Synthetic approaches to 5,7-disubstituted imidazo[5,1-f][1,2,4]triazin-4-amines

The preparation of 5,7-disubstituted imidazo[5,1-f][1,2,4]triazin-4-amines, exemplified by 5-[3-(benzyloxy)phenyl]-7-cyclobutylimidazo[5,1-f][1,2,4]triazin-4-amine, was developed through a linear and three convergent synthetic strategies, with the latter providing the greatest flexibility for diversification at the 5-position at the last step of the synthesis.     

Electron tunneling through sensitizer wires bound to proteins

We report a quantitative theoretical analysis of long-range electron transfer through sensitizer wires bound in the active-site channel of cytochrome P450cam. Each sensitizer wire consists of a substrate group with high binding affinity for the enzyme active site connected to a ruthenium-diimine through a bridging aliphatic or aromatic chain. Experiments have revealed a dramatic dependence of electron transfer rates on the chemical composition of both the bridging group and the substrate. Using combined molecular dynamics simulations and electronic coupling calculations, we show that electron tunneling through perfluorinated aromatic bridges is promoted by enhanced superexchange coupling through virtual reduced states. In contrast, electron flow through aliphatic bridges occurs by hole-mediated superexchange. We have found that a small number of wire conformations with strong donor–acceptor couplings can account for the observed electron tunneling rates for sensitizer wires terminated with either ethylbenzene or adamantane. In these instances, the rate is dependent not only on electronic coupling of the donor and acceptor but also on the nuclear motion of the sensitizer wire, necessitating the calculation of average rates over the course of a molecular dynamics simulation. These calculations along with related recent findings have made it possible to analyze the results of many other sensitizer-wire experiments that in turn point to new directions in our attempts to observe reactive intermediates in the catalytic cycles of P450 and other heme enzymes.     

A biomimetic approach to the synthesis of a mycolic acid motif

A new method for the stereoselective synthesis of the (R,R)-β-hydroxy-α-alkyl fatty acid fragment of mycolic acids, via an asymmetric anti-aldol reaction is reported. The ‘mycolic acid motif’ fragment was prepared in three steps and >98% ee.     

The use of polyhedral oligomeric silsesquioxane (POSS) as a soluble support for organic synthesis: A case study with a POSS-bound isocyanate scavenger reagent

The use of polyhedral oligomeric silsesquioxane (POSS) as a soluble support in organic synthesis is reported. A POSS-bound isocyanate was readily synthesised in one step from commercially available starting materials and was isolated in high yield and purity by simple filtration. It was found to perform well as a scavenger for excess amine in the solution phase synthesis of amides and sulfonamides, allowing product isolation in high yield and purity.     

Processive replication of single DNA molecules in a nanopore catalyzed by phi29 DNA polymerase

Coupling nucleic acid processing enzymes to nanoscale pores allows controlled movement of individual DNA or RNA strands that is reported as an ionic current/time series. Hundreds of individual enzyme complexes can be examined in single-file order at high bandwidth and spatial resolution. The bacteriophage phi29 DNA polymerase (phi29 DNAP) is an attractive candidate for this technology, due to its remarkable processivity and high affinity for DNA substrates. Here we show that phi29 DNAP-DNA complexes are stable when captured in an electric field across the α-hemolysin nanopore. DNA substrates were activated for replication at the nanopore orifice by exploiting the 3'-5' exonuclease activity of wild-type phi29 DNAP to excise a 3'-H terminal residue, yielding a primer strand 3'-OH. In the presence of deoxynucleoside triphosphates, DNA synthesis was initiated, allowing real-time detection of numerous sequential nucleotide additions that was limited only by DNA template length. Translocation of phi29 DNAP along DNA substrates was observed in real time at ?ngstrom-scale precision as the template strand was drawn through the nanopore lumen during replication.     

Structural characterization of methanol substituted lanthanum halides

The first study into the alcohol solvation of lanthanum halide [LaX₃] derivatives as a means to lower the processing temperature for the production of the LaBr₃ scintillators was undertaken using methanol (MeOH). Initially the de-hydration of {[La(μ-Br)(H₂O)₇](Br)₂}₂ (1) was investigated through the simple room temperature dissolution of 1 in MeOH. The mixed solvate monomeric [La(H₂O)₇(MeOH)₂](Br)₃ (2) compound was isolated where the La metal center retains its original 9-coordination through the binding of two additional MeOH solvents but necessitates the transfer of the innersphere Br to the outersphere. In an attempt to in situ dry the reaction mixture of 1 in MeOH over CaH₂, crystals of [Ca(MeOH)₆](Br)₂ (3) were isolated. Compound 1 dissolved in MeOH at reflux temperatures led to the isolation of an unusual arrangement identified as the salt derivative {[LaBr_2.75·5.25(MeOH)]^+0.25 [LaBr_3.25·4.75(MeOH)]^−0.25} (4). The fully substituted species was ultimately isolated through the dissolution of dried LaBr₃ in MeOH forming the 8-coordinated [LaBr₃(MeOH)₅] (5) complex. It was determined that the concentration of the crystallization solution directed the structure isolated (4 concentrated; 5 dilute) The other LaX₃ derivatives were isolated as [(MeOH)₄(Cl)₂La(μ-Cl)]₂ (6) and [La(MeOH)₉](I)₃·MeOH (7). Beryllium Dome XRD analysis indicated that the bulk material for 5 appear to have multiple solvated species, 6 is consistent with the single crystal, and 7 was too broad to elucidate structural aspects. Multinuclear NMR (¹³⁹La) indicated that these compounds do not retain their structure in MeOD. TGA/DTA data revealed that the de-solvation temperatures of the MeOH derivatives 4–6 were slightly higher in comparison to their hydrated counterparts.