Combined molecular mechanics (MM2) and molecular orbital (AM1) study of periplanone-B and analogues. Evaluation of biological activity from electronic properties and geometries

Abstract

Combined molecular mechanics (MM) and semiempirical molecular-orbital (MO) calculations have been applied to the investigation on the conformational and electronic properties of periplanone-B (1), a major component of the sex pheromone of American cockroach, and structurally related analogues 2, 3, 4 and 5. In the first step, the geometries of conformers of 1–5 were obtained by MM2 combined with a new algorithm for exhaustive generation of ring conformations, CONFLEX2, and an additional set of MM2 force-field parameters. The global minimum (1A) of the natural pheromone populates predominantly and is superimposable on the X-ray structure. Minor conformers 1B and 1C correspond to the rotamers at the isopropyl group of 1A. The global minimum of the analogue 2 was identified to have the structure 2A, which agrees well with the X-ray data. The structural comparison of the stable conformers of the analogues 2–5 with 1A revealed similar ring conformations in the most stable conformers of 2, 3 and 4, and the third one of 5. These results suggest that the ring structure characteristic of the conformer 1A and the conformer populations must be a significant factor in the biological activity of these analogues. In the next step, the electronic properties were calculated by the semiempirical MO (AM1) method. A significant correlation is found between the biological activity and one of the unoccupied frontier orbitals which is localized around C1–C10–C9 including the carbonyl and spiro-epoxy groups. A newly defined effective frontier parameter: EF^(N)_(s), which regards the orbital electron density, orbital energy, and ring conformation is found to correlate well with the biological activity of these analogues.