Hydrogen Bonding Phase Transfer Catalysis

Project Information

HBPTC

Grant agreement ID: 832994

DOI

10.3030/832994

Project closed

EC signature date 23 April 2019

Start date 1 July 2019

End date 31 December 2024

Funded under

• EXCELLENT SCIENCE - European Research Council (ERC)

Total cost

€ 2 499 070,00

EU contribution

€ 2 499 070,00

Coordinated by

THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD
United Kingdom

Periodic Reporting for period 4 - HBPTC (Hydrogen Bonding Phase Transfer Catalysis)

Reporting period: 2024-01-01 to 2024-12-31

Summary of the context and overall objectives of the project

Catalysis is highly important to all areas of modern life. It is estimated that 90% of all chemical process are catalysed, and the economic impact of catalysis is contributing 30–40% of global GDP. Today, the need for new technologies to address the change in use of raw materials and societal requirements has prompted chemists to re-evaluate how we approach chemical and refinery production, with a need for new catalysis approaches. High on the list is the need for new catalysis concepts and catalytic asymmetric reactions, novel or improved catalysts, and a better understanding of mechanisms applying structural, kinetic and computational studies. In this context, phase transfer catalysis (PTC) has proved advantageous. An outstanding challenge is the application of asymmetric catalysis to feedstock reagents as simple as inorganic salts that are not soluble in organic solvents, for example nucleophilic halogenation reagents such cost-effective KF.

The objective of this proposal was to provide solutions to this problem with a focus on fluorination with alkali metal fluoride and bio-inspired new concepts in catalysis, specifically Hydrogen Bonding Phase Transfer Catalysis (HBPTC). This was successfully achieved during the course of the proposal. Key accomplishments are the invention of new asymmetric catalytic processes for the fluorination of episulfonium, aziridinium, azetidinium, benzylic halide and alpha-halo carbonyls with KF in the presence of a chiral (bis)-urea catalyst or via synergistic dual catalysis. This new catalytic manifold was also extended to regiodivergent fluorination as well as inorganic nucleophiles other than alkali metal fluoride (e.g. sodium azide).

Rewardingly, our interest in enantioselective catalysis with alkali metal fluoride extended to the holygrail problem of fluorination with calcium fluoride. Exciting results were secured during the course of the project opening new opportunities for the manufacturing of fluorochemicals directly from acid grade fluorspar without the necessity to produce dangerous HF.

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

Conceptually, we propose that a chiral hydrogen bond donor (HBD) catalyst can transport an insoluble anionic nucleophile reagent as simple as an inorganic salt from the solid phase into solution, a process that generates a soluble reactive chiral hydrogen bonded anion nucleophile (Nu) complex now capable of enantioselective C-Nu bond formation with concomitant release of the chiral HBD catalyst. This strategy is different from known PTC strategies that require a cationic, anionic or crown ether phase transfer catalyst. To date, we have demonstrated that this novel catalytic manifold that we have coined “Hydrogen Bonding Phase Transfer Catalysis” (HB-PTC) enabled unpredented asymmetric catalytic C-F bond formation reactions using CsF or KF. We successfully desymmetrized a range of substituted aziridinium and azetidinium salts to access enantiopure beta- and gammma-fluorinated amines that are of high relevance for the pharmaceutical sector. We then dedicated extensive research to acquire mechanistic insight into the HB-PTC catalytic manifold by relying on in-depth NMR spectroscopy and X-ray crystallography. This study was key in providing valuable information on the contribution of individual hydrogen bond contacts on catalyst efficiency and thus inform and guide catalyst optimization. We also developed a detailed procedure to prepare and scale-up the synthesis of our most successful organocatalysts (now commercially available) up to the decagram scale. These were subsequently applied to the desymmetrization of 200g of β-haloamine to access β-fluoroamine in high yields and enantioselectivity. Further development including synergistic HB-PTC for the fluorination of less reactive electrophiles, extension to radiolabelling, and application to nucleophiles other than alkali metal fluorides.

This proposal inspired work aimed at preparing fluorochemicals directly from calcium fluoride (acid grade fluorspar) with a method bypassing the necessity to produce hydrogen fluoride. This accomplishment led to the creation of FluoRok, a spin-out from the University of Oxford.

The results of these studies were disclosed in high visibility journals including Science, J. Am. Chem. Soc., Nature Protocols and Nature Rev. Methods Primers, and were presented to numerous international conferences (including general public lectures) and to various Universities and industries.

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)

Asymmetric catalytic transformations using cost effective, safe and readily available inorganic nucleophiles is a challenge for which only very few solutions are available. This project has elevated this field of research with fundamentally new principles that have enhanced our understanding of fluoride chemistry, and the power of organocatalysis and phase transfer catalysis. We anticipate that, upon completion, this project will provide clear guidelines to chemists accross academia and industry for this novel chemistry to bring solutions to the challenges associated with the preparation of complicated chiral non racemic fluorinated molecules for various applications including drug discovery. We also project that HB-PTC will enable the asymmetric construction of carbon-heteroatom bonds other than carbon-fluorine.

Asymmetric Catalysis with Metal alkali Fluoride