Oxoaporphine is one of a class of isoquinolines. The alkaloids, fused nitrogen-containing tetracyclic compounds, are found in a wide variety of plants and have received considerable synthetic attention due to their profound biological activities. The proposal, based on the well-known anticancer activities natural product, liriodenine, would focus on developing the novel syntheses of 3- and 4-hydroxylisoquinolines and applying the methods to the synthesis of 4- and 5-methoxy-7-oxoaporphines. These alkaloids would be conducted for the preliminary screening tests for their anticancer activities. It’s helpful to develop the novel anticancer drugs. The plan can be categorized in the following three directions: (A) Synthesis of 4-hydroxylisoquinolines: We propose using the technique of flash vacuum thermolysis to synthesize 4-hydroxylisoquinolines via the electrocyclic reaction of ketene generated by the loss of ethanol from imine, followed by the hydrogen rearrangement. It is not only a novel method to obtain 4-hydroxylisoquinolines, but it also helps us to realize the influence of substituents in the benzene ring or the C=N double bond on the electrocyclic reaction without solvent effects. (B) Synthesis of 3-hydroxylisoquinolines: To our knowledge, the reaction of benzyne with 2-aza-1,3-butadiene is seldom found in literature. We design a novel synthetic method to acquire 3-hydroxylisoquinolines via condensation of the active benzyne with 2-aza-1,3-bis(t-butyldimethylsilyloxy)-1,3-butadiene followed by hydrolysis. It is a convenient methodology for the synthesis of 3-hydroxylisoquinolines. In addition, we’ll also discuss the lactim-lactam tautomerism of the substituted 3-hydroxylisoquinolines on the basis of their UV spectra in various solvents. (C) Synthesis and anticancer activity test of oxoaporphine: Oxoaporphine is one of the important biologically active alkaloids in pharmaceutical studies. We apply the synthetic methods in hydroxylisoquinolines to the synthesis of oxoaporphine, and proceed with the preliminary screening tests of these alkaloids for their anticancer activities. We provide a new route approaching to the tetracyclic alkaloids, and discuss the structure-activity relations in the proposal. It would be helpful to develop better oxoaporphine drugs.
