Promiscuity of sesquiterpene cyclases using cyclopropylidene farnesyl pyrophosphate Catherine Victoria 1 , Clara Oberhauser 2 , Vanessa Harms 2 , Andreas Kirschning 2 1 Leibniz Universität Hannover / Institut für Organische Chemie, Germany, 2 Institute of Organic Chemistry (OCI) and Centre of Biomolecular Drug Research (BMWZ) Terpenes are the largest class of natural products with more than 80,000 characterized compounds. This group of natural products derives from linear carbon skeletons that are transformed by terpene cyclases. These unique enzymes use elongated isoprenoid units based on an achiral C 5n pyrophosphate precursor that undergoes multiple changes in bonding, hybridization, and stereochemistry during the cyclization cascade. A new and appealing concept utilizes unnatural FPP derivatives, thus providing access to unnatural terpenes and terpene backbones and testing the promiscuity of terpene cyclases. To date, our group has focused on sesquiterpenes (C15 backbone) derived from farnesyl pyrophosphate. Eight sesquiterpene cyclases (BcBot2, PenA, Cop4, Cyc1, GcoA, Tps32, Tri5, Hvs1) were selected for the unique mode of cyclization they catalyze. Biotransformations of several synthesized unnatural C 15 pyrophosphates, including the introduction of heteroatoms, were performed, and the new terpenoid products were described and characterized in our previous work. 1 In the present study, we focus on a specific group of unnatural farnesyl derivatives containing a terminal cyclopropylidene unit. The new FPP derivatives were successfully synthesized 2 and biotransformation yielded unexpected new polycyclic products exhibiting a unique sesquiterpene backbone. References 1. (a) C. Oberhauser, V. Harms, Kirschning, et al ., Chem. Int. Ed. 2018 , 57 , 11802–11806; (b) V. Harms, B. Schröder, A. Kirschning, et. al. , Org. Lett . 2020 , 22 , 4360–4365.; (c) V. Harms, V. Ravkina, A. Kirschning, et al. , Org. Lett. 2021 , 23 , 3162–3166.; (d) V. Harms, A. Kirschning, J. Dickschat, Nat. Prod. Rep. 2020 , 37 , 1080-1097. 2. Cane, T. E. Bowser, Bioorg. Med. Chem. Lett. 1999 , 9 , 1127-1132.
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