Christian Rummey

Peroxomolybdenum Complexes as Epoxidation Catalysts in Biphasic Hydrogen Peroxide Activation: Raman Spectroscopic Studies and Density Functional Calculations

Density functional calcula- tions and Raman spectroscopic data were correlated with the unique cata- lytic epoxidation activity of peroxomo- lybdenum complexes (MoO(O2)2(O- ER3)) (EaN, P, As; Ra n-dodecyl) in a biphasic chloroform - 1-octene/aque- ous hydrogen peroxide system. Crystal structure determinations on (MoO(O2)2(OPtBu3)(OCMe2)) and two complexes containing chelating hemila- bile ether - phosphane oxide and ether - arsane oxide ligands (MoO(O2)2- {iPr2E(O)CH2CH2OCH3}) (Ea P, As) are reported. A mechanistic study with these model complexes reveals the im- portance of free coordination sites for peroxide activation. Calculations and Raman spectroscopic data indicate the tendency of coordinatively unsaturated species (MoO(O2)2(L)) to dimerize in noncoordinating solvents. The catalytic activity in the presence of water as competing ligand could be correlated with the calculated proton affinity of the ligands OER3 (Ra N, P, As). Elucida- tion of the vibrational behavior of the structurally characterized peroxo com- plexes was supported by normal-coordi- nate analyses.

3D QSAR Investigations on Antimalarial Naphthylisoquinoline Alkaloids by Comparative Molecular Similarity Indices Analysis (CoMSIA), Based on Different Alignment Approaches†

3D QSAR models based on the CoMSIA descriptor fields were established using a diverse data set of 53 antimalarial biaryl compounds (tested in vitro against a chloroquine-resistant strain of Plasmodium falciparum), consisting mainly of naphthylisoquinoline alkaloids, but also including phenylanthraquinone structures and naphthylindenes. For the alignment, two commercially available automated approaches, FLEXS and GASP, were compared; initially none of them succeeded in treating the important phenomenon of axial chirality correctly, but after some manual refinement of the alignments initially obtained, the best overall model, based on a modified FLEXS alignment, showed a q(2) (cross-validated r(2)) of 0.818 (eight components), using only the hydrophobic and the H-bond donor and acceptor fields. Using a test set of five compounds the model showed a squared multiple correlation coefficient for the test set (predictive r(2)) of 0.578. The analysis of the 3D contour maps permitted interesting conclusions about the effects of particular functional groups on the biological activity and will now guide the design of novel, hopefully even more active compounds.

On the stereoselectivity of 4-penten-1-oxyl radical 5-exo-trig cyclizations

Ring closure reactions were investigated in a combined computational (density functional theory) and experimental study, to uncover the origin of diastereoselection in 5-exo-trig cyclizations of methyl and tert-butyl-substituted 4-penten-1-oxyl radicals. Selectivity data were calculated on the basis of transition state theory, the Curtin-Hammett principle, and Maxwell-Boltzmann statistics, to provide an excellent correlation between computed and experimental cis-trans ratios. The data show that the 2,3-trans-, 2,4-cis-, and 2,5-trans-diastereoselection exerted by CH3 and C(CH3)3 groups increases along substituent positions 1 < 2 < 3, with the effect of tert-butyl substituents being more pronounced. Theory states that the favored mode of cyclization proceeds via intermediates that are characterized by an offset of atoms C2 and C3 into opposite directions from the plane of O1 (radical center)/C5 (olefinic C)/C4 (allylic C). This arrangement allows alkyl substituents and the =CH2 entity to adopt positions that are associated with the fewest and least severe synclinal and synperiplanar interactions. A transition structure notation is proposed based on conformational characteristics of the heterocycle, the intermediates structurally resemble the closest, i.e. tetrahydrofuran. The new transition state model serves as an alternative to cyclohexane-based guidelines and adequately addresses hitherto unsettled instances properly, such as the lack in diastereoselectivity observed in the 1-phenyl-4-penten-1 -oxyl radical 5-exo-trig ring closure.

Evaluation of extended parameter sets for the 3D-QSAR technique MaP: implications for interpretability and model quality exemplified by antimalarially active naphthylisoquinoline alkaloids.

The 3D-QSAR technique MaP (Mapping Property distributions of molecular surfaces) characterises biologically active compounds in terms of the distribution of their surface properties (H-bond donor, H-bond acceptor, hydrophilic, weakly hydrophobic, strongly hydrophobic). The MaP descriptor is alignment-independent and yields chemically intuitive models. In this study, the impact of different operational parameters on the interpretability and model quality was investigated. Based on a set of antimalarially active naphtylisoquinoline alkaloids the effect of hydrophobicity assignment as well as the differentiation of H-bond propensity was evaluated according to a full factorial design. It turns out, that including different categories for H-bond donor strength significantly improved interpretability, reduced model complexity, and made possible the derivation of a novel pharmacophore hypothesis for this dataset. Further analysis of the factorial design reveals, that MaP models are robust to parameter changes and generate consistent models for different parameter settings.

Structural investigation of a configurationally stable seven-membered bridged biaryl of relevance for atroposelective biaryl syntheses

The atroposelective ring opening of lactone-bridged biaryl systems is the key step in the total synthesis of a series of axially chiral biaryl natural products and useful reagents or catalysts for asymmetric synthesis. For a more in-depth understanding of the mechanism and stereochemical course of this remarkable cleavage reaction, a seven-membered ether analog of such useful biaryl lactones has been investigated structurally, both experimentally, by X-ray diffraction analysis, and by ab initio calculations (B3LYP/6-31G*). In a nearly perfect agreement, both methods show that these seven-membered bridged biaryls do not constitute helicene-like distorted molecules, but ‘true’ biaryls, whose sufficiently long lactone or ether bridge allows the two aromatic systems to adopt a large dihedral angle to each other, without any noticeable deviation from planarity for the two aromatic systems - in contrast to related six-membered analogs, which can rather be considered as helicene-like twisted polycyclic systems.