Development of novel asymmetric organocatalytic reactions based on ketimines and para-quinone

Since around the turn of the millennium, organocatalysis developed rapidly and have been seen as one of the most powerful tools in modern organic synthesis. As part of our group’s research projects aiming at developing novel organocatalytic reactions, my Ph.D. research focuses on this field and four research projects are described in this thesis. In the first project, the Mannich addition of ethyl nitroacetate to N-Boc ketimines, followed by a denitration reaction to construct chiral 3-disubstituted-oxindoles was achieved. In the presence of a cinchona derivatives, this new protocol can be performed on gram-scale and the practical applicability of this method was demonstrated with the formal synthesis of AG-041R.In the second project, we developed a highly stereoselective method to synthesize 3,3’-pyrrolidinyl-dispirooxindoles containing three stereocenters with two adjacent spiro-centers. In the presence of the commercial available (DHQD)2PHAL, this one-pot reaction, containing a Mannich/Boc-deprotection/aza-Michael sequence occurred easily, delivered the desired products in good yields and good to excellent stereoselectivities. In the third project, a highly stereoselective construction of an all-carbon quaternary stereocenter was realized via a bifunctional squaramide mediated 1,6-addition of 3-substituted oxindoles to para-quinone methides. Based on this method, a wide range of chiral oxindoles, featuring a diarylmethine motif, could be synthesized in a scalable manner with high efficiencies, excellent diastereoselectivities and very good enantioselectivities. We presumed that the para-quinone methides might be activated through a hydrogen bonding. In the fourth project, organocatalytic asymmetric synthesis of chromans was achieved via a domino oxa-Michael/1,6-addition reaction. In the presence of 5 mol% of a thiourea catalyst, isatin-derived enoates and hydroxyl-substituted para-quinone methides were coupled to afford a series of 4-phenyl chromans in high yields and excellent stereoselectivities (up to >99% ee). In this domino process, three contiguous stereocenters, including one all carbon spiro center, were constructed with very good stereocontrol