Enabling Methods for Cleaner Chemical Synthesis
Submitting InstitutionUniversity of Cambridge
Unit of AssessmentChemistry
Summary Impact TypeTechnological
Research Subject Area(s)
Chemical Sciences: Analytical Chemistry, Organic Chemistry, Other Chemical Sciences
Summary of the impact
The pioneering work of Steven Ley on polymer-supported reagents and
technology has helped change the way we achieve cleaner chemical
processes. The concepts and
techniques invented in Cambridge allow more sustainable processes to be
concomitant reduction in purification steps, shorter reaction times and
diminished solvent usage.
The work has led to a spin-out company (Reaxa), seeded the creation of a
number of other
companies, and resulted in the development of several devices for
continuous flow synthesis that
are now commercially available via Mettler-Toledo (USA) and Cambridge
Reactor Design (UK).
This technology is having an impact in industry, with continuous flow
processing increasingly being
used for full-scale commercial production.
Steven Ley (1702 Professor of Chemistry at the University of Cambridge
since 1992) and his group
began work in the mid 1990s to discover improved enabling methods for
cleaner and more
sustainable chemical synthesis. Using recyclable polymer supported
reagents in combination with
flow chemistry methods, he was able to conduct multi-step synthesis
sequences leading to the
synthesis of complex biologically active compounds. This was achieved
without recourse to
techniques such as chromatography, crystallisation, distillation or
reaction quenching, common to
more conventional synthesis methods at the time. The first paper
describing some of these
methods appeared in 19971 and within one year he had shown that
the concept could be extended
to up to six linear steps (a world record at the time) without recourse to
conventional and wasteful
downstream processing.2 This work attracted modest research
funding from the EPSRC through a
ROPA grant (GR/M50614/01) and a more substantial follow-up grant
concept for this work and its potential application for multi-step
synthesis using polymer supported
reagents with flow chemistry was the subject of a patent from his first
spin-out company in 1999.3
The grants awarded to Ley's group facilitated very rapid development of
the techniques and
resulted in a highly cited review.4 The methods were promptly
adopted by the academic community
(as evidenced by ISI listing 700 citations in 2011 alone) and by industry
with Ley's own company
leading the charge (see above). His spectacular synthesis of epothilone C,
a potent anti-tumour
agent, in just 15 linear steps using only polymer supported reagents, was
a true demonstration of
the technology and a landmark publication because it changed many people's
organic synthesis using cleaner and more efficient methods.5
More significantly Ley then went on to show even further advances were
possible by using these
polymer supported reagents and related scavenger materials. This was
achieved by constructing
packed cartridges containing these species and, by appropriate machinery,
through these tubes in a flow chemistry manner; multi-step flow synthesis
was made possible.6 By
2006 he developed flow chemistry and immobilised reagents to deliver
pharmaceutical agents and
complex natural products such as oxomaritidine in just seven steps using
approach.7 This seminal paper opened up a whole new set of
opportunities for molecular assembly
as a result of Ley's work. It also generated substantial interest at the
EPSRC, who began to fund
initiatives in the area and a large EPSRC grant in 2003 (GR/S40343/01), to
research in Ley's group.
As these techniques were being developed and adopted worldwide, further
in Cambridge from Ley's group led to the discovery of a new range of
encapsulated reagents and
greatly improved polymer supported scavengers, some of which were
research support for this area has been recently awarded to Ley's group
from the EPSRC
(EP/K009494/1). These immobilised systems were very effective in batch and
flow conditions and
this discovery led to the formation of a second spin-out company, Reaxa,
based in Manchester in
2005. The products are now marketed and sold worldwide for green chemistry
References to the research
1. Polymer-Supported Perruthenate (PSP): A New Oxidant for Clean Organic
Hinzen and S.V. Ley, J. Chem. Soc., Perkin Trans. I, 1997,
2. Clean Six-Step Synthesis of a Piperidino-thiomorpholine Library using
Reagents, J. Habermann, S.V. Ley and J.S. Scott, J. Chem. Soc., Perkin
Trans. I, 1998, 3127-3130.
3. Patent No. WO 99/58475, Preparation of compounds using polymer
4. Multistep Organic Synthesis using Solid Supported Reagents and
Scavengers: A New
Paradigm in Chemical Library Generation, S.V. Ley, I.R. Baxendale, R.N.
Jackson, A.G. Leach, D.A. Longbottom, M. Nesi, J.S. Scott, R.I. Storer and
S.J. Taylor, J.
Chem. Soc., Perkin Trans. I, 2000, 3815-4195.
5. A Total Synthesis of Epothilones using Solid-Supported Reagents and
Scavengers, R.I. Storer,
T. Takemoto, P.S. Jackson and S.V. Ley, Angew. Chem. Int. Edn,
2003, 42, 2521-2525. (*)
6. New Tools and Concepts in Modern Organic Synthesis, S.V. Ley and I.R.
Reviews, 2002, 1, 573-586.
7. A Flow Process for the Multi-Step Synthesis of the Alkaloid Natural
Product Oxomaritidine: A
New Paradigm for Molecular Assembly, I.R. Baxendale, J. Deeley, C.M.
Ley, S. Saaby and G. Tranmer, J. Chem. Soc., Chem. Commun, 2006,
9. EnCat patent: Microencapsulated catalyst, methods of preparation and
methods of use thereof.
July 9 2002 WO203006151.
(*) References that best indicate the quality of the research.
• Grant No: GR/M50614/01; PI: Professor Steven V Ley; Grant Title: ROPA:
Multistep Organic Synthesis Using Polymer Bound Reagents; Period of Grant:
01 April 1999 - 31
March 2001; Grant Value: £103,821
• Grant No: GR/N02030/01; PI: Professor Steven V Ley; Grant Title:
Multistep Organic Synthesis
Using Solid Supported Reagents: A New Paradigm in Chemical Library
Generation; Period of
Grant: 01 June 2000 - 31 May 2003; Grant Value: £410,911
• Grant No: GR/S40343/01; PI: Professor Steven V Ley; Grant Title: An
Programme in Cambridge; Period of Grant: 1 October 2003 - 30 September
• Grant No: EP/K009494/1; PI: Professor Steven V Ley; Grant Title:
Flow Processes for Access to Forbidden Chemistries, New Reactivities and
Complexity Generation; Grant Period: 1 January 2013 - 31 December 2013;
Details of the impact
Chemical synthesis is at the heart of modern society, being essential in
the development and
manufacture of everything from modern electronics to pharmaceutical
agents. The research
programme started by Ley in the mid 1990s sought to provide a sea change
in the way molecules
could be assembled in a multi-step fashion.1 Key to the success
of the approach was the use of an
ensemble of immobilised reagents and scavengers to synthesise molecules
requirement for extensive downstream processing techniques, which are
wasteful in terms of
materials, energy, time and labour costs. Moving from conventional
production to continuous flow-based processing has had worldwide impact,
with companies across
the chemical space — from research operations to full-scale production —
now realising the benefits
and implementing continuous flow processing techniques within their
facilities. Substantial benefits
have been accrued in terms of safety, energy savings, scale-up and low
solvent usage, all leading
to more sustainable chemical practices.
Technology Seeded New Companies
This technology helped to seed the formation of a number of UK start-up
focused on flow methods. Many new UK start-up companies, such as Vapourtec
UK), Uniqsis (2007, Cambridge, UK), Cyclofluidic (2008, Welwyn Garden
City, UK), Microsaic
(2004, Woking, UK), and HEL (1987, Borehamwood, UK) were set up to exploit
the potential of
flow chemistry. These companies continue to trade and the UK is now
leading the world in
developing new, innovative equipment for flow chemistry. Ley has had
direct input into Cyclofluidic
as a member of its Scientific Advisory Board.
In 2005, Steven Ley set up the spin-out company Reaxa to exploit work on
the nickel, palladium,
platinum and osmium encapsulated reagents EnCat, and QuadraPure reaction
scavengers. These provide a unique solution to minimise waste during
chemical reactions, and
allow precious spent catalysts to be easily recovered, facilitating
recycling and being ideal for flow
chemistry applications. The scavengers are now sold by Johnson Matthey
after it acquired the
patent in 2011, and Reaxa itself was acquired by Indian company S. Amit
Speciality Chemicals Pvt
Ltd, also in 2011, which has continued to support and promote these
important reagents, now sold
Adoption and Application of Technology in the Commercial Sector
There are numerous examples of the use of these reagents in the
commercial sector. Two
examples published in 2012 are Pfizer's use of palladium EnCat to effect a
reaction in the synthesis of potent inhibitors of LpxC that have potential
as antibiotics2, and the use
of the same EnCat in the synthesis of a range of orally available CHK1
inhibitors by a team at the
Institute of Cancer Research.3
The QuadraPure scavengers have also been employed in industrial
processes. Novartis, for
example, published work on the clean-up of Heck reactions in 2008, which
QuadraPure TU was the most effective adsorbent.4 Another
example is Pfizer's use of QuadraPure
TU to remove traces of palladium in the process scale-up of
[beta]2-adrenoceptor agonist PF-00610335.5
New Products Created and Commercialised
Further evidence of the impact of Ley's work on polymer supported
reagents and scavengers
under flow chemistry conditions is that a local company, Cambridge Reactor
commercialised two products which had their genesis in his laboratories.
These are the
"Gastropod" for conducting mixed gas/liquid flow reactions with in-line
supported catalysts and
"Polar Bear" for achieving low temperatures (-89ºC) without cryogens for
flow mode multi-step
synthesis. Both these units have attracted wide interest as judged by ISI
citations to this work
(Gastropod 145, Polar Bear 30).
Similarly, in collaboration with Mettler Toledo, Ley's flow chemistry
techniques have driven the
need for improved in-line analysis, which has resulted in further
commercial products for flow IR
monitoring being introduced to the market.6 The impact on his
work in this area has also aided the
development of mini-mass spectrometers for in-line flow analysis. The
details of this joint
collaboration with Microsaic Systems are reported.7&8 This
equipment is now commercially
available giving the UK a lead in the development of these new advances in
Sources to corroborate the impact
References in the public domain
Users/Beneficiaries who can be contacted to corroborate claims
- Clean Six-Step Synthesis of a Piperidino-thiomorpholine Library using
Reagents, J. Habermann, S.V. Ley and J.S. Scott, J. Chem. Soc.,
Perkin Trans. I, 1998,
- Potent Inhibitors of LpxC for the Treatment of Gram-Negative
Infections, M.F. Brown, U.
Reilly, J.A. Abramite, J.T. Arcari, R. Oliver, R.A. Barham, Y. Che, J.M.
Collantes, S.W. Chung, C. Desbonnet, J. Doty, M. Doroski, J.J.
Engtrakul, T.M. Harris, M.
Huband, J.D. Knafels, K.L. Leach, S. Liu, A. Marfat, A. Marra, E.
McElroy, M. Melnick, C.A.
Menard, J.I. Montgomery, L. Mullins, M.C. Noe, J. O'Donnell, J. Penzien,
L.M. Price, V. Shanmugasundaram, C. Thoma, D.P. Uccello, J.S. Warmus,
Wishka, J. Med. Chem., 2012, 55(2), 914-923.
- Discovery of
Orally Bioavailable CHK1 Inhibitors, M. Lainchbury, T.P. Matthews, T.
Boxall, M.I. Walton, P.D. Eve, A. Hayes, M.R. Valenti, A.K. de Haven
Brandon, G. Box,
G.W. Aherne, J.C. Reader, F.I. Reynaud, S.A. Eccles, M.D. Garrett, I.
Collins, J. Med.
Chem., 2012, 55(22), 10229-40.
- Removal of Soluble Palladium Complexes from Reaction Mixtures by
Adsorption, M.J. Girgis, L.E. Kuczynski, S.M. Berberena, C.A. Boyd, P.L.
Scherholz, D.E. Drinkwater, X. Shen, S. Babiak and B.G. Lefebvre, Org.
Proc. Res. Dev.,
2008, 12, 1209-1217.
- Development of a Potential Manufacturing Route to PF-00610355: A Novel
Agonist, P. D. de Koning, N. Castro, I.R. Gladwell, N.A. Morrison, I.B.
Moses, M.S. Panesar, A.J. Pettman, and N.M. Thomson, Org. Proc. Res.
Dev., 2011, 15,
- ReactIRTM Flow Cell — A New Analytical Tool for Continuous
Flow Chemistry Processing,
C.F. Carter, H. Lange, I.P. Baxendale, S.V. Ley, J. Goode, N. Gaunt, B.
Proc. Res. Dev., 2010, 14, 393-404.
- Microsaic Systems (http://www.microsaic.com).
- Continuous Flow Reaction Monitoring using an On-Line Miniature Mass
Browne, S. Wright, B.J. Deadman, S. Dunnage, I.R. Baxendale, R.M. Turner
and S.V. Ley,
Rapid Commun. Mass Spectrom, 2012, 26, 1999-2010.
- Director, Cambridge Reactor Design Ltd, Cottenham, UK.
- Technical Applications Consultant, Mettler Toledo Ltd, Leicester, UK.
- SVP, Head of Worldwide Medicinal Chemistry Pfizer, Cambridge MA, USA.
- Fellow, Novartis Pharma AG, Basel, Switzerland.