Asymmetric Synthesis Of 3,3-disubstituted Oxindoles And Expanding Chiral-at-metal Lewis Acid Catalysts

The 3,3-disubstituted oxindole subunit is an attractive scaffold that constructs the core of many bioactive natural products and a series of drugs.Consequently,the asymmtric synthesis of 3,3-disubstituted oxindole has been highly concerned by researchers.The direct asymmetric Mannich reaction of isatin-derived ketimines is one of the most effective strategies.However,it’s still challenging to produce enantiopure samples which meet to the requirements of biological tests in one single chemical transformation.In Chapter 1,some representative natural products and bioactive molecules that containing 3,3-disubstituted oxindole structural motifwere introduced and the corresponding asymmetric synthetic methodologies were briefly reviewed.In Chapter 2,asymmetric Mannich reaction of isatin-derived ketimines and 2-acyl imidazoles catalyzed by novel chiral-at-rhodium Lewis acid catalyst were investigated.Firstly,a class of asymmetric Mannich reaction based on N-Boc protected ketimines was developed with good to excellent yield and very good stereoselectivities(94->99%ee,17:1->200:1 dr).Afterward,screeningof protection groups of ketimines reveals methyl carbamate is the best one with respect to the reaction rate and enatioselectivity.Finally,a wide range of 2-acyl imidazoles and N-CO2Me protected ketimines were tested.To our delight,almost all the reactions could be performed in the presence of 1 mol%△-RhO catalyst and provide the desired chiral 3,3-disubstituted oxindoles with 93-99%yield,43:1->200:1 dr and 98.4->99%ee.This work demonstrates the advantages and potential of novel chiral-at-rhodium Lewis acid catalyst in asymmetric constructing continuous chiral centers,and also provides an effective protocol for the synthesis of bioactive oxindoles.In Chapter 3,benzimidazoles bis-cyclometalated novel chiral-at-iridium(Ⅲ)Lewis acid complex(A-IrNPh)was firstly synthesized and applied to asymmetric catalysis preliminarily.This novel catalyst performed better than the published catalyst(A-IrS etc)in asymmetric Michael addition.Unfortunately,for the enantioselective a-amination,only poor enantioselectivity(12%ee)amination product was obtained probably because the background reaction was strong and reactive site of β-ketoester couldn’t be well steric shielded by tert-Butyl group from cyclometalated ligand of △-IrNPh.In order to improve the enantioselectivity of asymmetric a-amination,seeking for new reactions or substrates are necessary.In Chapter 4,the summary and outlook are presented.