Highly efficient on-DNA amide couplings promoted by micelle forming surfactants for the synthesis of DNA encoded libraries

DNA encoded libraries (DELs) represent powerful new technology for finding small molecule ligands for proteins and are increasingly being applied to hit finding in medicinal chemistry. Crucial to the synthesis of high quality DELs is the identification of chemical reactions for their assembly that proceed with very high conversion across a range of different substrates, under conditions compatible with DNA-tagged substrates. Many current chemistries used in DEL synthesis do not meet this requirement, resulting in libraries of low fidelity. Amide couplings are the most commonly used reaction in synthesis of screening libraries and also in DELs. The ability to carry out highly efficient, widely applicable amide couplings in DEL synthesis would therefore be highly desirable. We report a method for amide coupling using micelle forming surfactants, promoted by a modified linker, that is broadly applicable across a wide range of substrates. Most significantly, this works exceptionally well for coupling of DNA-conjugated carboxylic acids (N-to-C) with amines in solution, a procedure that is currently very inefficient. The optimisation of separate procedures for coupling of DNA-conjugated acids and amines by reagent screening and statistically driven optimisation is described. The generality of the method is illustrated by the application to a wide range of examples with unprecedented levels of conversion. The utility of the (N-to-C) coupling of DNA-conjugated acids in DEL synthesis is illustrated by the three cycle synthesis of a fully DNA-encoded compound by two cycles of coupling of an aminoester, with intermediate ester hydrolysis, followed by capping with an amine. This methodology will be of great utility in the synthesis of high fidelity DELs.

Highly efficient forward and reverse on-DNA amide couplings were developed exploiting hydrophobic linkers in combination with the micelle forming surfactant TPGS-750M. The method is highly effective for a wide range of substrates in the synthesis of DNA-encoded libraries.     

The interaction between adsorbed OH and O2 on TiO2 surfaces

Reduced TiO₂(110) surfaces usually have OH groups as a result of H₂O dissociation at oxygen vacancy defects. Because of excess electrons due to OH adsorption, OH/TiO₂ exhibit interesting properties favorable to further O₂ or H₂O adsorption. Both O₂ and H₂O can adsorb and easily diffuse on the OH/TiO₂ surface; such behavior plays a significant role in photocatalysis, heterogeneous catalysis, electronic devices and sensors. Indeed, the processes of H₂O dissociation, O₂ and H₂O diffusion on such TiO₂ surfaces, in the presence of OH groups, are important issues in their own right. Herein, the most recent experimental and theoretical progresses in understanding the interactions between adsorbed OH groups and O₂, or H₂O, over TiO₂(110) surfaces and their implications will be reviewed.     

Ab initio optical rotatory dispersion and electronic circular dichroism spectra of (S)-2-chloropropionitrile

Coupled-cluster and density-functional methods have been used to determine specific rotations and electronic circular dichroism (ECD) rotational strengths for (S)-2-chloropropionitrile. Coupled-cluster specific rotations using both the length- and velocity-gauge representations of the electric-dipole operator, computed with basis sets of triple-zeta quality containing up to 326 functions, compare very well with recently reported gas-phase cavity-ring-down polarimetry data. ECD rotational strengths for the six lowest-lying excited states are found to vary in sign, and the second excited state, which has a larger rotational strength than the first by a factor of 4, was found to yield a much larger contribution (by a factor of 10) to the overall negative specific rotation observed both experimentally and theoretically. However, both valence and Rydberg states appear to make substantial contributions to the total rotation, often of opposite sign from the converged/linear-response result. Furthermore, the sum-over-states approach was found to be inadequate for reproducing the specific rotations derived from the linear-response approach, even when 100 excited states (well beyond the estimated ionization limit) were included in the summation. Density-functional specific rotations using the B3LYP functional with basis sets of quadruple-zeta quality containing up to 588 functions are found to be too large compared to experiment by approximately a factor of 2. This error appears to be related to both the underestimation of the electronic excitation energies, as well as concomitant overestimation of the corresponding ECD rotational strengths. Although earlier studies reported good agreement between density-functional specific rotations and experiment when electric-field-dependent functions were used in conjunction with a double-zeta-quality basis set, the results reported here, which are near the basis-set limit, suggest that this agreement may be fortuitous.     

The current state of ab initio calculations of optical rotation and electronic circular dichroism spectra

The current ability of ab initio models to compute chiroptical properties such as optical rotatory dispersion and electronic circular dichroism spectra is reviewed. Comparison between coupled cluster linear response theory and experimental data (both gas and liquid phase) yields encouraging results for small to medium-sized chiral molecules including rigid species such as (S)-2-chloropropionitrile and (P)-[4]triangulane, as well as conformationally flexible molecules such as (R)-epichlorohydrin. More problematic comparisons are offered by (S)-methyloxirane, (S)-methylthiirane, and (1S,4S)-norbornenone, for which the comparison between theory and experiment is much poorer. The impact of basis-set incompleteness, electron correlation, zero-point vibration, and temperature are discussed. In addition, future prospects and obstacles for the development of efficient and reliable quantum chemical models of optical activity are discussed, including the problem of gauge invariance, scaling of the coupled cluster approach with system size, and solvation.     

Crystalline orientation effects on conical structure formation in femtosecond laser irradiation of silicon and germanium

Irradiation of Si(1 0 0), Si(1 1 1), Si(1 1 0), Ge(1 0 0), and Ge(1 1 1) is compared for 150 fs, 800 nm wavelength pulses in a rough vacuum atmosphere. The surface crystalline orientation of the material is found to affect the final morphology, with (1 1 1)- and (1 1 0)-surface orientations exhibiting a much higher tendency for conical structure formation under multiple-pulse irradiation. Using cross-sectional transmission electron microscopy, the structures on Si(1 1 1) are found to have primarily crystalline cores with the same crystalline orientation as the substrate. The results show that the crystalline orientation of the target should be considered in laser machining applications.     

The proposed Penning trap mass spectrometer facility at TASCC

The proposed Penning trap mass spectrometer, to be located at the TASCC facility of the Chalk River Laboratories, is described. The facility will be used for precise atomic mass determinations among both stable and unstable nuclides. The unstable nuclides would be produced in heavy ion reactions using the TASCC facility. The products from these reactions would be collected using an He-jet transport system loaded with NaCl aerosols. After transport to a background free area, the nuclides of interest would be laser desorbed and resonantly ionized. Subsequently, these ions would be accumulated in a Paul trap, cooled and injected into a precision Penning trap mass spectrometer for mass analysis.     

The impact of comet Shoemaker-Levy 9 on Jupiter

We have performed computational shock-physics simulations of the hypervelocity (60 km/s) impact of 1–3 km, water-ice spheres entering a hydrogen-helium Jovian atmosphere. These conditions simulate the best current estimates for the collision of fragments of periodic comet Shoemaker-Levy 9 with Jupiter in July, 1994. We used the Eulerian shock-physics code CTH, and its parallel version PCTH to perform 2-D analyses of penetration and breakup, and 3-D analyses of the growth of the resulting fireball during the first 100 seconds after fragment entry. We can use our simulations to make specific predictions of the time interval between fragment entry and fireball arrival into line-of-sight from the earth. For a fragment larger than about 1 km, we believe that the time of fireball arrival above Jupiter's limb will be directly observable from earth. Measurements of this time by observers, in conjunction with our simulations, may allow mass of cometary fragments to be determined.This article was processed using Springer-Verlag T_EX Shock Waves macro package 1.0 and the AMS fonts, developed by the American Mathematical Society.