FOOTLOOSE · Synthesis of sp3-Rich Organofluorine Compounds through Homologation of Boronic Esters
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2017-07-27 → 2019-07-26
- EU contribution
- €183,455
- Participants
- 1
- Scheme
- MSCA-IF-EF-ST
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Results in brief
Synthesis of sp3-Rich Organofluorine Compounds through Homologation of Boronic Esters
Fluorine containing organic compounds continues to find broad application in drug discovery, agrochemicals and materials science. Fluorine atom present in about half of the most successful drugs (blockbuster drugs). These organofluorine compounds take advantage of the unique properties imparted by the presence of one or more Carbon-Fluorine (C–F) bonds. The replacement of a Carbon-Hydrogen (C–H) or Carbon-Hydroxy (C–OH) with a C–F bond is one of the most rewarding modifications during the hit-to-lead stage in medicinal chemistry programs. The success is reflected in the rapidly increasing number of Food and Drug Administration (FDA) approved fluorine-containing drugs in recent years, with 17 out of 59 new cases in 2018 alone. Hence, the development of methods for transforming easily accessible functional groups into either a fluorine atom or a fluorine-containing group (e.g. CF3) is highly important for the betterment of future healthcare. Since many applications of these compounds are dependent on the absolute and relative configuration (three dimensional (3D) structure) of the fluorine-containing group, methods that can introduce such groups in a stereoselective (3D-selective) manner are particularly attractive. Although a range of methodologies have been applied to the stereoselective synthesis of organofluorine compounds, a notable omition is the stereospecific Lithiation-Borylation of boronic esters, a reaction which has enjoyed considerable success in making complex molecule. The main challenge in extending this method to fluorinated substrates is associated with the stability of the corresponding starting materials (fluorinatedorganolithiums) which is decomposing while it is being formed in the reaction. Unfortunately, it is difficult to render stereoselective method without addressing starting material stability issue. Our strategy is to find the system as well as suitable conditions to have increased stability of starting material.
Data: CORDIS, © European Union
Project objective
Organofluorine compounds are highly sought after owing to diverse and numerous applications that take advantage of the unique properties imparted by the presence of one or more C–F bonds. The chemical stability and conformational landscape of molecules, together with the small size of the fluorine atom, has the made the replacement of a C–H or C–OH bond with a C–F one of the most rewarding modifications during the hit-to-lead stage in medicinal chemistry programs. Because many applications are dependent on the absolute and relative configuration of the fluorine-containing group, methods that can introduce such groups in a stereoselective manner are particularly attractive. The host laboratory has shown that substituted carbon chains can be grown one carbon atom at a time with exquisite control of relative and absolute configuration through iterative homologation of boronic esters with stereochemically-defined lithiated carbamates or benzoates. The latter are formed at low temperature, either through sparteine-mediated enantioselective deprotonation of primary carbamates/benzoates or the enantiospecific deprotonation or tin–lithium exchange of enantiomerically pure secondary carbamates/ benzoates. Although the process works well for extending a carbon chain with incorporation of carbon-based substituents, the incorporation of carbon atoms bearing electronegative substituents, such as oxygen- or fluorine-containing groups, is challenging. Herein we propose a programme of research to investigate the preparation of enantiomerically enriched organofluorine molecules, specifically those containing trifluoromethyl groups, through lithiation–borylation. The challenges outline above would make such a programme the ideal sharpening stone for the further development of lithiation–borylation. Indeed, a protocol that can introduce carbon atoms bearing electronegative groups would bring us a big step closer to assembly-line synthesis being able to make any molecule.
Original text from CORDIS.
Participants
- UNIVERSITY OF BRISTOL · BRISTOLCoordinatorUnited Kingdom
Links
Data: CORDIS, © European Union