Chemoselective Derivatization of Folded Synthetic Insulin Variants with Potassium Acyltrifluoroborates (KATs)

Synthetic folded insulin variants containing an ornithine‐hydroxylamine residue are readily modified in aqueous buffers by amide‐forming ligations with potassium acyltrifluoroborates (KATs). The synthetic insulin analogs were prepared by Fmoc‐SPPS, α‐ketoacid‐hydroxylamine (KAHA) ligation, and a prosthetic C‐peptide that delivers the correct disulfide pattern and allows facile incorporation at the B0 position of Glargine M2 of a new ornithine hydroxylamine protected with a photolabile group. The folded insulin is readily modified by photo‐deprotection followed by amide‐forming KAT ligation to give insulin variants labeled with dyes, lipids, and PEGs, as well as the formation of a covalent dimer.     

Dielectric relaxation spectroscopy of aqueous micellar electrolyte solutions: A novel application to infer Dukhin number and zeta potential of a micelle

The complex permittivities of aqueous SDS solutions, with and without the addition of sodium chloride (NaCl), are measured in the frequency range from 200 MHz to 14 GHz. The SDS concentrations are chosen such that the SDS molecules aggregate to micelles. In this frequency range, the measured spectra allow for the identification of two different relaxation processes. That is, the relaxation of the water molecules at frequencies above 1 GHz and the micellar relaxation at frequencies lower than 1 GHz. It is found that the addition of NaCl to the system mostly affects the micellar relaxation process. In detail, the time constant as well as the amplitude of the relaxation decrease by adding NaCl. These effects are attributed to the change in the solution conductivity that changes the properties of the micelle's electrical double layer. We also extract the Dukhin number of the micelles as a function of surfactant and electrolyte content from the measurements. The Dukhin number is a dimensionless group that describes the influence of the surface conductivity on a phenomena. A regression between Dukhin numbers and free sodium ions is found so that all data collapses on a single curve independent of the surfactant concentration. The surface conductivity is a manifestation of the electrical double layer and we use the Bikerman equation to infer the zeta potential of the micelles. Comparison to literature data shows very good agreement and proves that dielectric relaxation spectroscopy can be engaged to infer the zeta potential of micelles. Abbreviations: CMC critical micelle concentration, DRS dielectric relaxation spectroscopy, EDL electrical double layer     

Stereoselective Cascade Cyclizations with Samarium Diiodide to Tetracyclic Indolines: Precursors of Fluorostrychnines and Brucine

A series of γ-indolylketones with fluorine, cyano or alkoxy substituents at the benzene moiety was prepared and subjected to samarium diiodide-promoted cyclization reactions. The desired dearomatizing ketyl cascade reaction forming two new rings proceeded in all cases with high diastereoselectivity, but with differing product distribution. In most cases, the desired annulated tetracyclic compounds were obtained in moderate to good yields, but as second product tetracyclic spirolactones were isolated in up to 29 % yield. The reaction rate was influenced by the substituents at the benzene moiety of the substrate as expected, with electron-accepting groups accelerating and electron-donating groups decelerating the cyclization process. In case of a difluoro-substituted γ-indolylketone a partial defluorination was observed. The intermediate samarium enolate of the tetracyclic products could be trapped by adding reactive alkylating agents as electrophiles delivering products with quarternary carbons. In the case of a dimethoxy-substituted tetracyclic cyclization product a subsequent reductive amination stereoselectively provided a pentacyclic compound that was subsequently N-protected and subjected to a regioselective elimination. The obtained functionalized pentacyclic product should be convertible into the alkaloid brucine by four well-established steps. Overall, the presented report shows that functionalized tetracyclic compounds with different substituents are rapidly available with the samarium diiodide cascade cyclization as crucial step. Hence, analogues of the landmark alkaloid strychnine, for example, with specific fluorine substitutions, should be easily accessible.     

Enzyme Promiscuity as a Remedy for the Common Problems with Knoevenagel Condensation

A new protocol based on lipase-catalyzed tandem reaction toward α,β-enones/enoesters is presented. For the synthesis of the desired products the tandem process based on enzyme-catalyzed hydrolysis and Knoevenagel reaction starting from enol acetates and aldehyde is developed. The relevant impact of the reaction conditions including organic solvent, enzyme type, and temperature on the course of the reaction was revealed. It was shown that controllable release of the active methylene compound from the corresponding enol carboxylate ensured by enzymatic reaction diminishes significantly the formation of the unwanted co-products. Furthermore, this protocol was extended by including a second tandem chemoenzymatic transformation engaging various aldehyde precursors. After a careful optimization of the reaction conditions, the target products were obtained with yields up to 86 % and with excellent E/Z-selectivity.     

Molecular hydrophobic attraction and ion-specific effects studied by molecular dynamics

Much is written about "hydrophobic forces" that act between solvated molecules and nonpolar interfaces, but it is not always clear what causes these forces and whether they should be labeled as hydrophobic. Hydrophobic effects roughly fall in two classes, those that are influenced by the addition of salt and those that are not. Bubble adsorption and cavitation effects plague experiments and simulations of interacting extended hydrophobic surfaces and lead to a strong, almost irreversible attraction that has little or no dependence on salt type and concentration. In this paper, we are concerned with hydrophobic interactions between single molecules and extended surfaces and try to elucidate the relation to electrostatic and ion-specific effects. For these nanoscopic hydrophobic forces, bubbles and cavitation effects play only a minor role and even if present cause no equilibration problems. In specific, we study the forced desorption of peptides from nonpolar interfaces by means of molecular dynamics simulations and determine the adsorption potential of mean force. The simulation results for peptides compare well with corresponding AFM experiments. An analysis of the various contributions to the total peptide-surface interactions shows that structural effects of water as well as van der Waals interactions between surface and peptide are important. Hofmeister ion effects are studied by separately determining the effective interaction of various ions with hydrophobic surfaces. An extension of the Poisson-Boltzmann equation that includes the ion-specific potential of mean force yields surface potentials, interfacial tensions, and effective interactions between hydrophobic surfaces. There, we also analyze the energetic contributions to the potential of mean force and find that the most important factor determining ion-specific adsorption at hydrophobic surfaces can best be described as surface-modified ion hydration.     

Dipolar and nonpolar altitudinal molecular rotors mounted on an Au(111) surface

We describe the preparation of a compound whose molecules consist of two metal sandwich stands carrying tentacles with affinity to metal surfaces and holding an axle that carries a dipolar or a nonpolar rotator. The dipolar rotor exists as three pairs of enantiomers, rapidly interconverting at room temperature. When mounted on a gold surface, each molecule represents a chiral altitudinal rotor, with the rotator axle parallel to the surface. The surface-mounted rotor molecules are characterized by several spectroscopic and imaging techniques. At any one time, in about one-third of the dipolar rotors the rotator is free to turn and the direction of its dipole can be flipped by the electric field applied by an STM tip, as revealed by differential barrier height imaging. Molecular dynamics calculations suggest that electric field normal to the surface causes members of one pair of enantiomers to rotate unidirectionally.     

Adiabatic triplet state tautomerization of p-hydroxyacetophenone in aqueous solution

The primary photophysical processes of p-hydroxyacetophenone (HA) and the ensuing proton transfer reactions in aqueous solution were investigated by picosecond pump-probe spectroscopy and nanosecond laser flash photolysis. Previous studies have led to mutually inconsistent conclusions. The combined data allow us to rationalize the excited-state proton transfer processes of HA in terms of a comprehensive, well-established reaction scheme. Following fast and quantitative ISC to the triplet state, (3)HA*, adiabatic proton transfer through solvent water simultaneously forms both the anion, (3)A(-)*, and the quinoid triplet enol tautomer, (3)Q*. The latter subsequently equilibrates with its anion (3)A(-)*. Ionization and tautomerization are likely to compete with the desired release reactions of p-hydroxyphenacyl photoremovable protecting groups.     

Molecular simulation and macroscopic modeling of the diffusion of hydrogen, carbon monoxide and water in heavy n-alkane mixtures

The self-diffusion coefficient of hydrogen (H(2)), carbon monoxide (CO) and water (H(2)O) in n-alkanes was studied by molecular dynamics simulation. Diffusion in a few pure n-alkanes (namely n-C(8), n-C(20), n-C(64) and n-C(96)) was examined. In addition, binary n-C(12)-n-C(96) mixtures with various compositions as well as more realistic five- and six-n-alkane component mixtures were simulated. In all cases, the TraPPE united atom force field was used for the n-alkane molecules. The force field for the mixture of n-alkanes was initially validated against experimental density values and was shown to be accurate. Moreover, macroscopic correlations for predicting diffusion coefficient of H(2), CO and H(2)O in n-alkanes and mixtures of n-alkanes were developed. The functional form of the correlation was based on the rough hard sphere theory (RHS). The correlation was applied to simulation data and an absolute average deviation (AAD) of 5.8% for pure n-alkanes and 3.4% for n-alkane mixtures was obtained. Correlation parameters vary in a systematic way with carbon number and so they can be used to provide predictions in the absence of any experimental or molecular simulation data. Finally, in order to reduce the number of adjustable parameters, for the n-alkane mixtures the "pseudo-carbon number" approach was used. This approach resulted in relatively higher deviation from MD simulation data (AAD of 18.2%); however, it provides a convenient and fast method to predict diffusion coefficients. The correlations developed here are expected to be useful for engineering calculations related to the design of the Gas-to-Liquid process.     

Switching the Mechanism of NADH Photooxidation by Supramolecular Interactions

A series of three Ru(II) polypyridine complexes was investigated for the selective photocatalytic oxidation of NAD(P)H to NAD(P)⁺ in water. A combination of (time-resolved) spectroscopic studies and photocatalysis experiments revealed that ligand design can be used to control the mechanism of the photooxidation: For prototypical Ru(II) complexes a ¹O₂ pathway was found. Rudppz ([(tbbpy)₂Ru(dppz)]Cl₂, tbbpy=4,4'-di-tert-butyl-2,2'-bipyridine, dppz=dipyrido[3,2-a:2′,3′-c]phenazine), instead, initiated the cofactor oxidation by electron transfer from NAD(P)H enabled by supramolecular binding between substrate and catalyst. Expulsion of the photoproduct NAD(P)⁺ from the supramolecular binding site in Rudppz allowed very efficient turnover. Therefore, Rudppz permits repetitive selective assembly and oxidative conversion of reduced naturally occurring nicotinamides by recognizing the redox state of the cofactor under formation of H₂O₂ as additional product. This photocatalytic process can fuel discontinuous photobiocatalysis.