Sulfonate Involved In A Number Of Cross-coupling Reaction In The Class Of Natural Small-molecule Synthesis

Transition metal-catalyzed cross-coupling reaction is one of the most important methods for the construction of C-C or C-heteroatom bonds.Aryl halides and triflates are common electrophiles for this kind of transformations.Over the past three decades, transition metal-catalyzed cross-coupling reaction has been widely used for the synthesis of natural products,pharmaceuticals and advanced materials.However,aryl arenesulfonates and mesylates are attracting more interesting.They can be easily prepared from cheap,readily available starting materials and are less expensive,more stable,and easier to handle than the corresponding triflates. Moreover,they have a wider substrate scope than aryl halides.On the other hand, their relative inactivity appears to be a great challenge to organic chemists.Thus,the main target of this dissertation is:methodology development of cross-coupling reactions of aryl arenesulfonates and mesylates and their applications for the synthesis of natural product-like compounds.The details of the five sections of this dissertation are as the following:Section 1:Review of the development of transition metal-catalyzed cross-coupling reaction of aryl arenesulfonates and mesylates,and introduction of natural product-like small molecules and several natural product structures with remarkable biological properties.Section 2:Studies of transition metal-catalyzed cross-couplings of aryl arenesulfonates or mesylates with organoboron compounds,aryl silanes.1.Investigated the Suzuki cross-coupling reaction of aryl tosylates with potassium aryl trifluoroborates.Both aryl tosylates with electron-donating group and aryl arenesulfonates with electron-withdrawing group coupled efficiently with various potassium aryl trifluoroborates by using a bulky electron-rich phosphine ligand. This reaction also shows good functional group tolerance.2.Realized Rh/NHC catalyzed cross-coupling reaction of aryl arenesulfonates with arylboronic acids.NHC ligand was found to be more efficient than phosphine ligand in this reaction.The results not only demonstrate the efficiency of the Rh catalyst in cross-couplings of aryl arenesulfonates,but also provide an interesting complement to the phosphine-based palladium or nickel catalyst systems.3.Reported the first example of Pd-catalyzed Hiyama reaction of aryl arenesulfonates or mesylates with aryl silanes.In the presence of TBAF,various aryl arenesulfonates and mesylates were transformed into the desired cross-coupling products.This method broadened the scope of electrophiles of Hiyama reaction significantly.Section 3:Synthesis of a series of natural product-like small molecules utilizing the reaction methods developed in Section 2.1.Synthesized 4-aryl coumarins and quinolin-2(1H)-ones via Pd-catalyzed Suzuki reaction of alkenyl tosylates with potassium aryl trifluoroborates.This method benefits from the attractive features and advantages of both substrates and shows good functional group tolerance.2.Synthesized a series of natural product-like small molecules(4-aryl coumarins, quinolin-2(1H)-ones,pyrones,and furan-2(5H)-ones) via Rh-catalyzed reaction of alkenyl tosylates with arylboronic acids or potassium aryl trifluoroborates.3.Developed a site-selective cross-coupling strategy for the concise synthesis of 3,4-disubstituted coumarins.This work opens the door for numerous synthetic applications to diversified structures.Section 4:Considering the remarkable biological properties of quinoline structure, we have developed an efficient and mild route for the access of quinolines utilizing FeCl₃ or Mg(ClO₄)₂ as a novel catalyst via Friedl(?)nder annulation.We also realized this transformation in water by using Lewis acid-surfactant-combined catalyst. Various polysubstituted and polycyclic quinolines were obtained in excellent yields.Section 5:Experiment procedure and characterization.Collaborated with biologists(National Center for Drug Screening),we have screened these natural product-like small molecules in properly selected biological assays.Encouraging,a small molecule inhibitor of PTP1B was discovered with an IC₅₀ value of 4.65μM.Further investigation is underway.