Study On Cascade Transformations Of Isochromenylium Intermediates

Isochromenyliums are a type of reactive intermediates, while recent research found that their tetrafluorobrates (ICTBs) are air-and moisture-stable. Both the isochromenyliums formed in situ by treatment of o-alkynylbenzaldehydes with certain electronphilic catalysts (lewis acidic transition metal or electronphilic X+) and stable ICTBs have been found to exhibit diverse and flexible reaction behaviors through various cascade transformations, generating unique and complex compound in a simple and efficient manner. Structrually, isochromenylium could be regarded as an electron-deficient oxa-diene equivalent, and the early reaction partners were restricted to electron-rich substrates. On the other hand, the traditional metal/chrial ligand complexes could not afford satisfactory asymmetric transformations owing to isochromenyliums’high reactivity and the lack of enough asymmetric induction resulting from the remote distance between chiral and reaction centers. And so, enantioselective transformations based on the planar isochromenyliums are still a challenge in organic chemistry. Based on our research interests and experience on ischoromenyliums, rational designs were proposed and careful explorations were attempted with aim to resolve the above two problems. The important points of this thesis work were as follows: In the first part, electronically unfavorable formal [4+2]-cyclization reactions between isochromenylium tetrafluoroborates and electrondeficient olefins have been achieved by assistance of a phenolic hydroxyl group in the olefin substrates. The newly developed cascade methodology is initiated by an intermolecular C-1O-glycosylation, and completed with an intramolecular Michael addition and an aldol condensation. The developed cascade methodology is advantageous in ease of operations, metal-free conditions, and high efficiency to generate corresponding2-oxabicyclo[3.3.1]nonane derivatives with multiple stereogenic centers including the quaternary carbons, and thus will be useful in future applications to the synthesis of bioactive natural products and drug-like molecules.The enantioselective addition of olefins to ICTBs was attempted based on the weak intermolecular interaction between catalysts and ICTBs. After a number of experiments, the asymmetric Diels-Alder reaction of olefins and in situ formed isochromenyliums was examined under the catalysis of Bransted acids. Moderate enantioselectivity was achieved and it was believed to stem from the asymmetric induction by chiral counteranion.The first catalytic asymmetric oxa Diels-Alder/nucleophilic substitution cascade reaction based on isochromenylium intermediate has been established with good to excellent enantioselectivities (up to>99.5%ee) in a broad spectrum of substrates. A cooperative binary catalysis with Pd(OAc)2and (5)-Trip successful assembled two separated substrates into an effective supramolecular asymmetric environment to facilitate the "intramolecular" oxa Diels-Alder cycloaddition through exchange of coordinating encounter anion followed by hydrogen bond formation. The mechanism study revealed that the appropriate acidity of Pd(OAc)2, bifunctional catalytic property and appropriate acidity of Trip were necessary for sastifactory stereoselectivity. The developed enantioselective cascade reaction has shown great efficiency in establishing densely multiple stereogenic centers including quaternary carbons and variable bridged ring systems, and thus provides an efficient one-step access to a new class of enantiopure conformation-constrained natural product-like tetrahydronaphthalene derivatives of medicinal interest such as podophyllotoxin analogues.