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Flow Photochemical Synthesis of the Functionalized Potentially Bioactive Benzobicyclo[3.2.1]octadiene Skeleton

Compounds with the bicyclo[3.2.l]-skeleton have been proven as potent inhibitors of dopamine and serotonin transporters and they also play a crucial role in treatment of CNS and Alzheimer’s diseases [1]. By utilizing photochemical synthesis a whole library of new polycyclic compounds with the benzobicyclo[3.2.1]octadiene moiety was obtained [2]. For the first time, flow photochemistry was applied as an even more powerful tool [3] for the synthesis of the cycloadducts 1-5 bearing this crucial bicyclo[3.2.l]-core. In comparison to the batch reaction, the flow reaction showed better results, both increasing the isolated yields and productivity and in lowering the reaction time. For all of the obtained novel potentially bioactive derivatives preliminary physico- chemical properties were also analyzed and the measurements of cholinesterases inhibitory activity (enzymes important at different stages of Alzheimer’s disease). Among them compound 3 showed the best acetylcholinesterase and butyrylcholinesterase inhibitory activity [4]. [1] a) G. A. Kraus, Y. S. Hon, J. Sy, J. Org. Chem. 1986, 51, 2625-2627. ; b) J. A. Miller, J. Harris, A. A. Miller, G. M. Ullaha, G. M. Welsh, Tetrahedron Letters 2004, 45, 4323-4327. ; c) M. Presset, Y. Coquerel, J. Rodriguez, Chem. Rev. 2013, 113, 525-595. [2] a) I. Šagud, M. Levačić, Ž. Marinić, I. Škorić, Eur. J. Org. Chem. 2017, 3787–3794. ; b) I. Škorić, M. Šmehil, Ž. Marinić, K. Molčanov, B. Kojić-Prodić, M. Šindler-Kulyk, J. Photochem. Photobiol. A, 2009, 207, 190–196. ; c) M. Šindler-Kulyk, L. Špoljarić, Ž. Marinić, Heterocycles 1989, 29, 679–682. [3] a) D. K. B. Mohamed, X. Yu, J. Li, J. Wu, Tetrahedron Letters 2016, 57, 3965-3977. ; b) E. N. DeLaney, D. S. Lee, L. D. Elliott, J. Jin, K. I. Booker-Milburn, M. Poliakoff, M. W. George, Green Chem. 2017, 19, 1431–1438. ; c) F. Lēvesque, P. H. Seeberger, Org. Lett. 2011, 13, 5008–5011. [4] I. Generalić Mekinić, F. Burčul, I. Blažević, D.Skroza, D. Kerum, V. Katalinić, Nat. Prod. Commun. 2013, 8, 471-474.

flow photochemistry, potentially bioactive photoproducts, benzobicyclo[3.2.1]octadiene skeleton

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