Merging organocatalysis and transition metals in enantioselective one-pot sequential reactions and new concepts in organocatalytic domino reactions

摘要

The main objectives of this doctoral thesis include the following: 1) The development of multicatalytic systems that combines the complementary advantages of organocatalysis and transition metals within a single reaction pot.2) The development of novel organocatalytic domino reactions that allow the generation of cascade products with multiple stereogenic centres.In the first part of the doctoral research, C3, C2- unsubstituted indole substrates were chosen for the development of single pot annulation strategies since indole is well known to possess multiple positional reactivities. Tapping upon this unique property of indoles, o-alkyne nitroolefin substrates were synthesized and tested in a sequential organo-/ Au(I) catalyzed sequential reaction. Interestingly, tetracyclic seven membered ring containing indole derivatives could be successfully synthesized with excellent enantioselectivities with this sequential methodology. Moreover, our methodology also exploits the C2 electrophilicity of the indole substrate, where a postulated Wagner-Meerwein type ring expansion methodology allowed the access of such medium ring products which are challenging if a pure organocatalytic methodology is used. In addition, biologically active tetrahydrocarbazoles could be accessed using an organocatalyzed/ Ag(I) mediated sequential one-pot strategy by the skillful selection of an iodo-nitroolefin substrate. In this protocol, a first organocatalyzed Friedel-Crafts type Michael addition of indoles allows the incorporation of stereogenic information into the product. The Ag(I) additive allows the thermodynamic abstraction of the iodide from the substrate, hence driving the Ciamician-Plancher rearrangement reaction which is rarely utilized in the literature. Furthermore, the first concise enantioselective three step total synthesis of a 5-HT6 receptor antagonist was accessed using this methodology. In the second part of the doctoral research, o-carbaldehyde nitroolefins were used to evoke a Michael/Henry domino reaction to access poly-functionalized indanes enantioselectively. One project required the use of C3, C2-unsubstituted indoles as a nucleophilic trigger to start the domino reaction. It was discovered that our cascade product furnished a cis-vicinal relative configuration which is different from other base catalyzed domino reactions known in literature which forms the all trans-vicinal indanes. This was attributed to the fact that hydrogen bonding catalysts can direct the domino reaction to form a cis-oriented transition state which allows access to the cis-vicinal product in the Henry cyclization step. Moreover, the kinetic product formed in our methodology can be easily epimerized using a strong base to the thermodynamic product. The last project is the utility of N-Boc-oxindoles as a nucleophile in a Michael/Henry domino reaction which forms indanes bearing four contiguous stereogenic centres. The investigation showed that only 0.5 mol% catalyst loading of a quinine-derived squaramide is required to generate such molecular complexity and most of the examples in the methodology only required 45 minutes towards completion. Hence the frontier of organocatalytic domino reactions were pushed to the limits comparable to transition metal catalysis.