Aromatic Polycyclic Regiospecific CH Oxidation And Total Synthesis Of Natural Polycyclic Phenolic Compounds

Traditional Chinese Medicine(TCM)is an alternative therapy mainly used natural active ingredients for prevention and treatment diseases under the guidance of TCM theory.Natural polycyclic phenolic compounds are one of the active ingredients isolated from the Chinese medicinal herbs.The structure analysis of polycyclic phenols shows that the main difficulty in their synthesis lies in hydroxyl groups.At present,the synthesis of hydroxyl groups is mostly limited to benzene ring-based compounds,and polycyclic compounds are not involved.The C-H functionalization using transition-metal-catalyzed and directing groups has been dramatically progressing and impacting the synthetic community,since it could provide functionalities on the inert C-H bond of complicated natural products.For example,the C-H oxygenation has become an effective method for the synthesis of simple phenolic compounds.In this study,the construction of regioselective C-O bonds on naphthaldehyde using aldehyde group as directing group was achieved by transition-metal-catalyzed C-H oxygenation.It provides a versatile tool to achieve several representative natural polycyclic phenolic compounds.The thesis consists of three parts:The first part is the ortho-C-H acetylation mediated by the directing group with naphthaldehyde as the backbone.In this part,the naphthaldehyde is firstly converted to imine,which is then acetylated at the ortho-position by using metallic palladium as a catalyst.The suitability of the substrates was examined and the results showed that both imines constructed on the basis of simple naphthaldehyde and aromatic polycyclic aldehydes achieved good acetylation of the ortho-position of the naphthalene ring under template reaction conditions.Since the electron density of ortho-position is relatively low in comparison with different sites of the naphthalene ring,the oxidation reactions at the ortho-position always require harsh conditions such as high temperature or strong bases.These conditions increase the labors and cost of reaction handling and also deteriorate the compatibility of substrates in the reaction.Our method adopts high valent iodine reagent as the oxidizing agent and realizes ortho-position acetylation of polycyclic compounds in a milder reaction condition.The second part is to utilize the transient directing group to achieve the peri-C-H oxidation reaction of naphthaldehyde.It avoids the additional assembly/disassembly of directing groups and allows to directly realize the 1,8-disubstituted naphthalene derivatives under milder conditions,the structure of which exhibit diverse biological activities.In short,these two parts together provide a robust method for the regiospecific synthesis of complex polycyclic phenolic compounds through direct C-H oxidation reactions.The final part of this thesis that utilized the regiospecific C-H oxyngenation in the total synthesis of natural polycyclic phenolic compounds,such as hemigossypol,naphthoflavone and naphthoquinone.We obtained the three different polycyclic phenolic compounds with high atom-economic steps and simple synthetic transformations.Compared with previouly reported methods,the current route stands for a series of high efficient and specific synthetic tools that could widely use in the synthesis of important natural products and medicinal entities derived from TCM molecules.