Catalytic Enantioselective Sigmatropic Rearrangements of Vinyl Sulfonium Ylides

Today 68% of the top 200 marketed drugs are chiral. Despite the importance of chirality in drug development existing synthetic technologies have very limited ability to produce chiral chemical scaffolds containing pharmacologically important functional groups. The goal of this project was to generate innovative technology that would make it possible to introduce pharmacologically important functional groups in an efficient and enantioselective fashion. In order to achieve this goal, we have chosen enantioselective metal carbene chemistry. Generally, heteroatom containing substrates such as sulfides, ethers or amines will react with metal carbenes and generate the corresponding ylides, which subsequently undergo in situ rearrangements or ring expansion reactions. However, under certain conditions, the carbene intermediates can functionalize C-H bond adjacent to heteroatoms instead of generating ylides. With this concept in mind, we have developed an efficient regio- and stereoselective method for distal allylic/benzylic C-H functionalization of silyl ethers using triazole and diazo derived rhodium(II) carbenoids. Furthermore, we have demonstrated the application of the C-H functionalized products for the synthesis of important heterocyclic scaffolds such as 3,4?disubstituted L ?proline analogues, which are a basic scaffold found in biologically active compounds like phenylkainic acid. The project was discontinued after the first year as the project manager moved to a tenured faculty position at this point. The project results were reported in an article in Angewandte Chemie (Angew. Chem. Int. Ed. 2020, 59, 7397 ?7402).

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Innovative synthetic technology is the driving force for the next generation drug discovery. In order to optimize new lead drug candidates, pharmaceutical manufacturers require synthetic transformations that allow for generation of a wide number of chemical scaffolds. The CESSY project will be instrumental in this quest by providing a reaction platform, which can produce a diverse range of asymmetric chemical reactions. CESSY is not only designed with an industrial perspective, it can also open up new areas in basic academic research. For example, amines and alcohols are nucleophiles in most traditional organic transformations, however in the CESSY technology, amines and alcohols behave like in situ generated electrophilic sources. With the existing reaction technology, most of the organic reactions, such as amination, alkoxylation, alkylation, and trifloromethylation need to be conducted via separate reaction methods. In CESSY, one method (non-racemic sulfonium ylide rerrangement) can provide all these reactions in asymmetric fashion. The key concept of CESSY is a one-pot sequence of asymmetric metal carebenoid generation, sulfonoium ylide formation and sigmatropic rearrangement. The execution of CESSY involves two stages: 1) a development stage which focuses on contributions to new areas in basic academic research and 2) an application stage which focuses on contributions to relevant industrial applications such as short synthetic routes to the core part of bioactive natural products and drug molecules. This proposal includes both the transfer of knowledge to the host institution and the training of the candidate in new advanced techniques. Results have the potential capacity to increase the competitiveness of metal carbenoid and sulfur ylide chemistry and provide room for further studies at the fundamental and applied research level of advanced synthetic organic chemistry and asymmetric metal catalysis.