Improved Synthesis And Application Of Cinchona Alkaloid Derived Bifunctional Phosphoramide Catalyst

This thesis focuses on the synthesis and application of cinchona alkaloid derived phosphoramide bifunctional catalysts, and includes the following three parts of research work:1) A series of cinchona alkaloid derived phosphoramide bifunctional catalysts are prepared, which are designed to modify our previously reported catalysts from three directions:a) varying the substituents of phosphoramide; b) introducing n-butyl and benzyl to the C2 position of the quinoline ring to tune the chiral environment of the catalyst; c) installing a phenolic hydroxyl group at C6 position of the quinoline ring to make multifunctional catalyst.2) A newly developed cinchonidine-derived phosphoramide bifunctional catalyst, readily available in two steps, is identified as an efficient catalyst for highly enantioseletive. Michael addition of both unprotected 3-arylthio-and 3-alkylthiooxindoles to nitroolefins, with catalyst loading down to 1.0 mol%. Therefore, a variety of quaternary oxindoles with a 3-sulfenyl-substituted quaternary center can be obtained with moderate diastereoselectivities (up to 8:1 dr) and excellent enantioselectivities (up to 98% ee). Importantly, this research confirms the role of phosphoramide as an effective H-bond donor to cooperate with tertiary amines to improve the reactivity and control the selectivity, and the stereoselectivities could be improved by increasing the amide alkoxy substitudents.3) The asymmetric Michael addition of differently substituted unprotected 3-prochiral oxindoles to nitroolefin was selected as a template reaction to investigate the differences and advantages between our bifunctional tertiary amine-phosphoramide catalyst and the corresponding bifunctional tertiary amine-H-bond donor catalysts with other representative H-bond donors such as phenol, amide and thiourea. Although other catalysts might be an excellent catalyst for a specific type of 3-substituted oxindoles involved reaction, only our bifunctional phosphoramide catalyst was a general excellent catalyst for the Michael addition to nitroolefins using all kinds of 3-substituted oxindoels, allowing highly enantioselective of various quaternary oxindoles bearing a tetrasubstituted carbon stereocenter at the C3-position, which further illustrates that phosphoramide has interesting properities worthwhile to explore. To investigate the role of the amide N-H bond, the corresponding N-methyl catalyst and phosphate catalyst were prepared and examined in the corresponding reactions. Based on these results, it was found that the amide N-H bond group played an indispensable role for the activity and selectivity.