Bridging the gap between supramolecular chemistry and current synthetic challenges: Developing artificial catalysts for the tail-to-head terpene cyclization

Project Information

TERPENECAT

Grant agreement ID: 714620

DOI

10.3030/714620

Project closed

EC signature date 30 October 2016

Start date 1 November 2016

End date 31 October 2021

Funded under

• EXCELLENT SCIENCE - European Research Council (ERC)

Total cost

€ 1 500 000,00

EU contribution

€ 1 500 000,00

Coordinated by

UNIVERSITAT BASEL
Switzerland

Periodic Reporting for period 4 - TERPENECAT (Bridging the gap between supramolecular chemistry and current synthetic challenges: Developing artificial catalysts for the tail-to-head terpene cyclization)

Reporting period: 2021-05-01 to 2021-10-31

Summary of the context and overall objectives of the project

Many important drugs originate from natural sources. Essential drugs like the cancer medication taxol/paclitaxel or the malaria drug artemisinin were isolated from plants and belong to the natural product family termed terpenes. In nature, such molecules are synthesized by a highly complex bio-machinery. Chemists are, in many cases, not able to mimic this complex machinery in the laboratory. Therefore, the production of such drug molecules is a difficult and resource-intensive endeavor.

The main objective of the project is to learn how to synthesize terpenes, a very important class of natural products, much more efficiently in the laboratory. To do so, we try to mimic the complex bio-machinery with much simpler catalysts in the laboratory. This may lead to the discovery of new drugs and more sustainable production routes.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

Work on WP1.1 has been completed. We identified the prerequisites for the catalytic activity of resorcinarene-like catalysts. Water that is part of the supramolecular assembly plays a crucial role in transporting the proton from the solvent onto the encapsulated substrate.
In WP1.2 we synthesized several novel chiral building blocks which assemble into hexameric capsules. Since the separation of the enantiomers proved to be a technical challenge, we explored alternatives. 1) Installation of chiral information at the feet of the resorcinarene. Three optically active capsules were synthesized. Unfortunately, they did not provide optically active cyclization products. However, this study led to the discovery of an interesting effect on the enantioselective iminium catalysis inside the capsule. 2) Attaching chiral information on the leaving group of the terpene substrate. 3) Utilizing easily accessible chiral, cyclic terpenes as cyclization substrates. This study provided very recently the first examples of optically active terpene cyclization products formed inside the capsule. These results also allowed us to start working on WP2 already. Recently, a breakthrough was achieved. We were able to achieve the first enantioselective THT cyclization inside a supramolecular capsule, achieving the main goal of WP1.2.
In WP1.3 a novel building block was synthesized successfully. It assembles to a very large cage-like structure that was investigated closely. However, its properties were not suitable for terpene cyclizations.
WP 1.4: This WP was deprioritized due to results from WP1.1 as it would lead to catalytically inactive capsules. It is not essential for work on WP2.
In WP2 we succeeded in expanding the natural variety of terpenes to access unprecedented derivatives.

In this project, we succeeded in producing complex terpene natural products much more efficiently than any other alternative means available. Even more interestingly, we successfully expanded the natural variety of terpenes to access unprecedented derivatives. One main application of the methodology developed is already published; a four-step synthesis of novel derivatives of the complex sesquiterpene natural product presilphiperfolan-1β-ol, enabled by our supramolecular capsule cyclization methodology. We are currently applying this methodology to further natural products and also potential fragrance compounds.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

In my opinion, the following results are the most important ones and expand the current state-of-the-art:
1) We identified the prerequisites for the catalytic activity of resorcinarene-like catalysts. Since it is the only supramolecular catalyst currently available for tail-to-head terpene cyclization, this was a very important breakthrough.
2) Based on our supramolecular catalysis approach, we developed a very short route (four steps) to the presilphiperfolanol family of natural products. This is much shorter than the available synthetic routes (13+ steps). This will enable us to explore a wide range of unnatural derivatives of this biologically interesting class of sesquiterpene natural products.

tiefenbacher-coverart-02.jpg