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From Simplicity to Complexity: Crafting Molecular Architectures via Cascade Polyene Cyclizations

Project description

Unlocking access to novel bioactive molecules

Synthetic chemists are like kids playing with building blocks, pulling off entities and adding others to form all sorts of architectures of interest. The game can get frustrating when certain pieces do not link properly to form a stable structure for a variety of reasons, blocking a chemist's access to novel molecules that could be. The EU-funded CRAFTMOL project plans to significantly expand the capabilities of one of the most important reactions used to build complex and diverse cyclical molecules from acyclical ones. Supported by computational methods, the team is targeting modifications of natural molecules for the construction of bioactive natural products.


Polyene cyclizations belong to the most powerful and fascinating chemical transformations to rapidly assemble molecular architectures. However, the very limited substitution pattern of known substrates and nature’s inability to accommodate heteroatoms or substituents other than methyl restrict molecular diversity, complexity and functionality. CRAFTMOL addresses these limitations by investigating a set of novel heteroatom-substituted and tri/tetrasubstituted polyenes. The participation of these structural units in the cyclization will unlock previously inaccessible reaction pathways and enable efficient, selective and practicable routes to anticancer, anti-inflammatory and antiviral molecules. We will first investigate substrates containing trisubstituted double bonds and explore their behavior in cyclizations involving a transannular/cross-termination step. Realization of this concept will provide a highly modular synthetic platform for the rapid construction of more than 15 bioactive natural products. For the second part, we will explore tetrasubstituted double bonds to realize first-time synthesis of a structurally diverse family of natural products with unique biological activities. We will accomplish these goals by taking advantage of our expertise in total synthesis of complex natural products and modern chemical methodology. The experiments will be guided by computational methods and supported by our high-pressure platform. CRAFTMOL is ground-breaking as it 1) unveils innovative reaction pathways, 2) provides efficient synthetic access to structurally diverse molecular architectures, 3) enables deep-seated structural modifications of natural molecules that are currently inaccessible via fermentation or semi-synthesis. CRAFTMOL will lead to a better understanding of polyene cyclizations, will inspire scientists to develop novel methods for the construction of highly valuable molecules and will therefore advance the entire field of chemical synthesis.



Net EU contribution
€ 1 998 767,00
Innrain 52
6020 Innsbruck

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Westösterreich Tirol Innsbruck
Activity type
Higher or Secondary Education Establishments
Other funding
€ 0,00

Beneficiaries (1)