Selenium-catalyzed Oxygen Atom Transfer Reaction And Related Medicinal Chemical Studies

In recent years,redox-economc,especially redox-neutral reactions,have received much attentions.Such reactions,while achieving efficient and green conversion,have prompted chemists to develop a series of breakthrough reaction modes.Nevertheless,it is still a great challenge to achieve redox neutrality at both the atomic and electronic levels,and it is necessary to find a suitable catalytic system to achieve the transfer of related atoms and electrons.The moderate electronegativity,diverse valence states,and unique bonding capabilities endow the chalcogen elements with special atomic and electron transfer capabilities,which provides the possibility for the redox economic chemical transformation with high electron and atom utilization efficiency and new ideas for the synthesis of organic molecules containing multiple functional groups.As one of the important raw materials for synthetic chemistry,anthranilic acid and its derivatives exist widely in more than 70 pharmaceuticals,50 clinical drugs,20 agrochemicals,diverse fragrances,and dyes.For such a significant chemical structure,although a variety of methods have been developed,it is still a great challenge to simultaneously realize it with high atomic,step and redox economy.In line with such guiding principles and combining with our previous studies on chalcogen chemistry,a self-redox protocol is developed for the synthesis of anthranilic acids(AAs)from onitrotoluenes.In addition,their application in the pharmaceutical field has been further expanded.The concrete research consists of the following two parts:Part I: Selenium-catalyzed oxygen atom transfer reaction to synthesize anthranilic acidsAn effective synthesis of AAs was realized in one step through the atom transfer under the catalysis of selenium with o-methyl(hetero)arylnitrates as the starting material.The use of extra oxidants and reductants was avoided with this self-redox process,which resulted higher compatibility with ideal atom-,step-and redox-economy.Hundred-gram-scale reaction have been realized with reasonable yield and effective recovery of the catalyst,which indicates its potential of industrial application.In addition,several studies including heavy atom labeling,electron paramagnetic resonance and DFT calculation were conducted to shed light on the mechanism,which provided a new mode of action for chemical conversion mediated by selenium and selenium-containing compounds.Part II: Medicinal chemical studies of anthranilic acid-derived drugs-thalidomide analogsVarious natural products and pharmaceuticals contain anthranilic acid skeleton with unique biological activities.To further expand its application in the field of medicine and combine with the current treatment status of malignanc-related diseases,we made modification on the thalidomide analogs derived of anthranilic acid and evaluated the antitumor activity of these compounds.The result indicated that the antitumor activity of the series of 4-alkylthio-or arylthiol-lenalidomide analogs has been improved to a certain extent compared with thalidomide analogs like lenalidomide and pomalidomide.Moreover,most of the 4-arylthiol-lenalidomide analogs show excellent anti-proliferative activity against leukemia cell lines besides the activity against multiple myeloma.And they may be used as a new generation of immunomodulatory drugs in the future for the treatment of a variety of blood system diseases.