Periodic Reporting for period 1 - PHOTO-CYCLE (Photocatalysis in Drug Discovery - Asymmetric Preparation of Bioactive Chiral Lactones and Cyclohexanols)
Okres sprawozdawczy: 2020-03-01 do 2022-02-28
We have pursued the PHOTO-CYCLE project under the guiding principle that compound development should be driven by discoveries and innovation in chemical methodology, providing real benefits to society through the discovery of new therapeutics. Additionally, the use of visible light to drive the chemical transformations involved in the project provide high environmental benefits.
The resulting synthetic platform will be used as an ideal starting point for assembling libraries featuring biologically privileged scaffolds. These scaffolds will comprise chiral polycyclic lactones and polyfunctionalized cyclohexanols, which, along with biological screening, will increase the probability of success in identifying drug-candidate structures.
Emphasis will be put on the importance of developing chemical methodology to lactones and polyfunctionalized cyclohexanols, its application towards drug synthesis, and environmental benefit of using visible light to drive chemical processes.
The goal of our research is to combine the potential of asymmetric organocatalysis and photocatalysis, two powerful fields of molecule activation, to design novel cascade reactions.
(1) A general iminium ion-based catalytic method for the enantioselective conjugate addition of carbon-centered radicals to aliphatic and aromatic enals was developed. The process uses an organic photoredox catalyst to generate radicals, in combination with ground state iminium ion, secures a consistently high level of stereoselective interception of a wide variety of radicals, including non-stabilized primary ones which are generally difficult to engage in asymmetric processes. The system also served to develop organocatalytic cascade reactions that combine an iminium-ion-based radical trap with an enamine-mediated step, affording stereochemically dense chiral products in one-step. This work has been published in Angew. Chem., Int. Ed. 2021, 60, 5357, and highlighted by Synfacts 2021, 17, 325.
(2) The system was expanded to enantioselective construction of remote δ-stereocenters utilizing cyclobutanol ring opening under visible light. The process could afford synthetic useful compounds containing δ-stereocenters as proved by the diverse derivatizations, including the chiral cyclohexanol as proposed in the target proposal triggered by an intramolecular cyclization. A series of enals, including aliphatic and aromatic, are well compatible in the reaction, affording the products in good efficiency and enantioselectivity. Mechanistic studies, including Cyclic Voltammetry, Stern-Volmer quenching, and quantum yield measurement undoubtly confirmed the proposed mechanism. Currently the manuscript is under preparation for publication.
(3) A photochemical enantioselective β-alkylation of enals using the strategy of radical umpolung was disclosed. This process was initiated by the photooxidation of supersilane and then halogen abstraction by the in situ generated silyl radical. After that, the active alkyl radical would be trapped by ground state iminium ion, followed by hydrogen atom transfer from supersilane to closed the catalytic cycle, which is a typical radical chain mechanism. On the other hand, a radical coupling of the 5π β-enaminyl radical intermediate and the active alkyl radical is also possible. Currently this reaction works well with BnBr to afford the target product in moderate yield and excellent enantioselectivity. We are still working on the optimization of such reaction to obtain improved results.
This project has and will create new career possibilities by providing the fellow with expertise in asymmetric photochemistry and drug discovery. He will have more opportunities in the academic and private sector due to the network of contacts and skillset that he has obtained during this project. This project has a particularly strong link to Knowledge and Technology Transfer (KTT), which is crucial for increasing the competitiveness of the European Economic Area (EEA).
The project enriched the fellow with competitive skills including knowledge on asymmetric photocatalysis, designing cascade reaction to structural dense molecules, mechanistic studies using photophysics methods, and so on, which undoubtedly expands his research area in future career. At the same time, the increasing ability of writing and communication with either researchers or funding-body will provide the fellow witth continuous scientific and financial support. The management and leadership obtained through this project will further help the fellow with his own group management. What’s more, the concept of combining fundamental synthetic research with drug discovery would be quite promising and useful. The almost two year’s experience in the frontier group would provide the fellow wiht an access to apply to national funding in China. He will start his own group in the near future and believes that all the skills and experience will help him enormously.