Kathrin H. Hopmann

Explicit versus implicit solvent modeling of Raman optical activity spectra.

Raman and Raman optical activity (ROA) spectra of molecules reflect not only molecular structure and conformation but also the dynamics and interactions with the solvent. For polar, biologically relevant molecules in aqueous environment, this often complicates the band assignment and interpretation of the spectra. In the present study, implicit dielectric and explicit solvent models are compared with respect to the influence of the choice of solvent model on the spectral shape. Lactamide and 2-aminopropanol were selected as model compounds, and the Raman and ROA spectra were measured for both enantiomers. Geometries of explicitly solvated clusters were derived from quantum-mechanical calculations, classical (MD), and Car-Parrinello (CPMD) molecular dynamics. The results indicate that although the dielectric model reasonably well reproduces the main spectral features, more faithful intensity profiles, including the inhomogeneous band broadening, are obtained from the explicit MD and CPMD clusters. Additionally, the CPMD clusters are capable of reproducing most spectral features better than the classical dynamics, provided the simulation time is long enough to allow for a complete sampling of the conformational space. The hydrogen-bonded water molecules of the first hydration shell significantly influence the spectral intensities, whereas the effect of loosely attached or distant solvent molecules is minor. In order to average the signal, however, a relatively large number of MD geometries need to be considered, as was also exemplified by simulations of the ROA spectrum of the achiral molecule glycine. An explicit solvent modeling of sizable systems thus requires extensive computations, which became possible only recently due to the development of efficient analytical computational techniques.

Determining the Absolute Configuration of Two Marine Compounds Using Vibrational Chiroptical Spectroscopy

Chiroptical techniques are increasingly employed for assigning the absolute configuration of chiral molecules through comparison of experimental spectra with theoretical predictions. For assignment of natural products, electronic chiroptical spectroscopies such as electronic circular dichroism (ECD) are routinely applied. However, the sensitivity of electronic spectral parameters to experimental conditions and the theoretical methods employed can lead to incorrect assignments. Vibrational chiroptical methods (vibrational circular dichroism, VCD, and Raman optical activity, ROA) provide more reliable assignments, although they, in particular ROA, have been little explored for assignments of natural products. In this study, the ECD, VCD, and ROA chiroptical spectroscopies are evaluated for the assignment of the absolute configuration of a highly flexible natural compound with two stereocenters and an asymmetrically substituted double bond, the marine antibiotic Synoxazolidinone A (SynOxA), recently isolated from the sub-Arctic ascidian Synoicum pulmonaria. Conformationally averaged nuclear magnetic resonance (NMR), ECD, Raman, ROA, infrared (IR) and VCD spectral parameters are computed for the eight possible stereoisomers of SynOxA and compared to experimental results. In contrast to previously reported results, the stereochemical assignment of SynOxA based on ECD spectral bands is found to be unreliable. On the other hand, ROA spectra allow for a reliable determination of the configuration at the double bond and the ring stereocenter. However, ROA is not able to resolve the chlorine-substituted stereogenic center on the guanidinium side chain of SynOxA. Application of the third chiroptical method, VCD, indicates unique spectral features for all eight SynOxA isomers in the theoretical spectra. Although the experimental VCD is weak and restricted by the limited amount of sample, it allows for a tentative assignment of the elusive chlorine-substituted stereocenter. VCD chiroptical analysis of a SynOxA derivative with three stereocenters, SynOxC, results in the same absolute configuration as for SynOxA. Despite the experimental challenges, the results convincingly prove that the assignment of absolute configuration based on vibrational chiroptical methods is more reliable than for ECD.

Quantum Chemical Modeling of the Dehalogenation Reaction of Haloalcohol Dehalogenase

The dehalogenation reaction of haloalcohol dehalogenase HheC from Agrobacterium radiobacter AD1 was investigated theoretically using hybrid density functional theory methods. HheC catalyzes the enantioselective conversion of halohydrins into their corresponding epoxides. The reaction is proposed to be mediated by a catalytic Ser132-Tyr145-Arg149 triad, and a distinct halide binding site is suggested to facilitate halide displacement by stabilizing the free ion. We investigated the HheC-mediated dehalogenation of (R)-2-chloro-1-phenylethanol using three quantum chemical models of various sizes. The calculated barriers and reaction energies give support to the suggested reaction mechanism. The dehalogenation occurs in a single concerted step, in which Tyr145 abstracts a proton from the halohydrin substrate and the substrate oxyanion displaces the chloride ion, forming the epoxide. Characterization of the involved stationary points is provided. Furthermore, by using three different models of the halide binding site, we are able to assess the adopted modeling methodology.

Density functional theory calculations on Mössbauer parameters of nonheme iron nitrosyls.

Density Functional Theory (DFT) calculations on transition metal nitrosyls often reveal unusual spin density profiles, involving substantial spatial separation of majority and minority spin densities. Against this context, there is a significant lack of studies where DFT calculations have been quantitatively calibrated against experimental spectroscopic properties. Reported herein are DFT calculations of Mössbauer isomer shifts and quadrupole splittings for 21 nonheme iron complexes (26 distinct iron sites) including 9 iron nitrosyls. Low- (S = 1/2) and high-spin (S = 3/2) {FeNO}(7) complexes, S = 1/2 {Fe(NO)(2)}(9) species, and polynuclear iron nitrosyls are all represented within the set of compounds examined. The general conclusion with respect to isomer shifts is that DFT (OLYP/STO-TZP) performs comparably well for iron nitrosyls and for iron complexes in general. However, quadrupole splittings are less accurately reproduced for nitrosyl complexes.

Full reaction mechanism of nitrile hydratase: a cyclic intermediate and an unexpected disulfide switch.

The full reaction mechanism of nitrile hydratase has remained elusive, despite extensive theoretical and experimental studies. A novel reaction mechanism for nitrile hydratase is proposed here, with remarkable features and very feasible barriers. Our results, obtained on the basis of large quantum-mechanical active site models, identify Cys-SO(-) as the nucleophile, performing a direct nucleophilic attack on the metal-coordinated nitrile. This implies the formation of an intriguing cyclic intermediate, which subsequently is cleaved through attack of the axial cysteine on the sulfenate, thereby forming a disulfide bond. In this mechanism, nitrile hydration occurs without directly involving a water molecule. Subsequent water-mediated disulfide cleavage regenerates the active site. This is the first example of a disulfide switch directly implicated in an enzymatic reaction mechanism.

Broken-Symmetry DFT Spin Densities of Iron Nitrosyls, Including Roussin’s Red and Black Salts: Striking Differences between Pure and Hybrid Functionals

Pure and hybrid exchange-correlation functionals, as typified by OLYP and B3LYP, respectively, yield dramatically different spin density profiles for a variety of paramagnetic iron nitrosyls. Not unexpectedly, based on the strongly noninnocent nature of the NO ligand, the strength of metal-NO spin coupling appears to vary widely as a function of the functional chosen. For the diamagnetic Roussins red salt, red salt esters, and black salt, OLYP and B3LYP yield very different Fe-Fe spin coupling strengths, with OLYP exhibiting a greater preference for a more spin-coupled description.

Determination of Absolute Configuration and Conformation of a Cyclic Dipeptide by NMR and Chiral Spectroscopic Methods

Increasing precision of contemporary computational methods makes spectroscopies such as vibrational (VCD) and electronic (ECD) circular dichroism attractive for determination of absolute configurations (AC) of organic compounds. This is, however, difficult for polar, flexible molecules with multiple chiral centers. Typically, a combination of several methods provides the best picture of molecular behavior. As a test case, all possible stereoisomers with known AC (RS, SR, SS, and RR) of the cyclic dipeptide cyclo(Arg-Trp) (CAT) were synthesized, and the performances of the ECD, infrared (IR), VCD, Raman, Raman optical activity (ROA), and nuclear magnetic resonance (NMR) techniques for AC determination were investigated. The spectra were interpreted with the aid of density functional theory (DFT) calculations. Folded geometries stabilized by van der Waals and electrostatic interactions between the diketopiperazine (DKP) ring and the indole group are predicted to be preferred for CAT, with more pronounced folding due to Arg-Trp stacking in the case of SS/RR-CAT. The RS/SR isomers prefer a twist-boat puckering of the DKP ring, which is relatively independent of the orientation of the side chains. Calculated conformer-averaged VCD and ECD spectra explain most of the experimentally observed bands and allow for AC determination of the tryptophan side-chain, whereas the stereochemical configuration of the arginine side-chain is visible only in VCD. NMR studies provide characteristic long-range (2)J(C,H) and (3)J(C,H) coupling constants, and nuclear Overhauser effect (NOE) correlations, which in combination with either ECD or VCD also allow for complete AC determination of CAT.

Correction of Vibrational Broadening in Molecular Dynamics Clusters with the Normal Mode Optimization Method

Vibrational properties of solutions are frequently simulated with clusters of a solute and a few solvent molecules obtained during molecular dynamics (MD) simulations. The raw cluster geometries, however, often provide unrealistic vibrational band broadening, for both ab initio and empirical force fields. In this work, partial optimization in normal-mode coordinates is used on empirical basis to reduce the broadening. The origin of the error is discussed on a simplified two-dimensional system, which indicates that the problem is caused by the anharmonic MD potential, mode coupling, and neglect of quantum effects. Then the procedure of partial geometry optimization on Raman and Raman optical activity (ROA) spectra is applied and analyzed for the solvated lactamide molecule. Comparison to experiment demonstrates that the normal-mode partial optimization technique with a suitable frequency limit can significantly reduce the broadening error. For lactamide, experimental and simulated vibrational bandwidths are compared; the most realistic theoretical spectra are obtained for partially optimized clusters with the vibrational wavenumber cutoff of about 200 cm(-1).

Synthesis of Indoles and Pyrroles Utilizing Iridium Carbenes Generated from Sulfoxonium Ylides

Metal carbenes can undergo a myriad of synthetic transformations. Sulfur ylides are potential safe precursors of metal carbenes. Herein, we report cascade reactions that involve carbenoids derived from sulfoxonium ylides for the efficient and regioselective synthesis of indoles and pyrroles. The tandem action of iridium and Brønsted acid catalysts enables rapid assembly of the heterocycles from unmodified anilines or readily accessible enamines under microwave irradiation. The key mechanistic steps are the catalytic transformation of the sulfoxonium ylide into an iridium-carbene complex, followed by N-H or C-H functionalization of an aniline or enamine, respectively, and a final acid-catalyzed cyclization. The present method was successfully applied to the synthesis of the densely functionalized pyrrole subunit of atorvastatin.

Absolute Configuration of a Cyclic Dipeptide Reflected in Vibrational Optical Activity: Ab Initio and Experimental Investigation

The ability of Raman optical activity (ROA) and vibrational circular dichroism (VCD) experiments to determine the absolute configuration of chiral molecules with multiple stereogenic centers was explored for four diastereoisomers of a conformationally flexible cyclic dipeptide, cyclo(Arg-Tyr(OMe)). The reliability of the interpretation depended on the correct description of the molecular conformation, which was found to be strongly affected by intramolecular interactions. In particular, when dispersion corrections were included in the density functional theory calculations, the simulated spectra matched the experimental observations well. Experimental and theoretical ROA and VCD spectra were well correlated for all the absolute configurations (RS, SR, SS, and RR) of protonated cyclo(Arg-Tyr(OMe)). These spectroscopies thus appear useful not only for reliable determination of the absolute configuration and conformation but also in revealing the role of hydrogen bonds and C-H···π interactions in the structure stabilization, which can potentially be used when designing enzyme inhibitors and supramolecular architectures.