Studies Directed Towards a Practical Synthesis of Brevicomins (II)1 : A Novel Synthesis of 1, 5-Dimethyl-8-Oxobicyclo [3.2.1]octane-6-one

The recent interest in pheromones,² as means of controlling insect pests, has prompted us to examine syntheses which could be both simple and practical. We recently reported a three-step synthesis of brevicomin (3), the aggregating pheromone of the pine bark beetle, Dendroctonus brevicomis.³     

Organic salts as powerful lanthanide shift donors

The interaction of Eu(fod)₃ with organic salts is studied.     

Explorations on the multidimensional potential energy surface of a chiral stationary phase

The multidimensional potential energy surface for a soluble analog of a chiral phase is computed with MM2 and MNDO. Minimum energy conformations are located. The minimum energy reaction pathway between these forms is located, and the templating ability of these phases is described.     

Structural features of organic anions: 7-Norbornadienyllithium

The structure of 7-norbornadienyllithium, a homoantiaromatic carbanion, is investigated with the semiempirical MNDO molecular orbital method. Alkene out-of-plane bendings persist even when the metal is fully solvated. The structural integrity of the monomer is retained in the dimer and solvated dimer; previously proposed dimers are inconsistent with lithium bonding and are not minimum energy structures on the MNDO hypersurface.     

A computational model of the nicotinic acetylcholine binding site

We have derived a model of the nicotinic acetylcholine binding site. This was accomplished by using three known agonists (acetylcholine, nicotine and epibatidine) as templates around which polypeptide side chains, found to be part of the receptor cavity from published molecular biology studies, are allowed to flow freely in molecular dynamics simulations and mold themselves around these templates. The resulting supramolecular complex should thus be a complement, both in terms of steric effects as well as electronic effects, to the agonists and it should be a good estimation of the true receptor cavity structure. The shapes of those minireceptor cavities equilibrated rapidly on the simulation time scale and their structural congruence is very high, implying that a satisfactory model of the nicotinic acetylcholine binding site has been achieved. The computational methodology was internally tested against two rigid and specific antagonists (dihydro--erytroidine and erysoidine), that are expected to give rise to a somewhat differently shaped binding site compared to that derived from the agonists. Using these antagonists as templates there were structural reorganizations of the initial receptor cavities leading to distinctly different cavities compared to agonists. This indicates that adequate times and temperatures were used in our computational protocols to achieve equilibrium structures for the agonists. Overall, both minireceptor geometries for agonists and antagonists are similar with the exception of one amino acid (ARG209).     

Elucidation of the chiral recognition mechanism of cinchona alkaloid carbamate-type receptors for 3,5-dinitrobenzoyl amino acids

A cinchona alkaloid having extraordinary chiral discriminatory powers (alpha = 32.6 for dinitrobenzoyl leucine) is developed as a chiral stationary phase (CSP) for chromatography. An explanation of how chiral discrimination takes place is presented. Using a soluble analogue of the CSP, we found that NMR spectrometry indicates that 1:1 complexes exist for both optical isomers interacting with the CSP, that the free base form of the CSP exists in an open/closed ratio of 35/65 but that the protonated, bound-state form is exclusively in the anti-open conformation, and that significant intermolecular NOEs exist for the more stable diastereomeric complex but not for the less stable complex. Stochastic molecular dynamics simulations were carried out in solvents of low and high dielectric. The chromatographic retention orders and free energy differences of analyte binding to CSP were reproduced computationally as were the observed intra- and intermolecular NOEs. Data from the simulation were used to evaluate the intermolecular forces responsible for analyte binding as well as to discern fragments of the CSP doing most of the work of holding the complexes together. The enantiodifferentiating forces and the parts of the CSP most responsible for chiral discrimination are described. Moments of distributions of key dihedral angles and distances between centroids were used to assess the relative rigidity of the competing diastereomeric complexes. Simultaneous multiple-contact ion-pairing, hydrogen bonding, and pi-stacking are possible for the longer retained enantiomer only. An X-ray crystallographic study of the more stable complex confirms the conclusions derived from chromatography, NMR spectroscopy, and molecular modeling.