CH7: Design and Application of a Tool for the Qualitative and Quantitative Analysis and Prediction of the Effect of Ligand Structure on the Catalytic Activity of Metal Complexes
Submitting InstitutionUniversity of Bristol
Unit of AssessmentChemistry
Summary Impact TypeTechnological
Research Subject Area(s)
Chemical Sciences: Analytical Chemistry, Macromolecular and Materials Chemistry, Physical Chemistry (incl. Structural)
Summary of the impact
The selection of ligand(s) for the transition metal complexes that are
frequently employed as catalysts for the production of fine chemicals is a
key activity ultimately governing the financial viability of the process.
Traditionally, the method for discovery of ligands with the appropriate
balance of cost and efficiency has been achieved empirically via
screening. This Impact Case Study reports on the development of a novel
methodology for the qualitative and quantitative analysis and prediction
of the effect of ligand structure on the catalytic activity of
late-transition metals. It has been applied in process and discovery
chemistry in pharmaceutical and agrochemical industries in the UK (and
beyond). The analysis allows rapid, and therefore cost efficient,
identification of ligands and catalysts with the potential to bypass
intellectual property issues.
- The underpinning research was carried out in the period 2003 to 2013.
- Key Researchers were Lloyd-Jones, Orpen, Harvey,
Fey, Paul Murray (AstraZeneca and CatSci Ltd) and Bob Osborne
(AstraZeneca catalyst discovery).
The impact followed on from pure research in the instigation and development
of a `Ligand Knowledge Base' by Orpen
). The Ligand Knowledge Base aims to capture the properties of
donor ligands coordinating to transition metal centres by way of a
collection of up to 29 descriptors. The descriptors evaluated and used are
computationally-derived from a range of coordination environments in order
to maximise their transferability and hence utility for the investigation of
the ligands. These descriptors are analysed using different statistical
approaches, both individually to determine their chemical context, and
collectively by principal component analysis thereby allowing the derivation
of maps of `ligand space' for different ligand sets.
Lloyd-Jones acted as a consultant to AstraZeneca Process Research
and Development during 2003-2010. Through discussion with Process Research
and Development scientists at the AstraZeneca Avlon and Charnwood sites,
it became evident that catalyst discovery and optimisation for medicinal
chemistry projects and scale-up, predominantly involving Pd-based systems,
was heavily dependent on, or influenced by, statistical or anecdotal
approaches. It was proposed that with funding from AstraZeneca, the Ligand
Knowledge Base could: (i) be substantially increased in ligand class,
ligand space, and ligand population density and (ii) be applied to model
systems for the types of Pd-coupling process that were of interest to
AstraZeneca so that the feasibility of qualitative and quantitative
analysis and prediction of the effect of ligand structure on the catalytic
activity could be explored. Between 2006 and 2010 AstraZeneca provided
£763k to fund this research in the laboratories of Lloyd-Jones and
Orpen, Harvey and Fey at Bristol (2). In
parallel, AstraZeneca invested £1m in the provision of a semi-automated
catalyst testing facility at Avlon to service catalytic reactions in
projects within the company that were proving unreliable or low-yielding
for drug discovery or for scale-up for clinical trials.
A successful proof of concept emerged from the Bristol-based four-year
fully-funded "Phase 1" study (2006-2010) in terms of: (i) approximate
prediction of relative activity for various ligands in a model allylation
reaction (3), and (ii) successful application of the Ligand
Knowledge Base-based ligand map (4) to a number of active projects
within AstraZeneca, leading to vastly improved ligand choice for a
scale-up process (see Section 5, Source 1).
A second phase ("Phase 2", 2010-2012) of underpinning research was
supported by a Knowledge Transfer Partnership grant of £116k that allowed
the laboratory-based postdoc (Gareth Owen-Smith) from Phase 1, to develop
the application of the Ligand Knowledge Base for amination reactions at
AstraZeneca, by working full-time at Avlon in their semi-automated
catalyst testing facility. This led to a number of improvements in the way
in which data were collected for qualitative and quantitative analysis of
ligand effects in rate (5); it also allowed the Ligand Knowledge
Base-analysis methodology to be disseminated to all of the other chemistry
sites at AstraZeneca in the UK and Sweden.
During the period of the Knowledge Transfer Partnership grant, and based
on the extensive experience in catalyst development generated by
collaboration with the Bristol based team during Phases 1 and 2 (6),
Murray established "CatSci" in May 2011 (see section 5, Source 2). This
spin-out from AstraZeneca was established as a start-up company based in
Cardiff which has led to a third phase ("Phase 3", 2012-2014) of
underpinning research being supported (£175k) by a Welsh Government
"Research, Development and Innovation Grant" in collaboration with CatSci
to support Fey in a project to link calculated catalyst property
descriptors with optimally designed catalyst screening data, and thus to
develop novel catalysts. This project is allowing CatSci to more
effectively apply its expertise in the development and optimisation of
transition-metal catalysed reactions, and thus assist in the efficient
evolution of this industrial spin-out activity.
References to the research
(1) Development of a ligand knowledge base, Part 1: Computational
descriptors for phosphorus donor ligands, N. Fey, A. Tsipis, J. N. Harvey,
A. G. Orpen, and R. A. Mansson, Chem. Eur. J. 2006, 12,
291-302, DOI: 10.1002/chem.200500891.
(2) Computational Descriptors for Chelating P,P- and P,N-Donor
Ligands, N. Fey, J. N. Harvey, G. C. Lloyd-Jones, P. l. Murray, A. G.
Orpen, R. Osborne and M. Purdie, Organometallics 2008, 27,
1372-1383, DOI: 10.1021/om700840h.*
(3) Counterintuitive Kinetics in Tsuji-Trost Allylation: Ion-pair
Partitioning and Implications for Asymmetric Catalysis, L. A.
Evans, N. Fey, J. N Harvey, D. Hose, G. C. Lloyd-Jones, P. Murray, A G.
Orpen, R. Osborn, G. J. J. Owen-Smith, and M. Purdie, J.
Am. Chem. Soc., 2008, 130, 14471-14473, DOI:
(4) The Newman-Kwart Rearrangement of O-aryl thiocarbamates:
Substantial Reduction in Reaction Temperatures via Pd Catalysis, J. N.
Harvey, J. Jover, G. C. Lloyd-Jones, J. D. Moseley, P. Murray and J. S.
Renny, Angew. Chem., Int. Ed., 2009, 48, 7612-7615, DOI:
(5) Expansion of the Ligand Knowledge Base for Monodentate P-Donor
Ligands, J. Jover, N. Fey, J. N. Harvey, G. C. Lloyd-Jones, A. G. Orpen,
G. J. J. Owen-Smith, P. M. Murray, D. R. J. Hose, R. Osborne, and M.
Purdie, Organometallics, 2010, 29, 6245-6258, DOI:
(6) Expansion of the Ligand Knowledge Base for Chelating P,P-Donor
Ligands (LKB-PP), J. Jover, N. Fey, J. N. Harvey, G. C. Lloyd-Jones, A. G.
Orpen, G J. J. Owen-Smith, P. Murray, D. R. J. Hose, R. Osborne, and M.
Purdie, Organometallics, 2012, 31, 5302-5306, DOI:
Details of the impact
There are three sites of impact:
This company can now identify ligands for transition metal catalysis
(mostly with Pd, Rh, Ru and Ir) more efficiently. The Ligand Knowledge
Base principal component analysis feeds into a Design of Experiment
programme that defines the `chemical space' within which ligands will be
tested and how most efficiently to explore this space. This could not be
done well previously because there were no 'coordinates' for the ligand
space (unlike, for example, the parameterisations available for solvents).
AstraZeneca estimated at the end of Phase 2, that this advance has already
led to about £250k cost saving and it anticipates on-going savings will be
in the region of millions of pounds, through faster development of
scale-up processes with reduced development time and costs and ultimately
a reduction in manufacturing costs with the potential to reduce the
environmental impact of their processes.
The impact of these developments were recognised in the form of an
AstraZeneca Science & Technical Award (to Murray and Osborne) in
October 2010. The award nomination read "The design and application of
high quality ligand descriptors in this way is a scientific breakthrough
and leading academics refer to this innovation as `revolutionary'. This
capability is now in routine operation and supporting Discovery in
gaining access to high value areas of chemical space". Murray,
quoted in an internal AstraZeneca document announcing the award, suggested
that savings derived from the breakthrough are "estimated at around
$200k per project to produce 60 kilos of drug substance for a clinical
trial. This saving would rise with a market launch to $2.5m for 600
kilos or $25m for six tonnes", (a).
this company, which predominantly arose from activities conducted in the
labs of Murray at AZ under the auspices of the Ligand Knowledge Base
programme, has a mission "To establish new and improved chemical
reactions and processes through a world-leading understanding and
application of transition metal catalysis". A major component in the
portfolio of services offered by CatSci is "Optimisation of processes
through predictive catalysis: Identification and development of
an optimised catalytic process and for the interrogation of reaction
space in line with Quality by Design principles delivered through
exploiting unique predictive catalysis techniques". These techniques
derive directly from Phases 1 and 2 of the collaboration, and solely use
the Ligand Knowledge Base descriptors and principal component
analysis-derived ligand maps developed at Bristol. Initial investment in
facilities has been £0.52m in equipment and 5 staff, with £1.2m of
business already secured. Further investment by the Welsh Government has
been made in a CatSci-University of Bristol collaborative project to
develop an improved ligand screening protocol for homogeneous catalysis,
integrating fully the computational evaluation of catalyst properties with
CatSci's high-throughput automated catalyst screening and analysis
facilities. Focusing on the need to ensure 'manufacturability' in the
chemical industries, this two-year project aims to deliver efficient,
stable and selective catalysts that are economically viable for process
scale-up and discovery (b).
Concepts arising during the initial phases of the research led to the
design of unique `catalyst capture/release' technology. This concept is
now being studied in the School of Chemistry and made ready for the market
by Phosphonics via a collaboration supported by the TSB/EPSRC through the
Technology Strategy Board "Sustainable Manufacturing for the Process
Industry" programme. This £700k project ("Recyclable Catalyst
Technology for Cross-Coupling Reactions at Manufacturing Scale")
draws together Phosphonics, CatSci, Syngenta, AstraZeneca, Albany
Molecular Research and the University of Bristol, to explore and design
novel functionalised silica materials that allow purification of reaction
products by temporary capture of the Pd catalyst in heterogeneous form,
capable of triggered release back in an active form into solution. The
technology will be employed in semi-continuous format, with application
possible across multiple process industries. Initial applications towards
the manufacture of pharmaceuticals & agrochemicals will be a
demonstrable output during 2013-2015 (c).
Sources to corroborate the impact
(a) For AstraZeneca, Dr Mark Purdie, AstraZeneca Macclesfield.
Project manager for the collaboration into predictive catalysis with
Bristol (Phases 1 and 2) and Christina Fröjd, publication of internal (AZ)
document online regarding AZ Science and Technical Award, October 25th
(b) For CatSci, Dr Jonathan Moseley, Research Director of CatSci
Ltd. (Phases 1, 2 and 3).
(c) For Phosphonics, Dr Robin Wilkes, Business Director,
Pharmaceuticals & Fine Chemicals, Phosphonics Limited.