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Driving asymmetric photoreactions by merging organo- and gold-catalysis

Periodic Reporting for period 1 - PHOTO ORGANO-GOLD (Driving asymmetric photoreactions by merging organo- and gold-catalysis)

Reporting period: 2016-05-06 to 2018-05-05

We are in a changing era for drug discovery:1 the growing perception is that basic, fundamental chemical research will play a greater role in pharmaceutical development. In this context, one current challenge is to develop a new kind of chemistry that yields a screening collection comprising optimal chiral molecules that increase the probability of success in identifying drug-candidate structures in a mild and efficient way,2 to promote the sustainability of the society. On the other hand, the chemistry community recognized how visible light-mediated photoreactions can open a new dimension for organic synthesis. The past decade have witnessed a remarkable prosperity in this area.3
In view of these, under the generous support of MSCA-IF (Project ID: 702405) from European Commission, Dr. Zhong-Yan Cao has conducted two-year postdoc research under the supervision of Prof. Dr. Paolo Melchiorre in the Institute of Chemical Research of Catalonia (ICIQ), attempting to challenge the above issue by developing conceptually new catalytic asymmetric photoreactions. Specifically, different from commonly used strategy for driving photoreactions with external photoredox catalysts4 to generate the reactive species, the photochemical activity of electron donor-acceptor (EDA) complexes provides an alternative way to generate radicals under mild conditions and without the need of external photoredox catalysts.5 Nevertheless, reported methods classically relied on the formation of intermolecular EDA complexes, generated upon aggregation of two suitable substrates/intermediate (see picture 1 for details). How to extend the strategy in an intramolecular way along with exploiting the synthetic application of the strategy was still elusive. As a proof-of-concept, the current project offers the first demonstration that photon-absorbing intramolecular EDA complex is potential for synthetic applications.

J. W. Scannell, A. Blanckley and B. Warrington, Nature Reviews Drug Discovery 2012, 11, 191.
2 T. E. Nielsen and S. L. Schreiber, Angew. Chem. Int. Ed. 2008, 47, 48.
3 C. K. Prier, D. A. Rankic and D. W. C. MacMillan, Chem. Rev. 2013, 113, 5322
4 M. H. Shaw, J. Twilton and D. W. C. MacMillan, J. Org. Chem. 2016, 81, 6898.
5 C. G. S. Lima, T. Lima, M. Duarte, I. D. Jurberg and M. W. Paixão, ACS Catal. 2016, 6, 1389.
In the past two years, Zhong-Yan had always involved in the use of intramolecular EDA complex to design new catalytic asymmetric methods for the preparation of biological active molecules preparation. After extensive studies, the researcher has finally identified that the crucial for success is inspired from the Melchiorre group’s previous finding1 that the bifunctional carbaozle amine catalyst can generate, upon condensation with enones, chiral iminium ions, which bears intramolecular EDA moiety and shows a broad absorption band in the visible region. Under the supervision of Prof. Dr. Melchiorre and generous support of ICIQ, the researcher demonstrates for the first time, that an intramolecular EDA complex can be used for designing useful asymmetric methodology.
The strategy allows the much easier assemble of biologically active chiral molecules, comparing with the reported methods (for details, please see picture 2). For instance, compound A has been patented due to the prevention of ophthalmic disease.2 However, as documented, starting from α-ketone ester, it needs seven steps to get the racemic A with only 1.2% total yield. In sharp contrast, with our methodology as the key step, the procedure can not only be shortened to 2 steps, but also give rise to the enantioenriched (R)-A in 57% total yield. On the other hand, product B can be easily prepared from commercial available 3,5,5-trimethylcyclohex-2-en-1-one, and the following highly diastereoselective reduction using L-selectride led to trans-alcohol C with 71% ee. Giving that the bioactivity of cis-C for the treatment and prevention of influenza,3 the prepared trans-C could be potentially helpful for the related biological activity test. These interesting results have been submitted to the peer-reviewed high impact chemistry journal and will be open access after publication.
1 J. J. Murphy, D. Bastida, S. Paria, M. Fagnoni and P. Melchiorre, Nature 2016, 532, 218.
2 T. Quach, J. Berman and D. S. Garvey, 2013, WO 2013/081642 A1.
3 L. Chen, X. Lin, Z. Qiu, G. Tang, L. Wang, J. Wu and W. Yang, 2011, WO 2011/095576 A1.
From the point view of academic research, the project demonstrated that an iminium-ion based intramolecular EDA complex can be used to trigger a photochemical asymmetric radical addition process, offering the first example of synthetic applications triggered by the photochemical activity of an intramolecular EDA complex. Practically, it provides new tools for the synthesis of complex molecular architectures. We believe this novel finding can potentially be expanded to a range of other reactions and the obtained chiral molecules might be helpful for further related biological test.

Acknowledgement: Dr. Zhong-Yan Cao sincerely thanks the supported from MSCA-IF (Project ID: 702405), ICIQ, as well as the selfless help from the whole Melchiorre group.