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Harnessing Non-Covalent Interactions for Control of Regioselectivity and Site-Selectivity in Catalysis

Periodic Reporting for period 2 - NonCovRegioSiteCat (Harnessing Non-Covalent Interactions for Control of Regioselectivity and Site-Selectivity in Catalysis)

Reporting period: 2019-07-01 to 2020-12-31

Nature has perfected the use of attractive non-covalent interactions for the control of selectivity in enzymatic catalysis. In relative terms, we synthetic chemists are just starting to get to grips with the potential that they offer for control in chemical catalysis, even though they have long been appreciated in the fields of biological and supramolecular chemistry. Specifically, the past fifteen years have seen remarkable advances in the use of attractive non-covalent interactions as key activating and controlling elements in enantioselective catalysis. These developments have demonstrated that non-covalent interactions orchestrated by small molecule catalysts can be tremendously powerful for inducing enantiocontrol. In this project, we argue that whilst control of enantioselectivity is very important, control of regioselectivity (defined here as positional selectivity within a particular functional group) and site-selectivity (within a wider molecule) are very important too and are under-served by methods. Both enantiomers are always accessible as a racemate by default, but obtaining a specific positional isomer may only be possible using external control, if the intrinsic reaction selectivity dictates otherwise. These selectivity aspects are particularly relevant due to the increasing number of methods for functionalisation of C-H bonds, in which the defining challenge in the field is now obtaining selectivity for one in the presence of many. The vision of this project is to take inspiration from the successful employment of attractive non-covalent interactions that have been gained from enantioselective organocatalysis and harness them for control of regioselectivity and site-selectivity in the context of both transition metal catalysis and, more challengingly, radical chemistry.

This is important for society because the development of new medicines to treat disease is central to quality of life and stable society. The methods that will be developed in the project have direct and unequivocal relevance to the synthesis of medicinally important compounds. It will make it much easier and quicker to synthesise drug-like scaffolds and thus enable more candidates to me made in a given timeframe and with complete control of selectivity. Thus, it has the genuine potential to expedite the drug discovery process. Faster and cheaper development of life-saving medications has an impact on society that it is difficult to understate.

The overall objectives of the project are as follows:
1. We will combine reactive and versatile transition metals with bespoke ligands which will interact with a common functional group in the substrate via a key non-covalent interaction. The resulting reaction of the substrate and catalyst will be rendered pseudointramolecular, permitting regioselectivity or site-selectivity to be controlled through judicious catalyst design.
2. We will develop novel catalytic strategies to control the selectivity of intermolecular radical reactions. We will intramolecularise radical reactions by the use of temporary non-covalent interactions to unite the substrate and incoming radical in order to solve outstanding problems in aromatic and aliphatic radical C-H functionalisation.
3. The methods developed above will be applied to the late-stage functionalisation of pharmaceutically relevant molecules as a demonstration of their utility in drug discovery.
Extensive investigations have been carried out in relation to WP1-A and have included several projects to control the regioselectivity of iridium-catalysed borylation using non-covalent interactions. This encompassed the use of ion-pairing interactions to direct borylation to the meta-position through catalyst-substrate ion pairing (published in the Journal of Organic Chemistry, 201, doi: 10.1021/acs.joc.9b009878). Also we have used ion-pairing interactions between the substrate and a bulky countercation to direct borylation to the distant and challenging para position (Journal of the American Chemical Society, 2019, doi: 10.1021/jacs.9b07267). Para-selective borylation is extremely difficult and we have successful developed a very general approach to this challenging problem. Since the outset of the project we have been carefully a strategy to attempt to use a combination of hydrogen bonding and ion-pairing interactions to direct C-H borylation in a manner which is both regioselective and enantioselective. After a lot of development we finally achieved our goal and the work was published earlier this year in the Science (doi: 10.1126/science.aba1120) the highest impact general science journal. In this strategy we are using a chiral cation in partnership with the anionic ligand previously developed to exercise control over both selectivity aspects.

We have also been carrying out extensive investigations into WP1-C, controlling site-selectivity in palladium catalysed reactions. The first results of this were published in late 2018 (Journal of the American Chemical Society, 2018, 140, 13570) and achieved the difficult challenge of site-selectivity between two identical carbon-halogen bonds at remote positions on an arene, for a range of common cross-coupling reactions, which are reactions very commonly used in the synthesis of pharmaceuticals. We have since been building on this discovery and shown that the same mode of control, using electostatic interactions, can also be used together with C-H activation methodology and this work was published earlier this year (Chemical Science, 2020, doi: 10.1039/D0SC00105H).

WP2-A, developing a regioselective Minisci reaction, has proved very fruitful. Due to the highly competitive nature of this area of research, work commenced on this idea whilst the grant was under review. Furthermore, the strategy that we had planned allowed us not only to achieve regioselectivity but also to use a chiral catalyst and achieve enantioselectivity. This constituted the first example of an enantioselective Minisci reaction and the proof-of-concept manuscript describing this was submitted for publication the month before the grant started, in December 2017. This was accepted and published in Science (Science 2018, 360, 419-422). Since the grant started we have been further developing these proof-of-concept results. We engaged in a collaboration with researchers in the USA (Sigman group, University of Utah) on an approach using statistical analysis to develop a predictive model for our regioselective and enantioselective Minisci reaction. This was a very successful collaboration and the results were published last year (Journal of the American Chemical Society, 2019, doi: 10.1021/jacs.9b11658). We have also engaged in a collaboration with colleagues at Cambridge (Jonathan Goodman, Kristaps Ermanis) to probe the mechanism of this reaction both experimentally and computationally. This work is not complete and we are preparing for submission.

Work has commenced on WP2-B and the students involved carried out extensive ground work to try to establish a viable catalytic system with which to control positional selectivity in the proposed radical chemistry. This has been very challening but an alternative approach to that originally envisaged has led us to fruitful results, taking into account results obtained in WP1-A. This work is envisaged to be ready for publication by early 2021.
As detailed in the summary above, the work that has been output so far has elevated the work of the project beyond the state of the art.
For both WP1-A and WP1-C, key outcomes have already been published in papers in Science, The Journal of the American Chemical Society and Chemical Science.
For WP2-A, although the proof-of-concept paper was submitted before the project commenced, this was published in Science, highest impact general science journal, demonstrating the high level of visibility of the work going on in this part of the project. This work has been followed up by another study published in The Journal of the American Chemical Society and there are several more papers in the pipeline.
The publications of the scientific outcomes in such high impact and visible journals is indicative of the progress beyond the state of the art that the project is undertaking.
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