Avondlezing door prof.dr. Jan van Maarseveen georganiseerd door de Groningse Chemische Kring.
Tying molecular ropes: synthetic methodology development towards the natural lasso peptides
Lasso peptides share an N-terminal macrolactam of 7/9 residues through which the linear exocyclic C-terminal part is threaded and mechanically locked.1 It has been thoroughly studied that the intriguing lasso-fold that is present in the majority of natural lasso-peptides possesses an exceptional proteolytic and conformational stability. Their fascinating topology, high compactness, stability, and biological activities make them ultimate targets for synthetic methodology development. Although several groups embarked on this subject, the fact that almost twenty years after their structure elucidation no general synthesis has been published yet underscores their complexity.2 In other words, the 2016 Nobel prize-winning methodologies toward rotaxanes/catenanes that are mainly based on supramolecular mutual positioning of the ring-thread fragments, fall short. I will present to you our recently developed template-based clipping3 and backfolding4 concepts and a combination of both5 that should allow future synthetic access to mechanically interlocked peptides.
1) Si, Y., Kretsch, A. M., Daigh, L. M., Burk, M. J. & Mitchell, D. A. J. Am. Chem. Soc. 2021, 143, 5917–5927.
2) Van Maarseveen, J. H. Nat. Chem. 2021, https://doi.org/10.1038/s41557-021-00771-6.
3) a) Steemers, L.; Wanner, M.J.; Ehlers, A.W.; Hiemstra, H; Van Maarseveen, J.H. A short covalent synthesis of an all-carbon ring rotaxane. Org. Lett. 2017, 19, 2342-2345. b) Cornelissen, M. D.; Pilon, S.; Steemers, L.; Wanner, M. J.; Frölke, S.; Zuidinga, E.;Jørgensen, S. I.; van der Vlugt, J. I.; van Maarseveen, J. H. J. Org. Chem. 2020, 85, 3146.
4) a) Steemers, L.; Wanner, M.J.; Lutz, M.; Hiemstra, H; Van Maarseveen, J.H. Synthesis of spiro quasicatenanes and quasirotaxanes via a templated backfolding strategy. Nat. Communications, 2017, 8, 15392. b) Pilon, S.; Jørgensen, S. I.; van Maarseveen, J. H. Chem. Eur. J. 2021, 27, 2310.
5) Pilon, S.; Jørgensen, S. I.; van Maarseveen, J. H. ACS Org. Inorg. Au 2021, 1, 37-42.
Verkorte loopbaanbeschrijving van Prof. Dr. Jan H. van Maarseveen
Jan van Maarseveen obtained obtained his Ph.D. in 1994 at the University of Nijmegen on the total synthesis of indole alkaloids. From 1994-1999 he joined Solvay-Pharmaceuticals as a farmacochemist. In november 1999 he moved back to academia and was promoted in 2015 to full professor. His research focusses on the development of methodology to enable the synthesis of small and strained cyclic peptides together with the development of enantioselective catalytic methods with applications in alkaloid synthesis. Currently, the group is fully dedicated to covalent scaffold-based methodology development towards mechanically interlocked molecules. Jan obtained several prices of which the “Teacher of the year of the University of Amsterdam in 2012” award is the most prestiguous one. In 2016 he was awarded the KNCV Van Marum Medal for his contributions to chemistry outreach and excellence in teaching. His second passion is flying, in summertime in gliders and in wintertime powered gliders.
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