Chemical Science Symposium 2022

Enabling asymmetric synthesis: in flow enzymatic kinetic resolution of bicyclic-aziridines Milene Fortunato, João R. Vale, Filipa Siopa, Carlos A. M. Afonso University of Lisbon, Portugal The demand for enantiomerically pure compounds in the pharmaceutical industry increases the complexity of the synthetic routes. Among the methodologies to obtain enantiopure compounds, lipase mediated kinetic resolution offers a green process, with a well-established route, distinct advantages of high activity, selectivity, and mild operating conditions. [1] α-hydroxycyclopenteno-aziridines (bicyclic-aziridines) are an intermediary to achieve molecules with biological properties such as functionalized aminocyclopentitols ( e.g., peramivir, ticagrelor, neplanocin A and trehazolin).[2] The bicyclic-aziridines are obtained in a racemic mixture through a photochemical transformation of pyridinium salts, for which we developed a flow reactor for gram-scale preparation. [3] These bicyclic-aziridines have a free secondary alcohol in their structure, allowing for an enzymatic kinetic resolution, which could be achieved by using Novozym 435, an immobilized lipase, CAL B. The obtention of enantiopure bicyclic-aziridines unlocks synthetic routes to complex chiral structures. We herein disclose the enzymatic kinetic resolution of two bicyclic-aziridines: allyl bicyclic-aziridine and butyl bicyclic-aziridine, from early batch studies to flow (Figure 1 (B,D) and (C, E)). We successfully obtained with short residence times ( S )-allyl bicyclic-aziridine 98% enantiomeric excess ( ee ) and 46% isolated yield (Figure 1(C)), as well the obtention of ( R )-butyl bicyclic-aziridine acetate in 95% ee and 20% isolated yield (Figure 1(B)).

Figure 1. Obtention of enantiomeric pure bicyclic-aziridines: (A) Photochemical transformation of pyridinium salts in flow; Enzymatic kinetic resolution of (B) butyl-bicyclic -aziridine and (C) allyl-bicyclic -aziridine. Flow setup of enzymatic kinetic

resolution (D) and (E). Acknowledgements

The authors acknowledge Fundação para a Ciência e Tecnologia (FCT) for financial support (2021.06598.BD, PTDC/QUI-QOR/32008/2017, UIDB/04138/2020 and UIDP/04138/2020). The project leading to this application has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 951996. References 1. S. Seddigi, M.S. Malik, S.A. Ahmed, A.O. Babalghith, A. Kamal, Coord. Chem. Rev., 348 54 (2017). 2. U. Košak, M. Hrast, D. Knez, N. Maraš, M. Črnugelj, S. Gobec, Tetrahedron Lett. 56 529 (2015). 3. J. Zou, P.S. Mariano, Photobio. Sci. 7 393 (2008). 4. R. Ash, R. M. Barrer, C.G. Pope, Proc. R. Soc . London, Ser. A , 271 19 (1963) 5. L. Kaplan, J.W. Pavlik, K.E. Wilzbach, Am. Chem. Soc. 94 3283 (1972). 6. F. Siopa, J.P.M. António, C.A.M. Afonso , Org. Process Res. Dev. 22 551 (2018). c) M.A.G. Fortunato, C.-P. Ly, F Siopa, C.A.M. Afonso, Methods Protoc. 2 67 (2019).

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