Periodic Reporting for period 1 - ASYMFLU (Asymmetric Organocatalytic Fluorination with fluoride salts)
Reporting period: 2018-05-01 to 2020-04-30
Despite its almost complete absence in natural products and biological processes, fluorine is a key element in pharmaceuticals and agrochemicals, being present in as many as 35% of agrochemicals and 20–25% of marketed drugs. The introduction of fluorine into molecules has proven to strongly modify the properties of compounds such as lipophilicity, metabolic stability and bioavailability thus leading, among other benefits, to improved drug efficacy. Furthermore, 18F is the most frequently used radioisotope in PET (Positron Emission Tomography), a powerful imaging technique routinely used in hospitals around the world for tracking diseases at an early stage, support drug discovery and help designing personalized care. For these reasons, the scientific community has developed a wide array of transformations in order to introduce fluorine (including its 18F radionuclide) into organic molecules. Moreover, there is a growing demand for enantiopure drugs which are one of two mirror image molecules. In many cases,these have shown to be safer and more effective than their racemic counterparts (mixture of the two mirror images).
The constant rise of fluorine substitution in pharmaceutical drugs therefore requires the development of novel methodologies which employ safe, cost-efficient and readily available fluoride sources, thus avoiding the use of highly toxic and hard-to-handle hydrofluoric acid (HF). This research aimed at the use of one of the most cost effective class of fluorinating reagents, namely alkali metal fluorides, as sources of nucleophilic fluoride for asymmetric catalysis (thus biasing the introduction of fluorine towards only one of two mirror images). The project targets were met and a facile new access to β-fluoroamines, a privileged class of compounds contained in numerous therapeutics and bioactive compounds, was developed. The main challenge with the use of metal fluoride salts in synthesis was their insolubility in organic solvents. By designing a new catalyst capable of solubilizing a low cost fluoride source such as potassium fluoride while simultaneously controlling its reactivity, allowed for the first use of this reagent in asymmetric catalysis. The reaction has a simple set-up, is easily scalable and was successfully applied to the synthesis of numerous fluorinated drugs of well-known pharmaceuticals and bioactive compounds. This research opens new prospects to wider applications with other insoluble salts as reagents in organic synthesis as well as its translation to 18F radiochemistry to access new PET-tracers for imaging.
The constant rise of fluorine substitution in pharmaceutical drugs therefore requires the development of novel methodologies which employ safe, cost-efficient and readily available fluoride sources, thus avoiding the use of highly toxic and hard-to-handle hydrofluoric acid (HF). This research aimed at the use of one of the most cost effective class of fluorinating reagents, namely alkali metal fluorides, as sources of nucleophilic fluoride for asymmetric catalysis (thus biasing the introduction of fluorine towards only one of two mirror images). The project targets were met and a facile new access to β-fluoroamines, a privileged class of compounds contained in numerous therapeutics and bioactive compounds, was developed. The main challenge with the use of metal fluoride salts in synthesis was their insolubility in organic solvents. By designing a new catalyst capable of solubilizing a low cost fluoride source such as potassium fluoride while simultaneously controlling its reactivity, allowed for the first use of this reagent in asymmetric catalysis. The reaction has a simple set-up, is easily scalable and was successfully applied to the synthesis of numerous fluorinated drugs of well-known pharmaceuticals and bioactive compounds. This research opens new prospects to wider applications with other insoluble salts as reagents in organic synthesis as well as its translation to 18F radiochemistry to access new PET-tracers for imaging.
A novel mode of activation to solubilize and control the reactivity of alkali metal fluorides was developed. To achieve this, a new generation of hydrogen bond donors, namely N-alkylated bis-ureas were designed and synthesized. One of these catalyst is now commercially available (Sigma-Aldrich) and therefore available to the wider scientific community. We demonstrated for the first time that potassium fluoride, a safe, easy-to-handle and cost-effective fluoride source can be used for asymmetric catalysis. The main application has been in the synthesis of enantioenriched amines, which are common scaffolds found in numerous pharmaceuticals and natural products. This breakthrough opened the field to one of the cheapest source of fluorine, potassium fluoride and the extension of this methodology to other substrates is currently in progress. Apart from publication on peer-reviewed journals, oral presentations at international conferences (Euchems 2018, Liverpool; ICOS 2018, Florence;IKCOC 2018, Kyoto; ACS 2019, San Diego) and outreach events have allowed a broad dissemination of the results. More in general, this new generation of catalysts opens new opportunities for catalysis well beyond fluorination chemistry and into the use of many inorganic salts which have never been employed as nucleophiles in organic chemistry because of their insolubility in organic solvents.
The use of alkali metal fluorides for asymmetric catalysis represents an unprecedented breakthrough in the field and opens new prospects for fluorination chemistry thus moving away from toxic and difficult-to-handle HF. This can have a strong impact on industry and society in general as it can make fluorination processes safer and more cost-effective. In order to push the boundaries of this chemistry, experiments on the deca-gram scale were already performed and further scale-ups are currently ongoing. The final goal is to prove that the developed organocatalytic platform has the potential in the future to be broadly applicable in industry on the kg scale as well as translatable to radiochemistry with the synthesis of 18F-radiotracers.