Israel Agranat

Intellectual property and chirality of drugs.

Chirality has emerged as a key issue in drug design, discovery and development. Chiral switches are drugs that are already approved and claimed as racemates but that have been redeveloped as single enantiomers. The legal state of the art of patentability of chiral switches, as derived from US and European precedents, is reviewed. The issues of intellectual property in the pending chiral switches of the blockbuster drugs ibuprofen, fluoxetine and omeprazole are analysed.

Conformational Space and Dynamic Stereochemistry of Overcrowded Homomerous Bistricyclic Aromatic Enes − A Theoretical Study

The conformational spaces and dynamic stereochemistry of representative overcrowded homomerous bistricyclic aromatic enes (1, X = Y) are investigated, applying the semiempirical PM3 method. The experimental energy barriers for E,Z isomerizations, enantiomerizations, and conformational inversions of 1 and related compounds, derived from DNMR and other kinetic studies, are reviewed. This study focuses on the analysis of the minima, transition states, and dynamic mechanisms of the conformational isomerizations of bifluorenylidene (2), dixanthylene (3), dithioxanthylene (9), and bi-5H-dibenzo[a,d]cyclohepten-5-ylidene (11). The four representative bistricyclic enes differ in the sizes of their central rings and in their bridging groups. The mechanisms of the interconversions of the twisted, anti-folded, and syn-folded conformations and of thermal E,Z isomerizations (topomerizations), enantiomerizations, and conformational inversions (including combinations) are elucidated. The calculated energy barriers for E,Z topomerizations of 2, 3, 9, and 11 are 25.3, 16.4, 24.3, and 39.3 kcal/mol, respectively. The corresponding barriers for enantiomerizations or conformational inversions are 4.9, 15.9, 24.3, and 37.6 kcal/mol, respectively. In most cases, the agreement with experimentally determined values is within 1−3 kcal/mol. New mechanisms are proposed for the E,Z isomerizations and conformational inversions of anti-folded 3, 9, and 11, involving low-symmetry folded/twisted transition states and the respective syn-folded intermediates.

Cyclic Conjugation Effects in Cyclacenes

Abstract Cyclic conjugation is studied in Huckel and Mobius cyclacenes as well as in a few other related open-chain and cyclic belt-shaped hydrocarbons (e.g., zig-zag cyclarenes). the main conclusions are that (a) the energy effect of the conjugation along the perimeter of cyclacenes is relatively large, (b) conjugation along the 6 -, 10 - and 14-membered cycles has a much greater effect, in spite of the fact that these cycles embrace bonds that formally are not involved in cyclic conjugation. Mobius cyclacenes are non-alternant hydrocarbons and their odd-cycles have a significant contribution to conjugation. the contribution of conjugation in individual cycles to the total resonance energy is briefly discussed.

ENANTIOMERIZATION OF ENVIRONMENTALLY SIGNIFICANT OVERCROWDED POLYCHLORINATED BIPHENYLS (PCBS)

The rotational barriers of overcrowded PCBs are predicted by ab initio methods including electron correlation, thus settling the controversy between theory and experiment. For 2,2′,3,3′,4,6′-hexachlorobiphenyl (PCB 132), an enantiomerization barrier of 185 kJ/mol is calculated by B3LYP/6-31G*, in excellent agreement with the experimental data. Chirality 9:350–353, 1997.

Fulvenes and thermochromic ethylenes—XXXVIII : A simple triapentafulvalene

Abstract 1,2,3-Tetrachloro-5,6-diphenyltriapentafulvalene (III) has been synthesized, and its physical properties determined. The contribution of a dipolar form (IV) to the actual state of the molecule has been discussed.

Electrostatic chiral distinction: Tetrahedral model dimers

Although chiral distinction plays a pervasive role in chemistry, a complete understanding of how this takes place is still lacking. In this work, we expand the earlier described minimal requirement of so called four-point interactions (vide infra). We focus on chiral point charge model systems as a means to aid in the dissection of the underlying, operative principles. We also construct models with defined symmetry characteristics. By considering extensive constellations of diastereomeric complexes, we are able to identify emerging principles for chiral distinction. As previously postulated, all the diastereomeric complexes, regardless of their nominal contact-points, possess a chiral distinction energy. In the comparison of complexes, we find that, contrary to chemical intuition, the magnitude of chiral distinction does not correlate with the stability of the complexes, i.e., consideration of low energy complexes may not be an effective way to evaluate chiral distinction. Similarly, we do not find a correlation between the number of contact-points and chiral distinction. Moreover, favorable interactions and facile chiral distinction appear to be unrelated. We also see some tendency for greater chiral distinction in less symmetric systems, although this may not be general. These studies can now form the basis to fold in higher levels of complexity into the models so as to gain further insights into the nature of chiral distinction.

Stabilization of the cyclopropenum and cyclopropenone ring systems by ferrocene : A 13C nuclear magnetic resonance study

Abstract The 13C NMR spectra of diferocenylcyclopropenone (1) and the triferrocenylcyclopropenium (2) and ferrocenyldiphenylcyclopropenium (3) cations in non-acidic media are analyzed with special reference to the information they afford concerning charge distribution in these species. A delocalization of the positive charge into the remote unsubstituted five-membered rings of 2 and 3 is indicated. The role of the metal as a conduit for this effect is suggested.

The structure of octachloropentafulvalene

Abstract The structure of octachloropentafulvalene has been redetermined by a 3-dimensional X-ray crystallographic analysis. The space group is monoclinic, C2/c, and cell parameters are a = 14·998, b= 7·9110, c= 11·8068 A, β= 103·38°. The X-ray intensity data were measured on a computer-controlled diffractometer using Mo radiation. The least-squares structure refinement used anisotropic temperature factors for C and Cl and gave a final R of 0·036. Corrections were applied for absorption, Cl dispersion and secondary isotropic extinction. The central CC is twisted by 37° as a result of Cl⋯Cl repulsions from one C5Cl4 half to the other. The central CC length, 1·365 A, is only slightly larger than the standard 1·34 A ethylenic value. The bond distance increase can be explained in terms of a decrease in π-bond character accompanying the CC twist. Carbon-carbon distances in the 5-ring have typical values for the cyclopentadienylidene moiety; there is no evidence for single-double bond delocalization.

Thermochromism of overcrowded bistricyclic aromatic enes (BAEs). A theoretical study

A criterion for thermochromism has been derived from ab initio DFT B3LYP/6-31G* calculations of the anti-folded, syn-folded and twisted conformations of thermochromic and non-thermochromic overcrowded bistricyclic aromatic enes (BAEs) 1–8: the thermochromic species is the twisted conformation, a necessary condition being a small energy difference, <30 kJ mol−1, between the global minimum anti-folded and the thermochromic conformations.

Measures of pyramidalization

This article reviews common definitions of pyramidalization. An appraisal of the quantification of pyramidalization follows, and the formulation of a new measure of pyramidalization. The versatility of the new measure is tested using correlation with some molecular properties.