Catalyst Diversity from Chiral Palladacycles
Lead Research Organisation:
University of East Anglia
Department Name: Chemistry
Abstract
Catalytic methodologies have a very major impact on improving the efficiency and cost effectiveness of synthesis, a key (usually the key) technology for the development of new medicines, agrochemicals, materials, fragrances and, in turn, further catalysts. This programme will generate a platform for the discovery of chiral palladium catalysts for use in asymmetric synthesis based upon a new method of catalyst formation. This will allow numerous catalysts to be generated in just one step from palladium-based complexes, the synthesis of which has been pioneered within the Richards group. Access to a diverse array of palladium catalysts will enable the optimisation of selectivity and the minimisation of the quantity of catalyst required in a host of reactions. In addition, the new catalyst generation protocol will enable facile immobilisation, boosting further the sustainability of the chemistry through catalyst recovery and reuse. The new platform will be applied to the selective synthesis of novel and varied chiral (i.e. handed) structures, diversity generation lying at the heart of the process of discovering new bioactive compounds for application in drug discovery programmes.
Planned Impact
Beyond academia, beneficiaries will include the pharmaceutical industry, the agrochemical industry, and more specialist companies focused on the synthesis of fine chemicals and compound libraries. Novel catalysts may exploited for wealth creation through the discovery and manufacture of high value products. These include new medicines, and also related compounds that enable a full scientific understanding of a disease and its treatment. Other ways in which this work will directly benefit society by addressing global challenges is through potential application to the discovery and manufacture of new materials and agrochemicals, and through the specialist expertise to be garnered by the PDRA and PI. Interwoven with these societal benefits is the economic impact through the support of sectors of UK industry that are vital for employment and the UK balance of payments.
Organisations
People |
ORCID iD |
| Chris Richards (Principal Investigator) |
Publications
Arthurs R
(2022)
Application of a Ferrocene-Based Palladacycle Precatalyst to Enantioselective Aryl-Aryl Kumada Coupling
in European Journal of Inorganic Chemistry
Richards C
(2017)
Catalyst Optimisation for Asymmetric Synthesis by Ligand Chirality Element Addition: A Perspective on Stereochemical Cooperativity
in Chemistry - A European Journal
Arthurs R
(2021)
Copper(I) Complexes of P -Stereogenic Josiphos and Related Ligands
in European Journal of Organic Chemistry
Arthurs RA
(2017)
Deuterium as a Stereochemically Invisible Blocking Group for Chiral Ligand Synthesis.
in Organic letters
Arthurs R
(2018)
Enantiopure Planar Chiral and Chiral-at-Metal Iridacycles Derived from Bulky Cobalt Sandwich Complexes
in Organometallics
Arthurs R
(2019)
Ferrocenyloxazoline-Derived Planar Chiral Palladacycles: C-H Activation, Transmetalation, and Reversal of Diastereoselectivity
in Organometallics
Richards C
(2017)
Frontispiece: Catalyst Optimisation for Asymmetric Synthesis by Ligand Chirality Element Addition: A Perspective on Stereochemical Cooperativity
in Chemistry - A European Journal
Arthurs RA
(2020)
Planar chiral palladacycle precatalysts for asymmetric synthesis.
in Organic & biomolecular chemistry
Arthurs RA
(2018)
Stereoselective and Stereospecific Reactions of Cobalt Sandwich Complexes: Synthesis of a New Class of Single Enantiomer Bulky Planar Chiral P-N and P-P Ligands.
in Chemistry (Weinheim an der Bergstrasse, Germany)
Arthurs RA
(2020)
Stereoselective Synthesis of All Possible Phosferrox Ligand Diastereoisomers Displaying Three Elements of Chirality: Stereochemical Optimization for Asymmetric Catalysis.
in The Journal of organic chemistry
| Description | The central objective of this programme was the utilisation of planar chiral palladacycles as precursors for the generation of new catalysts for use in asymmetric synthesis. To this end, in the early stages of the programme, we developed methods for the efficient asymmetric synthesis of planar chiral palladacycles. In addition, this was extended to the synthesis of related iridacycles as potential precursors to iridium-based catalysts for use in asymmetric catalysis. As part of this methodology we developed a practical method to control planar chirality formation using deuterium as a stereochemically invisible blocking group. Further to this a detailed review of the literature revealed the significance of chiral cooperativity by chiral element addition as a method for improving the enantioselectivity of a catalyst. To explore the potential of this as a catalyst optimisation technique we developed methodology to synthesise all four possible diastereoisomers of a bidentate ligand containing three elements of chirality, and obtained preliminary evidence that these elements may be combined iteratively and cooperatively to improve the enantioselctivity of a catalysed reaction. Returning to the central objective we then demonstrated the application of chiral non-racemic palladacycles as precatalysts for the in situ generation of chiral bidentate ligand coordinated Pd(0) species. These in turn were applied as catalysts for asymmetric allylic alkylation (up to 97% ee) and asymmetric aryl-aryl cross-coupling (ca. 80% ee). These are the first time palladacycles has been used in this way, key outcomes demonstrating the central objective of this work. |
| Exploitation Route | A new way of thinking about chiral cooperativity for catalyst development in asymmetric synthesis. The efficient generation of planar chiral diastereoisomers as the basis of exploiting chiral cooperativity. Novel planar chiral palladacycles, iridacycles and related ligands are now available for cooperative projects in asymmetric synthesis. Planar chiral palladacycles are precatalysts for the in situ generation of chiral ligand ligated Pd(0) complexes, active catalysts for use in asymmetric synthesis. |
| Sectors | Chemicals,Pharmaceuticals and Medical Biotechnology |
| Description | The key objectives of this work were to develop methodology for the in-situ generation of ligated metal catalysts from precursor metallacycles and demonstrate the viability of these in asymmetric synthesis. Two publications in 2020 and 2022 report on the achievement of these objectives starting with palladacycles, the resulting catalysts being applied to asymmetric C-C bond forming reactions. These outcomes are supported by additional findings on methodology development for the synthesis of other metallacycles, and on studies utilising the predictable and additive nature of chiral cooperativity as a method for optimising catalyst selectivity. Taken together these provide a basis for rapid catalyst synthesis and optimisation applicable to several areas of asymmetric catalysis for the generation of bioactive compounds, including pharmaceuticals. The cooperative exploitation of these outcomes with respect to methodology extension and application to pharmaceutical discovery is ongoing. |
| First Year Of Impact | 2022 |
| Sector | Chemicals,Pharmaceuticals and Medical Biotechnology |
| Impact Types | Societal,Economic |