Photocatalyzed Radical Deoxyfluorination of Activated Diols
The incorporation of a fluorine atom into a therapeutic lead is commonly used in medicinal chemistry to modulate its properties. As a result, 20-30% of drugs contain at least one fluorine atom. The development of effective methods allowing the synthesis of complex fluorinated molecules remains highly desirable in Organic Chemistry. In this context, an innovative radical deoxyfluorination reaction of activated diols in the form of Benzylidene Acetals (BAs) has been envisaged. Formally, this reaction substitutes one of the two C(sp3)-O bonds of the substrate with a C(sp3)-F bond. Its proof of concept was established using photocatalyzed conditions. Building on the consortium's expertise, the first objective of the project is to explore the synthetic potential of this new reaction. Thus, the reaction conditions will be optimized and the scope of the transformation will be investigated. Experimental and theoretical mechanistic studies will also be carried out to gain a better understanding of the radical fluorination processes. As BAs are widely used in sugar chemistry as a protective group for 1,n-diol units (n = 2, 3), the second objective envisaged by the consortium is to exploit the aforementioned fluorination method to prepare Fluorinated Glycosyl Donors (FGDs), analogues of Rare Sugars (RSs) featuring a tertiary alcohol at the position 3 of the pyranose ring. Although these RSs are present in many glycosylated natural products, where they are essential for biological activities, neither the synthesis nor the glycosylation of the targeted FGDs have been reported to date. The reactivity of FGDs in glycosylation reactions will next be studied. The synthesis of a disaccharide incorporating a 3-fluoro substituted RS will be carried out in order to assess the impact of a fluorine atom on the stability of the glycosidic bond. This study should provide the first insights on the utility of FGDs in glycochemistry.
3/6 complete
Imported from OpenAIRE Italy | Grant ANR-25-CE07-4944.
Open sourceOverview
Grant agreement ANR-25-CE07-4944 | F-PhoRDiol
Open sourceThe incorporation of a fluorine atom into a therapeutic lead is commonly used in medicinal chemistry to modulate its properties. As a result, 20-30% of drugs contain at least one fluorine atom. The development of effective methods allowing the synthesis of complex fluorinated molecules remains highly desirable in Organic Chemistry. In this context, an innovative radical deoxyfluorination reaction of activated diols in the form of Benzylidene Acetals (BAs) has been envisaged. Formally, this reaction substitutes one of the two C(sp3)-O bonds of the substrate with a C(sp3)-F bond. Its proof of concept was established using photocatalyzed conditions. Building on the consortium's expertise, the first objective of the project is to explore the synthetic potential of this new reaction. Thus, the reaction conditions will be optimized and the scope of the transformation will be investigated. Experimental and theoretical mechanistic studies will also be carried out to gain a better understanding of the radical fluorination processes. As BAs are widely used in sugar chemistry as a protective group for 1,n-diol units (n = 2, 3), the second objective envisaged by the consortium is to exploit the aforementioned fluorination method to prepare Fluorinated Glycosyl Donors (FGDs), analogues of Rare Sugars (RSs) featuring a tertiary alcohol at the position 3 of the pyranose ring. Although these RSs are present in many glycosylated natural products, where they are essential for biological activities, neither the synthesis nor the glycosylation of the targeted FGDs have been reported to date. The reactivity of FGDs in glycosylation reactions will next be studied. The synthesis of a disaccharide incorporating a 3-fluoro substituted RS will be carried out in order to assess the impact of a fluorine atom on the stability of the glycosidic bond. This study should provide the first insights on the utility of FGDs in glycochemistry.