Synthesis of sp3-Rich Organofluorine Compounds through Homologation of Boronic Esters

Project Information

FOOTLOOSE

Grant agreement ID: 749862

DOI

10.3030/749862

Project closed

EC signature date 14 March 2017

Start date 27 July 2017

End date 26 July 2019

Funded under

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Total cost

€ 183 454,80

EU contribution

€ 183 454,80

Coordinated by

UNIVERSITY OF BRISTOL
United Kingdom

Periodic Reporting for period 1 - FOOTLOOSE (Synthesis of sp3-Rich Organofluorine Compounds through Homologation of Boronic Esters)

Reporting period: 2017-07-27 to 2019-07-26

Summary of the context and overall objectives of the project

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.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

We considered using trifluoromethyl oxirane (CF3-epoxide) as a starting material in lithiation-borylation reactions since it is stable at ultra-low temperature (-100 oC). In order to minimize the decomposition of lithiated trifluoromethyl oxirane, we decided to trap it with the boronic ester as it was being generated at low temperature. We began our studies by establishing conditions for lithiation-borylation of trifluoromethyl oxirane and boronic esters. After screening various conditions including temperature, time, solvent, catalyst, and activator, we have successfully developed optimized reaction conditions for the stereoselective synthesis of organofluorine compounds from the reaction of lithiated trifluoromethyl oxirane and boronic ester at low temperature (-78 oC). Lithiation-Borylation has been applied for the first time to the obtention of fluorinated boronic esters, by avoiding undesired decomposition by taking advantage of the stability of α-trifluoromethyl epoxides. We have applied this method to a wide variety of boronic ester starting materials containing various biologically relevant functional groups. To demonstrate the potential of the prepared fluorinated boronic ester further, we have transformed this into novel fluorinated quaternary carbon centre bearing biologically important functionals.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

The new method we have developed for the preparation of fluorinated compounds have high impact in medicinal chemistry and material chemistry. The chemistry discovered during this project has opened new significant chemical space. The discoveries are expected to significantly impact the chemical and the pharmaceutical industry introducing new avenues to the synthesis of previously inaccessible compounds. And the fluorinated organic molecules prepared in this project has the potential for further pharmaceutical reagent development. The chemistry detailed has tremendously impacted academia, triggering growing interest about the topics discovered.

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