Periodic Reporting for period 4 - NonCovRegioSiteCat (Harnessing Non-Covalent Interactions for Control of Regioselectivity and Site-Selectivity in Catalysis)
Reporting period: 2022-07-01 to 2023-09-30
Nature has perfected the use of attractive non-covalent interactions for the control of selectivity in enzymatic catalysis. Recent 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. We believe that control of regioselectivity and site-selectivity are very important too and are under-served. 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.
This is important for society because the development of new medicines is central to quality of life. The methods that will be developed in the project have direct relevance to the synthesis of medicinally important compounds, making it easier and quicker to synthesise drug-like scaffolds and enable more candidates to me made in a given timeframe.
Key objectives:
1. To 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. In the resulting reaction regioselectivity (and potentially also enantioselectivity) may be controlled through judicious catalyst design.
2. To 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.
We have successfully achieved a number of the ambitious goals that we laid out, in the context of challenging and topical transformations. The concepts and strategies that we have explored and developed have led to exciting new avenues for selectivity control that have really opened up new research lines . This is true for diverse areas of chemical reactivity, encompassing both transition metal catalysis and radical chemistry. This work has established our group as one of the leading groups in applying attractive non-covalent interactions to address selectivity challenges in modern catalysis and methodology.
This is important for society because the development of new medicines is central to quality of life. The methods that will be developed in the project have direct relevance to the synthesis of medicinally important compounds, making it easier and quicker to synthesise drug-like scaffolds and enable more candidates to me made in a given timeframe.
Key objectives:
1. To 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. In the resulting reaction regioselectivity (and potentially also enantioselectivity) may be controlled through judicious catalyst design.
2. To 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.
We have successfully achieved a number of the ambitious goals that we laid out, in the context of challenging and topical transformations. The concepts and strategies that we have explored and developed have led to exciting new avenues for selectivity control that have really opened up new research lines . This is true for diverse areas of chemical reactivity, encompassing both transition metal catalysis and radical chemistry. This work has established our group as one of the leading groups in applying attractive non-covalent interactions to address selectivity challenges in modern catalysis and methodology.
Now that the grant has finished, for this final summary the work performed will be broken into the two major halves of the original proposal - 1) Transition metal catalysis and 2) Radical reactions.
1 Transition metals - This built on our foundational results relating to ir-catalysed borylation. We used ion-pairing interactions between substrate and a bulky countercation to direct borylation to the challenging para position (JACS, 2019). A major development in this area was to combine our previous ionic ligand design with a chiral cation to control both site-selectivity and enantioselectivity (Science, 2020). We have since collaborated with Dr. Kristaps Ermanis who performed detailed DFT studies on the origin of the selectivity (ACS Catal. 2023). These developments using ion-paired ligands enabled an expansion of the scope of this work plan to include a different type of C-H activation reaction, C-H amination. Proof of concept was shown for enantioselective benzylic C-H amination using Rh-catalysis (JACS, 2021) and then expanded to enantioselective aziridination (JACS, 2023). We have unpublished work showing that a range of groups can direct this chemistry and that the nature of the cation is able to impact site selectivity and even chemoselectivity. This work plan also involved palladium catalysis. We first tackled the challenge of site-selectivity with two similar aromatic carbon-halogen bonds (JACS 2018), introducing a new concept "electrostatically directed palladium catalysis", which could be coupled with C-H activation (Chem. Sci. 2020). We showed that tuning of the size of the alkali metal cation used could be used tune site-selectivity in complex polyhalogenated substrates (JACS, 2020). In this work the phosphine that was optimal was sSPhos, a sulfonated version of SPhos. The original proposal envisaged pairing these sulfonated phosphines with chiral cations to induce asymmetry but we realised here that actually sSPhos is itself a chiral molecule. With this realisation we developed a resolution of sSPhos and demonstrated that the enantiopure ligand is highly effective for a enantioselective Suzuki-Miyaura coupling to form 2,2'-biphenols (JACS, 2022). We have recently shown that it is a very general ligand for arylative dearomatisation (JACS, 2023) and are exploring further applications of sSPhos in asymmetric catalysis. During COVID we wrote reviews covering transition metal catalysis methods that use noncovalent interactions (ACS Catal. 2020) and on asymmetric C-N bond formation with metal nitrenoids (Chem. Sci. 2023)
2 Radical Reactions - One part of the proposal relating to WP2 was in connection with control of regioselectivity in the Minisci reaction. Due to the highly competitive nature of this area of research, work commenced on this idea whilst the grant was under review and the strategy that we had outlined allowed us not only to achieve regioselectivity but also to use a chiral catalyst and achieve enantioselectivity. This was the first example of an enantioselective Minisci reaction (Science, 2018). We then collaborated with researchers in the USA to develop a predictive model for this reaction (JACS, 2019) and with colleagues at Cambridge to probe the mechanism experimentally and computationally (JACS, 2020). Our original protocol use carboxylic acid derivatives and we developed a protocol allowing hydrogen atom transfer to be used in a formal coupling of two C-H bonds, requiring control of regioselectivity in both the HAT step and the Minisci reaction (JACS 2021). We expanded this to α‐hydroxy radicals (ACIE, 2022). To round this we wrote an account (Acc. Chem. Res. 2023). A review covered use of attractive non-covalent interactions for enantioselective catalysis of radical reactions (Nature Chem. 2020). A second phase of this work related to control of regioselectivity in the functionalisation of C-H bonds using non-covalent approaches. We have made breakthroughs in control of regioselectivity in the aromatic amination using N-centered radicals, engineering the system to incorporate attractive interactions resulting in ortho-selective amination of phenol derivates (JACS, 2021), sulfonic acid derivatives (ACIE, 2022) and benzoic acid derivatives (Chem. Sci. 2023). This has significantly advanced the state-of-the-art in arene amination chemistry.
Dissemination of the project results has been achieved by two main pathways: 1) publication of the results in high impact journals that are widely read by not only those in the directly related field of the researcher but also more broadly by the scientific community, 2)the PI and project members giving oral presentation of the results in invited talks at high profile academic institutions around the world and conferences.
1 Transition metals - This built on our foundational results relating to ir-catalysed borylation. We used ion-pairing interactions between substrate and a bulky countercation to direct borylation to the challenging para position (JACS, 2019). A major development in this area was to combine our previous ionic ligand design with a chiral cation to control both site-selectivity and enantioselectivity (Science, 2020). We have since collaborated with Dr. Kristaps Ermanis who performed detailed DFT studies on the origin of the selectivity (ACS Catal. 2023). These developments using ion-paired ligands enabled an expansion of the scope of this work plan to include a different type of C-H activation reaction, C-H amination. Proof of concept was shown for enantioselective benzylic C-H amination using Rh-catalysis (JACS, 2021) and then expanded to enantioselective aziridination (JACS, 2023). We have unpublished work showing that a range of groups can direct this chemistry and that the nature of the cation is able to impact site selectivity and even chemoselectivity. This work plan also involved palladium catalysis. We first tackled the challenge of site-selectivity with two similar aromatic carbon-halogen bonds (JACS 2018), introducing a new concept "electrostatically directed palladium catalysis", which could be coupled with C-H activation (Chem. Sci. 2020). We showed that tuning of the size of the alkali metal cation used could be used tune site-selectivity in complex polyhalogenated substrates (JACS, 2020). In this work the phosphine that was optimal was sSPhos, a sulfonated version of SPhos. The original proposal envisaged pairing these sulfonated phosphines with chiral cations to induce asymmetry but we realised here that actually sSPhos is itself a chiral molecule. With this realisation we developed a resolution of sSPhos and demonstrated that the enantiopure ligand is highly effective for a enantioselective Suzuki-Miyaura coupling to form 2,2'-biphenols (JACS, 2022). We have recently shown that it is a very general ligand for arylative dearomatisation (JACS, 2023) and are exploring further applications of sSPhos in asymmetric catalysis. During COVID we wrote reviews covering transition metal catalysis methods that use noncovalent interactions (ACS Catal. 2020) and on asymmetric C-N bond formation with metal nitrenoids (Chem. Sci. 2023)
2 Radical Reactions - One part of the proposal relating to WP2 was in connection with control of regioselectivity in the Minisci reaction. Due to the highly competitive nature of this area of research, work commenced on this idea whilst the grant was under review and the strategy that we had outlined allowed us not only to achieve regioselectivity but also to use a chiral catalyst and achieve enantioselectivity. This was the first example of an enantioselective Minisci reaction (Science, 2018). We then collaborated with researchers in the USA to develop a predictive model for this reaction (JACS, 2019) and with colleagues at Cambridge to probe the mechanism experimentally and computationally (JACS, 2020). Our original protocol use carboxylic acid derivatives and we developed a protocol allowing hydrogen atom transfer to be used in a formal coupling of two C-H bonds, requiring control of regioselectivity in both the HAT step and the Minisci reaction (JACS 2021). We expanded this to α‐hydroxy radicals (ACIE, 2022). To round this we wrote an account (Acc. Chem. Res. 2023). A review covered use of attractive non-covalent interactions for enantioselective catalysis of radical reactions (Nature Chem. 2020). A second phase of this work related to control of regioselectivity in the functionalisation of C-H bonds using non-covalent approaches. We have made breakthroughs in control of regioselectivity in the aromatic amination using N-centered radicals, engineering the system to incorporate attractive interactions resulting in ortho-selective amination of phenol derivates (JACS, 2021), sulfonic acid derivatives (ACIE, 2022) and benzoic acid derivatives (Chem. Sci. 2023). This has significantly advanced the state-of-the-art in arene amination chemistry.
Dissemination of the project results has been achieved by two main pathways: 1) publication of the results in high impact journals that are widely read by not only those in the directly related field of the researcher but also more broadly by the scientific community, 2)the PI and project members giving oral presentation of the results in invited talks at high profile academic institutions around the world and conferences.
As detailed in the summary above, the output has elevated the work of the project beyond the state of the art.
A number of key outcomes have been published, typically in the highest impact journals such as Science and the Journal of the American Chemical Society (JACS).
A number of key outcomes have been published, typically in the highest impact journals such as Science and the Journal of the American Chemical Society (JACS).