Studies On Chiral Thiourea-catalyzed Asymmetric Decarboxylative Mannich Reaction Of β-Carbonyl Carboxylic Acids With Cyclic Trifluoromethylketimines

Decarboxylation Mannich reaction has recently attracted much attention, because itcan imitate bio-process to construct C–C bonding under mild conditions. Among these,the organocatalytic asymmetric decarboxylative Mannich reaction has emerged as anactive research area due to its high atom economy and easy operation. What’s more,the resulting products-β-amino compounds can be easily converted to a wide array ofuseful building blocks.In this thesis, asymmetric decarboxylative Mannich reaction of-ketoacids withcyclic trifluoromethylketimines has been developed in the presence of thesaccharide-derived chiral bifunctional thiourea organocatalysts. A series ofenantioenriched3,4-dihydroquinazolin-2(1H)-one derivatives containing a quaternarystereogenic center were obtained with excellent yields (up to99%) andenantioselectivities (up to99%ee). The catalyst loading could be reduced to1mol%to give identical results. Notably, this method can be directly applied to the synthesisof anti-HIV drug DPC083, which is a class of non-nueleoside reverse transcriptaseinhibitors (NNRTIs). Furthermore, preliminary experiments (19F NMR and HRMS)have been performed to elucidate that nucleophilic addition of-ketoacid to the cyclicketimine occur prior to the decarboxylation of the β-ketoacid during thisdecarboxylative Mannich process.Next, the asymmetric decarboxylative Mannich reaction of malonic acid half estersand cyclic trifluoromethylketimines has also been described. By using thebifunctional chiral amino-thiourea catalyst, a wide range of enantioenriched β-aminoester derivatives containing chiral quaternary carbon chrial centers were obtained inup to99%yield and99%ee. Additionally, the highly enantioselective synthesis ofDPC083has been achieved using decarboxylative Mannich reaction as a key step.