The Synthesis And Conformational Studies Of Phenylcyclodode- Canone Derivatives,8-CF₂ Muscone And 5-CF₂ Dodecan-12-olide

Cyclododecane and cyclododecanone are both important macrocyclic compounds. Cyclododecane is widely used in supramolecular chemistry and biochemistry because of its specific cyclic structure. As a commercial compound, cyclododecanone is an important starting material for the preparation of macrolide, macrolactam, smaller cyclic ketones, as well as natural muscone, antitumor drug Rosphellin and anticancer drug Altohyrtin C. The stereochemistry study will be helpful for exploring their new applications in synthetic chemistry and can also provide some indications for other macrocyclic compounds. In this paper, the chemoselectivity, reaction selectivity of cyclododecanone derivatives and stereochemistry of the products were further explored. Muscone is an important natural perfumery compound, (3Z)-dodecen-12-olide is the pheromone emissioned by female emerald ash borer. In order to explore the structure-activity relationship,8-CF2 muscone and 5-CF2 dodecan-12-olide were synthesized.The reduction of α-phenyl/cyclohexyl cyclododecanone exhibited significant cis-selectivity. The syn/anti ratio is 96:4 when running the reaction with lithium tri-tert-butoxyaluminum hydride as reductant at -20℃. (Cis/trans)-1-phenyl-2-hydroxyl cyclododecanes were synthesized by recrystallization and configuration inversion esterification. The computational analysis and X-ray diffraction results indicated that the ring skeleton of (trans)-1-phenyl-2-hydroxyl cyclododecane is still [3333] conformation with the OH located at side-exo position, the Ph located at corner-anti position (compound Ⅰ).A series of di-/tri-substituted cyclododecanone were synthesized. Their ring skeletons had the [3333]-2-one conformation. The X-ray results of disubstituted cyclododecanone showed that the phenyl preferred to locate at the side-exo position (compound Ⅱ and Ⅲ), while the cyclohexyl is located at the side-exo position when the other substituent is benzyl (compound IV), the cyclohexyl will be located at the corner-syn position when the other substituent is bromide or iodide (compound X).2-Phenyl/cyclohexyl-cyclododecanone oxime and 3-phenyl/cyclohexyl-cyclododecanone-1,2-dione monooxime were synthesized. The computational analysis and X-ray results showed that 2-cyclohexylcyclododecanone oxime took the [3333]-2-one conformation (compound XI), while the conformation of 3-phenylcyclododecan-1,2-dione monooxime turned out to be [4233]-3,4-dione (compound XII).By analyzing the conformation of β-phenylcyclododecanone derivatives with X-ray diffraction and computational calculation, two dominant conformations for β-phenylcyclododecanone derivatives were founded. The crystal structures were shown as compound Ⅷ and Ⅸ.Six pairs of (syn/anti)-α-monosubstituted cyclododecanone isomers were synthesized, and the syn-and anti-isomerism of α-monosubstituted cyclododecanone were comfirmed by analyzing the X-ray strucutures of (syn)-a-benzylcyclododecanone(compound Ⅹ), (anti)-a-isonicotinoylcyclododecanone (compound Ⅺ) and (anti)-a-pyridinylmethylcyclododecanone(compound Ⅻ).In order to study the structure-odour relationship, the 8-CF2 muscone derivative with one specific conformation was obtained via an eleven-step synthesis route with 1,9-nonanediol as starting material. The odour evaluation result showed that the derivative exhibit better odour than the natural muscone.Emerald ash borer is an invasive insect and has caused serious damage to ash tree. (3Z)-dodecen-12-olide is the pheromone emissioned by female emerald ash borer. Both the geometric isomers and saturated analogue were attractive to the males. The 5-CF2 pheromone derivative was synthesized via a twelve-step synthesis route with 1,8-octanediol as starting material. The preliminary bioassay results indicated that the derivative have better attractive effect than the natural pheromone.