Report

Teaser, summary, work performed and final results

Periodic Reporting for period 2 - TERPENECAT (Bridging the gap between supramolecular chemistry and current synthetic challenges: Developing artificial catalysts for the tail-to-head terpene cyclization)

Teaser

Many important drugs origin from natural sources. Essential drugs like the cancer medication taxol/paclitaxel or the malaria drug artemisinin were isolated from plants. In nature, such molecules are synthesized by a highly complex bio-machinery. Chemist are, in many cases, not...

Summary

Many important drugs origin from natural sources. Essential drugs like the cancer medication taxol/paclitaxel or the malaria drug artemisinin were isolated from plants. In nature, such molecules are synthesized by a highly complex bio-machinery. Chemist 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 resource-friendly production routes.

Work performed

Work on WP1.1 has completed. We identified the prerequisites for 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. The final publication of WP1.1 will be submitting soon.
In WP1.2, we synthesized several novel chiral building blocks which assemble to 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 capsule 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. This study was initiated and is currently ongoing. 3) Utilizing easily accessible chiral, cyclic terpenes as cyclization substrates. This study provided very recently first examples of optically active terpene cyclization products formed inside the capsule. These results also allowed us to start working on WP2 already.
In WP1.3, one of the two desired building blocks was synthesized already. Interestingly, it seems to assemble differently than anticipated. Work to elucidate its assembled structure and to understand its encapsulation behavior is ongoing.
WP 1.4: This WP was deprioritized due to results from WP1.1. It is not essential for work on WP2 anymore.

Final results

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 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 break through.
2) Based on our supramolecular catalysis approach, we developed a very short route (four-steps) to the presilphiperfolanol family of natural products was developed. This is much shorter than the available synthetic routes (13 steps or more). This will enable us to explore a wide range of unnatural derivatives of this biologically interesting class of sesquiterpene natural products.