Palladium-catalyse Wacker Oxidation Reaction, Asymmetric Reaction Catalyzed By Thiourea Derivatives And Total Synthesis Of Bortezomib

This dissertation aims at the studies on Palladium-catalyse Wacker Oxidation Reaction, Asymmetric Reaction catalyzed by thiourea derivatives and total synthesis of Bortezomib which approved to be anticancer agents.The first part related to chemoselective Pd-catalyzed Wacker Oxidation which would build bis-benzannelated [5,6]-spiroketal core of rubromycins. We constructed substrate 1 via 8 steps, including Claisen Rearrangement, Hydroboration Oxidation, Julia-Lythgoe Olefination, Mitsunobu Reaction and so on. Then we used 1 as a model substrate, explored the conditions for the synthesis of bis-benzannelated [5,6]-spiroketal via intramolecular wacker reaction. The experiments showed that 10 mol% PdCl2/4.0 eq. benzoquinone/MeOH/reflux 2d was the optimal reactive condition so far, under which the spiroketal 2 was obtained in 31% yield. The subsequent researches are currently under investigation.The second part included three sections. The one was the enantioselective total synthesis of the asymmetric thiourea catalyst, which using asymmetric amine and isothiocyanate as key intermediate product. Purpose on expanded thiourea catalysts for new substrates, we synthesis 9 kinds of differentα,β-unsaturated substrates. Then, we led thiourea catalyst to asymmetric Micheal Addition Reaction, N-heterocyclization Reaction, Aza-Diels-Alder Reaction and Aldol-Micheal Tandem Reaction. Additionally, we applied the nucleophilic phosphines catalysts to some substrate in order to construct heterocyclic compounds and coupling comounds.The third part was mentioned the studies on the total synthesis of therapeutic antineoplastic agent Bortezomib which was used for treating patients with multiple myeloma and mantle cell lymphoma. We adopted a convergent synthesis strategy, using pyrazinecarboxylic acid, L-phenylalanine and alkylated boronic ester as starting material, experiencing Grignard Reaction, Esterification, Rearrangement promoted with ZnCl2, Coupling Reaction and other steps. We developed a straightforward and more efficient method for synthesising Bortezomib, sent masterstandard and technical supporting to the QA.Finally, all the works are summarized, all the phenomenon which had been presented are discussed and the experiences are concluded.