Study On The Synthesis And Biological Activity Of Spiro[5,6]dodecanone Derivatives

Spiro[5,6]dodecanone compounds in clinic and pharmacology exhibited excellent antineoplastic activity,inoxidizability,anti-HIV-1 integrase,and immunodepression and so on.Therefore it's meaningful to synthesize the spiro[5,6]dodecanone and its derivatives and explore their biological activity studies.By literature investigation,spirocycloalkane structural analogues have good biological activity.Therefore,the morpholin-3-one structure was introduced to the carbonyl position of dibenzoxepine-7-one derivatives to obtaina series of spiro[5,6]dodecanone derivatives with biological activity.A route for the synthesis of spiro[5,6]dodecanone and its derivatives was designed from acetophenone and phenolic compounds as the starting materials.First,acetophenones were brominated to give?-bromoacetophenones.Next the key intermediate dibenzoxepine-7-ones were obtained by an etherification/C-C coupling reaction of phenols and?-bromoacetophenones.Then 7-aminomethyldibenzoxepine-7-ol compounds were obtained by an addition cyanide reaction of the carbonyl group of dibenzoxepine-7-one compounds and a reduction of the cyano.Finally,spiro[5,6]dodecanone derivatives obtained by cyclization.The etherification/C-C coupling tandem reaction of synthetic dibenzoxepine-7-ones and cyclization of spiro[5,6]dodecanone as important reation steps were investigated.Wherein,the optimal conditions of Pd catalytic etherification/C-C Coupling cyclization reaction were used phenols and?-bromoacetophenones as raw materials,Pd?OAc?₂?10 mol%?as the catalyst,2 equiv of DDQ as the oxidant and 2 equiv of Cs₂CO₃ as the base in CH₃CN,under 25 W LED white light,it reacts at 80 ^oC for 10 hours.20 target compounds of spiro[5,6]dodecanone and its derivatives were obtained by the abovementioned route.The target compounds and the important intermediates were characterized and confirmed by using HRMS,IR,¹H NMR,¹³C NMR,etc.Finally,spiro[5,6]dodecanone and its derivatives were studied for their anti-HIV-1activity and structure-activity relationships.The experimental results show that spiro[5,6]dodecanone with-Cl,-F substituents has a good inhibitory effect on human HIV reverse transcriptase and can be used as a potential anti-HIV-1 drug.