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Fluorinated Heterocycles from Organosilanes: Novel synthetic approaches towards Fluorinated Lactones

Final Activity Report Summary - FLUHET (Fluorinated Heterocycles from Organosilanes: Novel Synthetic Approaches Towards Fluorinated Lactones)

The incorporation of fluorine into an organic molecule drastically perturbs its chemical, physical and biological properties. Naturally occurring organofluorine compounds are rare and the preparation of fluorine-substituted target molecules depends on modern synthetic chemistry. We are still lacking sufficient insight into fundamental aspects of fluorine chemistry and there is still a need for the development of novel technologies that allow for the introduction of fluorine into an organic compound.

The key synthetic advance emerging from our laboratories was the demonstration that organosilanes were extremely versatile precursors of a large number of fluorinated targets, such as fluoroalkenes, fluorodienes, propargylic fluorides, allylic fluorides as well as fluorinated carbo- and heterocycles. The first aim of this project was to study the use of organosilanes as starting materials for the preparation of fluorinated compounds. Indeed, we developed novel synthetic routes to fluorinated heterocyclic lactones from organosilanes using two complementary strategies. The first one was based on the iodocyclisation of allylic fluorides and the second one relied on the fluorine-induced cyclisation of allylsilanes.

The treatment of allylsilane A with an electrophilic source of fluorine, namely ‘Selectfluor’, afforded the allylic fluoride C when R was equal to Me. We then showed that this precursor could be submitted to an iodocyclisation reaction leading to the iodoether D. Theoritical calculations suggested that the fluorine acted as a very effective syn stereodirecting group. On the other hand, when R was different to Me, the carbocationic species formed upon fluorination could be trapped by the homoallylic alcohol function. The fluorinated tetrahydrofuran B was then isolated, the main isomer being the trans-product when the geometry of the double bond of the starting allylsilane was E.

We then focused our efforts on the cyclisation of beta-Hydroxy-alpha,alpha-Difluoro-Ynones E. We found out that, using gold catalysis, we were able to form the corresponding dihydropyranones G. In case Selectfluor was added to the reaction mixture the trifluorinated compounds H were isolated. This reaction constituted a cyclisation-fluorination cascade. On the other hand, we could redirect the reaction towards the formation of difluorinated dihydrofuranones F by using nucleophilic phosphine catalysis.

In conclusion, we developed novel routes to access fluorinated heterocycles. The new chemistry resulting from this research project could be used to prepare fluorinated carbohydrates as tools in enzyme mechanism studies, which is an area of research of particular relevance at this time.