Synthesis of 2-arylpiperidines by palladium couplings of aryl bromides with organozinc species derived from deprotonation of N-boc-piperidine

The organolithium species derived from proton abstraction of N-Boc-piperidine with s-BuLi and TMEDA can be transmetalated to the organozinc reagent, and this organometallic species can be coupled directly with aryl bromides in a Negishi-type reaction using palladium catalysis with the ligand tri-tert-butylphosphine (t-Bu3P-HBF4). The chemistry was applied to a very short synthesis of the alkaloid anabasine.     

Substrate specificity of the acyl transferase domains of EpoC from the epothilone polyketide synthase

The production of epothilone mixtures is a direct consequence of the substrate tolerance of the module 3 acyltransferase (AT) domain of the epothilone polyketide synthase (PKS) which utilises both malonyl- and methylmalonyl-CoA extender units. Particular amino acid motifs in the active site of AT domains influence substrate selection for methylmalonyl-CoA (YASH) or malonyl-CoA (HAFH). This motif appears in hybrid form (HASH) in epoAT3 and may represent the molecular basis for the relaxed specificity of the domain. To investigate this possibility the AT domains from modules 2 and 3 of the epothilone PKS were examined in the heterologous DEBS1-TE model PKS. Substitution of AT1 of DEBS1-TE by epoAT2 and epoAT3 both resulted in functional PKSs, although lower yields of total products were observed when compared to DEBS1-TE (2% and 11.5% respectively). As expected, epoAT3 was significantly more promiscuous in keeping with its nature during epothilone biosynthesis. When the mixed motif (HASH) of epoAT3 within the hybrid PKS was mutated to HAFH (indicative of malonyl-CoA selection) it resulted in a non-productive PKS. When this mixed motif was converted to YASH (indicative of methylmalonyl-CoA selection) the selectivity of the hybrid PKS for methylmalonyl-CoA showed no statistically significant increase, and was associated with a loss of productivity.     

Bifunctional Iminophosphorane-Catalyzed Enantioselective Nitroalkane Addition to Unactivated α,β-Unsaturated Esters**

Herein we describe the enantioselective intermolecular conjugate addition of nitroalkanes to unactivated α,β-unsaturated esters, catalyzed by a bifunctional iminophosphorane (BIMP) superbase. The transformation provides the most direct access to pharmaceutically relevant enantioenriched γ-nitroesters, utilizing feedstock chemicals, with unprecedented selectivity. The methodology exhibits a broad substrate scope, including β-(fluoro)alkyl, aryl and heteroaryl substituted electrophiles, and was successfully applied on a gram scale with reduced catalyst loading, and, additionally, catalyst recovery was carried out. The formal synthesis of a range of drug molecules, and an enantioselective synthesis of (S)-rolipram were achieved. Additionally, computational studies revealed key reaction intermediates and transition state structures, and provided rationale for high enantioselectivities, in good agreement with experimental results.     

Synthesis of Heptagon-Containing Polyarenes by Catalytic C−H Activation

Nanocarbons incorporating non-hexagonal aromatic rings - such as five-, seven-, and eight-membered rings - have various intriguing physical properties such as curved structures, unique one-dimensional packing, and promising magnetic, optical, and conductivity properties. Herein, we report an efficient synthetic approach to polycyclic aromatics containing seven-membered rings via a palladium-catalyzed intramolecular Ar−H/Ar−Br coupling. In addition to all-hydrocarbon scaffolds, heteroatom-embedded heptagon-containing polyarenes can be efficiently constructed with this method. Rhodium- and palladium-catalyzed sequential six- and seven-membered ring formations also afford complex heptagon-containing molecular nanocarbons from readily available arylacetylenes and biphenyl boronic acids. Detailed mechanistic analysis by DFT calculations showed the feasibility of seven-membered ring formation by a concerted metalation-deprotonation mechanism. This reaction can serve as a template for the synthesis of a wide range of seven-membered ring-containing molecular nanocarbons.     

Regioselective reactivity of an asymmetric tetravalent di[dihydroxotin(IV)] bis-porphyrin host driven by hydrogen-bond templation

Local molecular environment effects on the rates of ligand exchange at an asymmetric di[dihydroxotin(IV)] bis-porphyrin 5 are examined. The host 5 possesses four non-equivalent tin(IV)-ligand binding sites that are distinguished by their position relative to a shallow cavity, by the steric environment at each binding site and by electronic-structure differences between the constituent porphyrin and quinoxalinoporphyrin macrocycles. These design features of the asymmetric host are confirmed by X-ray crystal structure analysis. Binding experiments with monodentate carboxylic acids and bidentate dicarboxylic acids show significant differences in the rate of ligand exchange at each of the four tin(IV) binding sites. For monodentate carboxylic acids, binding preferentially occurs at the exterior porphyrin site. Further addition of carboxylic acid results in sequential binding at the quinoxalinoporphyrin sites and lastly at the interior site on the porphyrin, with high regioselectivity. These selective binding outcomes are immediately apparent by NMR spectroscopy. A series of 2D NMR spectroscopy experiments allowed identification of the preferred binding sites at the host. This positively identifies that steric hindrance and electron-withdrawing functionality on the porphyrin macrocycle impede ligand exchange. However, these effects are overcome by dicarboxylic acid guests, which form ditopic hydrogen-bond interactions between the intracavity hydroxo ligands in the initial stage of ligand exchange, leading to regioselective binding between the tin(IV) sites within the cavity. It is envisaged that the factors identified herein that define regioselective ligand exchange at host 5 will find wider application in supramolecular systems incorporating tin(IV) porphyrins.     

Time-dependent photoionization of azulene: competition between ionization and relaxation in highly excited states

Pump-probe photoionization has been used to map the relaxation processes taking place from highly vibrationally excited levels of the S(2) state of azulene, populated directly or via internal conversion from the S(4) state. Photoelectron spectra obtained by 1+2(') two-color time-resolved photoelectron imaging are invariant (apart from in intensity) to the pump-probe time delay and to the pump wavelength. This reveals a photoionization process which is driven by an unstable electronic state (e.g., doubly excited state) lying below the ionization potential. This state is postulated to be populated by a probe transition from S(2) and to rapidly relax via an Auger-like process onto highly vibrationally excited Rydberg states. This accounts for the time invariance of the photoelectron spectrum. The intensity of the photoelectron spectrum is proportional to the population in S(2). An exponential energy gap law is used to describe the internal conversion rate from S(2) to S(0). The vibronic coupling strength is found to be larger than 60+/-5 microeV.     

Breast Cancer Stem Cell Potent Copper(II)–Non‐Steroidal Anti‐Inflammatory Drug Complexes

The breast cancer stem cell (CSC) potency of a series of copper(II)–phenanthroline complexes containing the nonsteroidal anti‐inflammatory drug (NSAID), indomethacin, is reported. The most effective copper(II) complex in this series, 4 , selectivity kills breast CSC‐enriched HMLER‐shEcad cells over breast CSC‐depleted HMLER cells. Furthermore, 4 reduces the formation, size, and viability of mammospheres, to a greater extent than salinomycin, a potassium ionophore known to selectively inhibit CSCs. Mechanistic studies revealed that the CSC‐specificity observed for 4 arises from its ability to generate intracellular reactive oxygen species (ROS) and inhibit cyclooxygenase‐2 (COX‐2), an enzyme that is overexpressed in breast CSCs. The former induces DNA damage, activates JNK and p38 pathways, and leads to apoptosis.     

Excluded Minors and the Ribbon Graphs of Knots

In this article we consider minors of ribbon graphs (or, equivalently, cellularly embedded graphs). The theory of minors of ribbon graphs differs from that of graphs in that contracting loops is necessary and doing this can create additional vertices and components. Thus, the ribbon graph minor relation is incompatible with the graph minor relation. We discuss excluded minor characterizations of minor closed families of ribbon graphs. Our main result is an excluded minor characterization of the family of ribbon graphs that represent knot and link diagrams.     

Synthesis of putative chain terminators of mycobacterial arabinan biosynthesis

The synthesis of a variety of arabinose derivatives that have been modified at C-5 was achieved from d-arabinose. The 5-fluoro and 5-methoxy compounds were converted into the corresponding farnesyl phosphodiesters as putative chain terminators of mycobacterial arabinan biosynthesis. Biological testing of these materials revealed no effective anti-mycobacterial activity.     

Dimeric uranyl complexes with bridging perrhenates

The reaction between [UO2(ReO4)2.H(2)O] and two equivalents of either tri-n-butyl phosphine oxide (TBPO) or tri-iso-butyl phosphate (TiBP) results in the formation of [UO2(mu2-ReO4)(ReO4)(TBPO)2]2 (1) and [UO2(mu2-ReO4)(ReO4)(TiBP)2]2 (2) respectively. Both complexes crystallise as two structurally similar centrosymmetric dimers, the cores containing two uranyl moieties linked by bridging perrhenates. Two P=O donor ligands and one monodenatate perrhenate complete the pentagonal bipyramidal coordination sphere at each metal centre. Both complexes have also been characterised in the solid state by vibrational and absorption spectroscopy. Solution spectroscopic characterisation indicates that both perrhenate and phosphine oxide (1) or phosphate (2) remain coordinated, although it is not possible to state conclusively that the dimeric species remain intact. A low resolution structural study of a minor product from the reaction that yielded revealed a monomeric complex with only monodentate perrhenate coordination, [UO2(ReO4)2(H2O)(TiBP)2] (2'). These results represent the first structural evidence for the bridging coordination mode of perrhenate on coordination to an actinide and yields further insight into the possible solvent phase pertechnetate complexes that may exist in PUREX process phosphate rich solvent.