxide with an Sb=O/Sb+-O- bond.

Analysis of Oxygen-Pnictogen Bonding with Full Bond Path Topological Analysis of the Electron Density.

A variety of methods are available to investigate the bonding in inorganic compounds. In contrast to wavefunction-based analyses, topological analysis of the electron density affords the advantage of analyzing a physical observable: the electron density. Classical topological analyses of bonding interactions within the atoms in molecules framework typically involve location of a bond path between two atoms and evaluation of a range of real-space functions at the (3, -1) critical point in the electron density that exists on that bond path. We show here that counter-intuitive trends are obtained from the analysis of the electron density (ρ), the Laplacian (∇2ρ), and ellipticity (ε) at the O-E (3, -1) critical points in the coupled-cluster singles doubles electron densities of a series of compounds featuring a range of oxygen-pnictogen bond types: EO+, HEO, H2EOH, H3EOH+, and H3EO (where E = N, P, As, Sb, or Bi). If, instead, these real-space functions are evaluated along the length of the bond path, the discrepancies in the trends are resolved. We show that robust results are also obtained using electron densities from less computationally demanding density functional theory calculations. The increased computational efficiency allowed us to also investigate organic derivatives of these oxygen-pnictogen-bonded compounds and observe that the trends hold in these instances as well. We anticipate that these results will be of use to inorganic chemists engaged in the synthesis and evaluation of novel bonding interactions, particularly those involving heavy main-group elements.

Geometry of Pentaphenylantimony in Solution: Support for a Trigonal Bipyramidal Assignment from X-ray Absorption Spectroscopy and Vibrational Spectroscopic Data.

Pentaphenylantimony (SbPh5) has been previously crystallized in either a square pyramidal or trigonal bipyramidal geometry. Investigation of the solution-state structure of SbPh5 has been hampered by the extreme fluxionality of this compound, but previous vibrational spectroscopic studies concluded that it maintains a square pyramidal geometry in solution. This non-VSEPR-compliant geometry, which is also assumed by BiPh5 in the solid state, stands in contrast to the trigonal bipyramidal geometries of PPh5 and AsPh5. A range of phenomena have been invoked to explain this discrepancy, most notably, the increased importance of relativistic effects as group 15 is descended. We present crystallographic, spectroscopic, and computational data revealing that SbPh5 in fact assumes the VSEPR-compliant trigonal bipyramidal geometry in solution. In particular, Sb X-ray absorption spectroscopy (XAS) was used to obtain geometry-sensitive spectra that do not suffer from the slow spectroscopic time scale that has prevented NMR studies from elucidating the structure of this fluxional molecule. Sb K-edge and LIII-edge XAS spectra of crystalline solids featuring SbPh5 in either a square pyramidal (nonsolvate) or trigonal bipyramidal (cyclohexane hemisolvate or THF hemisolvate) form were compared to spectra of SbPh5 in solution. The solution-state spectra agree with those from solids containing trigonal bipyramidal SbPh5. The most diagnostic spectroscopic feature was the distribution of intensity in the Sb LIII pre-edge features. These distributions were rationalized using time-dependent density functional theory calculations that take into account spin-orbit coupling. Our use of Sb XAS not only resolves a long-standing physical inorganic question but also demonstrates more widely the utility of XAS in establishing the structures of fluxional main-group compounds. This conclusion was further supported by solid- and solution-state Raman data. Finally, we note that the present high-resolution diffraction data allow τ for nonsolvated SbPh5 to be revised to 0.216.

A "Push-Pull" Stabilized Phosphinidene Supported by a Phosphine-Functionalized ß-Diketiminato Ligand.

The use of a bis(diphenyl)phosphine functionalized ß-diketiminato ligand, [HC{(CH3 )C}2 {(ortho-[P(C6 H5 )2 ]2 C6 H4 )N}2 ]- (PNac), as a support for germanium(II) and tin(II) chloride and phosphaketene compounds, is described. The conformational flexibility and hemilability of this unique ligand provide a versatile coordination environment that can accommodate the electronic needs of the ligated elements. For example, chloride abstraction from [(PNac)ECl] (E=Ge, Sn) affords the cationic germyliumylidene and stannyliumylidene species [(PNac)E]+ in which the pendant phosphine arms associate more strongly with the Lewis acidic main group element centers, providing further electronic stabilization. In a similar fashion, chemical decarbonylation of the germanium phosphaketene [(PNac)Ge(PCO)] with tris(pentafluorophenyl)borane affords a "push-pull" stabilized phosphinidene in which one of the phosphine groups of the ligand backbone associates with the low valent phosphinidene center.

Frustrated Lewis Pair Oxidation Permits Synthesis of a Fluoroazaphosphatrane, [FP(MeNCH2CH2)3N].

Proazaphosphatranes, also known as Verkade's superbases, are among the strongest nonionic bases available. Their extreme basicity derives in part from their ability to form a P-N transannulation upon interaction of the P atom with an electrophile. Although haloazaphosphatrane cations of the form [XP(RNCH2CH2)3N]+ have previously been reported for X = Cl, Br, and I, no fluoroazaphosphatranes (X = F) have been prepared. Unlike treatment with Cl2, Br2, I2, and surrogates thereof, reaction of proazaphosphatranes with XeF2 results in decomposition. Analysis of the decomposition products suggested that fluoride ions may be the destructive agent. However, oxidation of a proazaphosphatrane/BPh3 frustrated Lewis pair affords [FP(RNCH2CH2)3N][FBPh3]. Systematic trends in the experimental and computed NMR and structural data are considered. A computational analysis suggests that the transannular P-N distance varies as a result of the flexibility of the molecules and their capacity to deform in the solid state.

Improving the Global Electrophilicity Index (GEI) as a Measure of Lewis Acidity.

The global electrophilicity index (GEI) has been further explored as a general and base-free metric for Lewis acidity. A number of computational methods, including post-Hartree-Fock, density functional theory, and time-dependent density functional theory, have been explored. In this fashion, we sought the method most applicable to a range of different Lewis acids with differing structural and electronic features, including boron trihalides, silicon tetrahalides, fluoroaryl boranes, and group 15 pentahalides. The most accurate and computationally efficient approach was found to use the energies of the orbitals from a geometry optimization at the B3LYP/def2-TZVP level of theory. In addition, the GEI is shown to act as an effective acidity metric that is complementary to the fluoride ion affinity. The GEI also proved to be a better gauge of Lewis acidity for softer bases, as confirmed by comparison to the iodide ion affinity of the group 15 pentahalides.

The Next Generation of Platinum Drugs: Targeted Pt(II) Agents, Nanoparticle Delivery, and Pt(IV) Prodrugs.

The platinum drugs, cisplatin, carboplatin, and oxaliplatin, prevail in the treatment of cancer, but new platinum agents have been very slow to enter the clinic. Recently, however, there has been a surge of activity, based on a great deal of mechanistic information, aimed at developing nonclassical platinum complexes that operate via mechanisms of action distinct from those of the approved drugs. The use of nanodelivery devices has also grown, and many different strategies have been explored to incorporate platinum warheads into nanomedicine constructs. In this Review, we discuss these efforts to create the next generation of platinum anticancer drugs. The introduction provides the reader with a brief overview of the use, development, and mechanism of action of the approved platinum drugs to provide the context in which more recent research has flourished. We then describe approaches that explore nonclassical platinum(II) complexes with trans geometry or with a monofunctional coordination mode, polynuclear platinum(II) compounds, platinum(IV) prodrugs, dual-threat agents, and photoactivatable platinum(IV) complexes. Nanoparticles designed to deliver platinum(IV) complexes will also be discussed, including carbon nanotubes, carbon nanoparticles, gold nanoparticles, quantum dots, upconversion nanoparticles, and polymeric micelles. Additional nanoformulations, including supramolecular self-assembled structures, proteins, peptides, metal-organic frameworks, and coordination polymers, will then be described. Finally, the significant clinical progress made by nanoparticle formulations of platinum(II) agents will be reviewed. We anticipate that such a synthesis of disparate research efforts will not only help to generate new drug development ideas and strategies, but also will reflect our optimism that the next generation of approved platinum cancer drugs is about to arrive.

Accessing Frustrated Lewis Pair Chemistry from a Spectroscopically Stable and Classical Lewis Acid-Base Adduct.

B(C6 F5 )3 and P(MeNCH2 CH2 )3 N form a classical Lewis adduct, (C6 F5 )3 BP(MeNCH2 CH2 )3 N. Although (C6 F5 )3 BP(MeNCH2 CH2 )3 N does not exhibit spectroscopic evidence of dissociation into its constituent acid and base, products of frustrated Lewis pair (FLP) addition reactions are seen with PhNCO, PhCH2 N3 , PhNSO, and CO2 . Computational studies show that thermal access to the dissociated acid and base permits FLP reactivity to proceed. These results demonstrate that FLP reactivity extends across the entire continuum of equilibria governing Lewis acid-base adducts.

Determination of the Molecular Structures of Ferric Enterobactin and Ferric Enantioenterobactin Using Racemic Crystallography.

Enterobactin is a secondary metabolite produced by Enterobacteriaceae for acquiring iron, an essential metal nutrient. The biosynthesis and utilization of enterobactin permits many Gram-negative bacteria to thrive in environments where low soluble iron concentrations would otherwise preclude survival. Despite extensive work carried out on this celebrated molecule since its discovery over 40 years ago, the ferric enterobactin complex has eluded crystallographic structural characterization. We report the successful growth of single crystals containing ferric enterobactin using racemic crystallization, a method that involves cocrystallization of a chiral molecule with its mirror image. The structures of ferric enterobactin and ferric enantioenterobactin obtained in this work provide a definitive assignment of the stereochemistry at the metal center and reveal secondary coordination sphere interactions. The structures were employed in computational investigations of the interactions of these complexes with two enterobactin-binding proteins, which illuminate the influence of metal-centered chirality on these interactions. This work highlights the utility of small-molecule racemic crystallography for obtaining elusive structures of coordination complexes.

Structural and mechanistic studies of polymerase η bypass of phenanthriplatin DNA damage.

Platinum drugs are a mainstay of anticancer chemotherapy. Nevertheless, tumors often display inherent or acquired resistance to platinum-based treatments, prompting the search for new compounds that do not exhibit cross-resistance with current therapies. Phenanthriplatin, cis-diamminephenanthridinechloroplatinum(II), is a potent monofunctional platinum complex that displays a spectrum of activity distinct from those of the clinically approved platinum drugs. Inhibition of RNA polymerases by phenanthriplatin lesions has been implicated in its mechanism of action. The present study evaluates the ability of phenanthriplatin lesions to inhibit DNA replication, a function disrupted by traditional platinum drugs. Phenanthriplatin lesions effectively inhibit DNA polymerases ν, ζ, and κ and the Klenow fragment. In contrast to results obtained with DNA damaged by cisplatin, all of these polymerases were capable of inserting a base opposite a phenanthriplatin lesion, but only Pol η, an enzyme efficient in translesion synthesis, was able to fully bypass the adduct, albeit with low efficiency. X-ray structural characterization of Pol η complexed with site-specifically platinated DNA at both the insertion and +1 extension steps reveals that phenanthriplatin on DNA interacts with and inhibits Pol η in a manner distinct from that of cisplatin-DNA adducts. Unlike cisplatin and oxaliplatin, the efficacies of which are influenced by Pol η expression, phenanthriplatin is highly toxic to both Pol η+ and Pol η- cells. Given that increased expression of Pol η is a known mechanism by which cells resist cisplatin treatment, phenanthriplatin may be valuable in the treatment of cancers that are, or can easily become, resistant to cisplatin.

1,1-Hydroboration and a Borane Adduct of Diphenyldiazomethane: A Potential Prelude to FLP-N2 Chemistry.

Diphenyldiazomethane reacts with HB(C6 F5 )2 and B(C6 F5 )3 , resulting in 1,1-hydroboration and adduct formation, respectively. The hydroboration proceeds via a concerted reaction involving initial formation of the Lewis adduct Ph2 CN2 BH(C6 F5 )2 . The highly sensitive adduct Ph2 CN2 (B(C6 F5 )3 ) liberates N2 and generates Ph2 CB(C6 F5 )3 . DFT computations reveal that formation of Ph2 CN2 B(C6 F5 )3 from carbene, N2 , and borane is thermodynamically favourable, suggesting steric frustration could preclude carbene-borane adduct formation and affect FLP-N2 capture.

Nucleotide Binding Preference of the Monofunctional Platinum Anticancer-Agent Phenanthriplatin.

The monofunctional platinum anticancer agent phenanthriplatin generates covalent adducts with the purine bases guanine and adenine. Preferential nucleotide binding was investigated by using a polymerase stop assay and linear DNA amplification with a 163-base pair DNA double helix. Similarly to cisplatin, phenanthriplatin forms the majority of adducts at guanosine residues, but significant differences in both the number and position of platination sites emerge when comparing results for the two complexes. Notably, the monofunctional complex generates a greater number of polymerase-halting lesions at adenosine residues than does cisplatin. Studies with 9-methyladenine reveal that, under abiological conditions, phenanthriplatin binds to the N(1) or N(7) position of 9-methyladenine in approximately equimolar amounts. By contrast, comparable reactions with 9-methylguanine afforded only the N(7) -bound species. Both of the 9-methyladenine linkage isomers (N(1) and N(7) ) exist as two diastereomeric species, arising from hindered rotation of the aromatic ligands about their respective platinum-nitrogen bonds. Eyring analysis of rate constants extracted from variable-temperature NMR spectroscopic data revealed that the activation energies for ligand rotation in the N(1) -bound platinum complex and the N(7) -linkage isomers are comparable. Finally, a kinetic analysis indicated that phenanthriplatin reacts more rapidly, by a factor of eight, with 9-methylguanine than with 9-methyladenine, suggesting that the distribution of lesions formed on double-stranded DNA is kinetically controlled. In addition, implications for the potent anticancer activity of phenanthriplatin are discussed herein.

Hydroboration of Phosphaalkynes by HB(C6 F5 )2.

The hydroboration of phosphaalkynes with Piers' borane (HB(C6 F5 )2 ) generated unusual phosphaalkenylboranes [RCH=PB(C6 F5 )2 ]2 that persisted as dimers in both solution and the solid state. These P2 B2 heterocycles underwent ring opening when subjected to nucleophiles, such as pyridine and tert-butylisocyanide, to yield monomeric phosphaalkenylborane adducts RCH=PB(C6 F5 )2 (L). DFT calculations were performed to probe the nature of the interaction of phosphaalkynes with boranes.

A Potent Glucose-Platinum Conjugate Exploits Glucose Transporters and Preferentially Accumulates in Cancer Cells.

Three rationally designed glucose-platinum conjugates (Glc-Pts) were synthesized and their biological activities evaluated. The Glc-Pts, 1-3, exhibit high levels of cytotoxicity toward a panel of cancer cells. The subcellular target and cellular uptake mechanism of the Glc-Pts were elucidated. For uptake into cells, Glc-Pt 1 exploits both glucose and organic cation transporters, both widely overexpressed in cancer. Compound 1 preferentially accumulates in and annihilates cancer, compared to normal epithelial, cells in vitro.

Chemical Synthesis of Staphyloferrin B Affords Insight into the Molecular Structure, Iron Chelation, and Biological Activity of a Polycarboxylate Siderophore Deployed by the Human Pathogen Staphylococcus aureus.

Staphyloferrin B (SB) is a citrate-based polycarboxylate siderophore produced and utilized by the human pathogen Staphylococcus aureus for acquiring iron when colonizing the vertebrate host. The first chemical synthesis of SB is reported, which enables further molecular and biological characterization and provides access to structural analogues of the siderophore. Under conditions of iron limitation, addition of synthetic SB to bacterial growth medium recovered the growth of the antibiotic resistant community isolate S. aureus USA300 JE2. Two structural analogues of SB, epiSB and SBimide, were also synthesized and employed to investigate how epimerization of the citric acid moiety or imide formation influence its function as a siderophore. Epimerization of the citric acid stereocenter perturbed the iron-binding properties and siderophore function of SB as evidenced by experimental and computational modeling studies. Although epiSB provided growth recovery to S. aureus USA300 JE2 cultured in iron-deficient medium, the effect was attenuated relative to that of SB. Moreover, SB more effectively sequestered the Fe(III) bound to human holo-transferrin, an iron source of S. aureus, than epiSB. SBimide is an imide analogous to the imide forms of other citric acid siderophores that are often observed when these molecules are isolated from natural sources. Here, SBimide is shown to be unstable, converting to native SB at physiological pH. SB is considered to be a virulence factor of S. aureus, a pathogen that poses a particular threat to public health because of the number of drug-resistant strains emerging in hospital and community settings. Iron acquisition by S. aureus is important for its ability to colonize the human host and cause disease, and new chemical insights into the structure and function of SB will inform the search for new therapeutic strategies for combating S. aureus infections.

Necroptosis-inducing rhenium(V) oxo complexes.

Rhenium(V) oxo complexes of general formula [ReO(OMe)(N^N)Cl2], where N^N = 4,7-diphenyl-1,10-phenanthroline, 1, or 3,4,7,8-tetramethyl-1,10-phenanthroline, 2, effectively kill cancer cells by triggering necroptosis, a non-apoptotic form of cell death. Both complexes evoke necrosome (RIP1-RIP3)-dependent intracellular reactive oxygen species (ROS) production and propidium iodide uptake. The complexes also induce mitochondrial membrane potential depletion, a possible downstream effect of ROS production. Apparently, 1 and 2 are the first rhenium complexes to evoke cellular events consistent with programmed necrosis in cancer cells. Furthermore, 1 and 2 display low acute toxicity in C57BL/6 mice and reasonable stability in fresh human blood.