Our interest is mainly focused on exploring the potential of supramolecular host structures for catalysis. We have focused on molecular capsules as hosts so far, but we have started expanding to other structures recently.
The main goal is not only to perform chemistry in these host structures, but to find solutions for current challenges in synthetic organic chemistry that are difficult to address with traditional tools.
Terpenes constitute the largest and most diverse class of natural products with several tens of thousands of different members. Important current drugs like taxol/paclitaxel (cancer treatment) or artemisinin (anti-malaria) have emerged from terpene natural products. Interestingly, the variety of terpene products in nature is formed from only a handful of relatively simple acyclic precursors: geranyl-pyrophosphate (PP) for monoterpenes (10 C-atoms), farnesyl-PP for sesquiterpenes (15 C-atoms) and geranylgeranyl-PP in case of diterpenes (20 C-atoms). These simple precursors are cyclized via complex cationic reaction cascades, termed tail-to-head terpene (THT) cyclizations, into the whole variety of terpene carbon structures. As an example the biosynthesis of taxol is shown here:
Such THT cyclizations are considered to be among the most complex chemical reactions occurring in nature. Most of the atoms of the acyclic terpene precursor change their hybridization or bonding during the cationic cyclization cascade. Nature has evolved enzymes termed terpene cylcases or synthases for this task. Man-made catalysts for the THT cyclization are lacking. Learning how to design such complex catalysts will not only enable us to mimic natural enzymes, but to enter uncharted territory of terpene chemistry. To influence the conformation of the flexible acyclic terpenes and to stabilize cationic transition states, enzymes surround the substrate more or less completely. Mimicking such a catalytically active pocket with artificial, non-peptidic catalysts represents a major challenge.
- Recently, we achieved a four step synthesis of the sesquiterpene natural product presilphiperfolan-1b-ol in only four steps, with the key cyclization (see below) taking place inside the supramolecular capsule cataylst. This natural product was previously only available via a long synthetic sequence (13 linear steps).
J. Am. Chem. Soc. 2020, 142, 5894.
- More examples of sesquiterpene cyclizations:
Nat. Catal. 2018, 1, 609.
- For background information, see our review article:
Nat. Prod. Rep. 2019, 36, 1619.
- For more examples, see publications.
As depicted in the Scheme above, after successful terpene cyclization, functionalization of the terpene framework depends to a large extent on C-H oxidations. Currently, one main challenge in the field of C-H oxidation is directing the oxidation to unactivated/deactivated positions.
- Recently, we were able to override the intrinsic reactivity for C-H oxidation in alkyl ammonium substrates utilizing a supramolecular tweezer catalyst; favoring oxidation at the deactivated positions C3/C4.
Angew. Chem. Int. Ed. 2020, 59, 12387.
Examples of further reactions catalyzed inside a molecular capsule
- Activation of benzylic and tertiary alkyl (sp3)C-F bonds
Front. Chem. 2019, 6, 639.
- Carbonyl-Olefin Metathesis
Angew. Chem. Int. Ed. 2018, 57, 14589.