| Research Abstract |
Fluorine closely mimics the steric requirement of hydrogen at enzyme receptor sites, but its strong electronegativity significantly alters the reactivity of neighboring centers. In addition, fluorine substitution increases lipid solubility, enhanced the rates of absorption and transport of the fluorinated derivatives. Therefore, fluorinated derivatives have been a subject of common interest to many groups because of special features of the fluorine in the field of pheromone chemistry. We accomplished the synthesis of both enantiomers of α, α-difluorinated analogue of eldanolide, which is a sex pheromone of the male African sugarcane borer, Eldana saccharina, using our original radical cyclization protocol. Electroantennogram (EAG) investigation of these pheromone analogues revealed that enantiomers of both of α, α-difluorinated analogues were as active as the natural eldanolide with the insect olfactory receptors. Electron spin density of these fluorinated analogues was completely diff
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erent from that of natural pheromone, while their molecular shape was suggested to be quite similar to the natural one based on the results of computational chemistry. The binding property of a pheromone molecule with a receptor protein based on its size and interaction with a specific part of the protein has been discussed from the standpoint of hydrogen bonding or coulomb energy. We therefore investigated the differences in eldanolide and its difluorinated analogue using computational chemistry and found that there was a great difference in the appearance of their molecular orbitals, the highest occupied molecular orbital (HOMO) of eldanolide with α, α-difluoro-eldanolide look quite similar, white the lowest unoccupied molecular orbital (LUMO) appear completely different We thus hypothesized that the appearance of the molecular orbital of the pheromone might play an important role in the binding property at the receptor site; the origin of molecular recognition on the pheromone receptor protein may by decided by the interaction of HOMO orbital from the pheromone molecules with LUMO orbital of the receptor site. To test this hypothesis, we decided to synthesize analogues which have different appearances on the HOMO level with the natural pheromone; 5, 5, 6-trifluoroeldanolide and 2, 2, 5, 5, 6-pentafluoroeldanolide were thus chosen as the synthetic targets of the present study. The results of EAG test of these point fluorinated eldanolides strongly suggest that the appearance of the molecular orbital is important for determining the binding property of a pheromone molecule with the receptor protein. Several atomic models of the recognition site with a pheromone receptor have been proposed, but no attention has been given to the interaction of the pheromone molecule with a receptor protein from the standpoint of molecular orbital. To the best of our knowledge, this is the first confirmation that the appearance of the molecular orbital on the HOMO level determines the recognition property on a pheromone receptor protein. Less
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