New Applications of Thiophene S,S-Dioxides in Synthetic Methodology and Natural Product Synthesis.

The synthesis of natural products is one of the most intensely researched areas of organic chemistry. This is because many natural products exhibit biological activity that could be of importance for human medicine.

Strategies that can assemble the core skeletons of natural products with high efficiency are very appealing, as they enable syntheses to be achieved in a relatively low number of synthetic transformations.

One recent example from the host group involves the use of thiophene dioxides (TDOs), which can undergo cycloaddition cascades to form a range of polycyclic natural product architectures, as recently demonstrated in the synthesis of the illudalane family of natural products.

The key driving force of these reactions is the extrusion of a molecule of SO2, which renders the cycloaddition irreversible.

Additional work on the use of TDOs in cycloadditions with indoles has enabled concise syntheses of various alkaloid natural products, thus providing a strong research foundation for synthesizing natural products using TDO chemistry.

Building on this precedent in the host group, this project first focuses on the reactivity of benzofurans in intermolecular cycloadditions with TDOs.

This requires electron-withdrawing functionalization of the TDO, which promotes the cycloaddition reaction with the electron-rich benzofuran.

However, it remains unclear how this TDO functionalization may influence the regioselectivity in reactions with different benzofurans.

The first aim of this project is to explore the limits of TDO reactivity, and to expand the scope of benzofuran reactants to further investigate regioselectivity aspects in their cycloadditions with TDOs.

The second aim of this project is to explore the application of TDO chemistry in synthesizing other natural products, such as scabrolide A, a terpenoid which exhibits anti-inflammatory activity. Previous synthetic routes to scabrolide A may be improved by applying a new TDO chemistry pathway.

Scabrolide A has a polycyclic, highly oxygenated core, which could potentially be constructed via TDO cycloaddition, including asymmetric assembly of the terpenoid's tricyclic motif.

The synthesis of the target terpene will be completed through an annulation strategy, or use of a more complex TDO synthesis, which contains the remaining part of the molecule.

Alongside this synthesis-oriented work, the project will also explore the more general reactivity of TDOs with strained alkenes, further developing the synthetic potential of these interesting heterocycles. This project falls within the EPSRC Synthetic Organic Chemistry research area.

The research described above is focusing on developing novel synthetic methodologies based on the new reactivity found in TDO chemistry.