Prof. Patrick G. Steel
(email at firstname.lastname@example.org)
The Steel group has a broad spread of interests ranging from the development and applications of new methods for organic synthesis to the design and synthesis of small molecule probes and modulators (inhibitors) of biological processes to applications in applied synthetic biology. The work is supported by both the research councils (EPSRC, BBSRC, MRC) and industry (Syngenta, GSK)
We have a longstanding interest in the chemistry of low-coordination silicon compounds as applied to organic synthesis. Owing to their transient existence, such π-bonded silicon compounds have primarily been the subject of research into fundamental aspects of structure and reactivity with little attempt to explore their potential in organic synthesis. We have been particularly interested in studying the cycloaddition chemistry of silenes (compounds with a silicon carbon double bond). These prove to be powerful reagents for stereocontrolled alkene functionalization and we have used this methodology in the synthesis of a variety of natural products.1 A current challenge is to develop methods which provide access to the silene under milder catalytic conditions to increase the functional group tolerance of this approach.2 Much of this chemistry is undertaken in collaboration with groups Europe notably Prof. Henrik Ottosson at Uppsala University in Sweden.
Catalytic generation and trapping of a silene
Synthesis and Application of Boronic Acids
Aryl and heteroaryl boronate esters are very important organic intermediates in organic synthesis that have been deployed in many useful transformations including the Suzuki-Miyaura cross-coupling reactions, Cu-catalyzed C-O and C-N coupling reactions, and Rh-catalyzed conjugate additions to carbonyl compounds. As a result there is a need for efficient methods to prepare them. We have been studying the iridium catalyzed direct borylation of arene C-H bonds as a powerful route to these compounds. Recent results have included the development of one-pot single solvent procedures for the conversion of arenes into biaryls, arylpropionates and propanols in high yields.3 Current efforts are addressed at exploring other sequential chemistries, the design of better ligand sets to control regiochemistry and the development of faster, more effective catalysts using cheaper metals such as copper. Throughout all of this we collaborate closely with our Durham colleague Prof Todd Marder and also with other chemists elsewhere including Profs Zenyang Lin (Hong Kong) and Lei Lui (Beijing).
One-pot Ir-catalysed arene borylation Rh-Catalysed conjugate addition -reduction sequences
We are engaged in a number of projects that fall under the broad umbrella of chemical biology. In all of these a key goal is an understanding of how biological processes and the interactions between biological target and the small molecule are occurring at a molecular level. Much of this work is undertaken in collaboration. For example, within the Durham Centre for Crop Improvement Technologies we have collaborated with Patrick Hussey to generate fluorescent probes to study plant peroxisome dynamics and explore herbicides targeting plant cell wall biosynthesis.4
Image showing co-localisation (yellow staining) of peroxisome probe PTS1-mCherry (red) and Durham synthesised BODIPYprobe (green) in Nicotiana benthamiana stomata cells. Scale bar 10 mm.
Similarly, in partnership with Robert Edwards (York University) we are studying enzymes associated with herbicide detoxification and resistance with a specific goal to synthesise new herbicide synergists to understand and overcome multiple herbicide resistance in grass weeds.5
Away from the plant kingdom we have a major collaboration with Dr Paul Denny (Durham University), MRCT Ltd and GSK to develop new therapies for leishmaniasis and human African trypanosomiasis (African Sleeping Sickness). These are some the Worlds most serious neglected diseases with over 350 million people considered to be at risk. Towards this end we have identified enzymes associated with complex sphinglipid biosynthesis as potential new drug targets and are currently developing inhibitors that have the potential to make a difference to some of the worlds poorest people.6
- [a] H. Ottosson and P. G. Steel, 'Silylenes, Silenes, and Disilenes: Novel silicon based reagents for organic synthesis?' Chem. Eur. J., 2006, 12, 1576-1585. [b] R. D. C. Pullin, J. D. Sellars, and P. G. Steel, 'Total Synthesis of (±)-Epipicropodophyllin' Org. Biomol. Chem., 2007, 5, 3201-3206. [c] J. D. Sellars and P. G. Steel, 'Application of Silacyclic Allylsilanes to the Synthesis of b-Hydroxy-d-Lactones: Synthesis of Prelactone B', Tetrahedron., 2009, 65, 5588-5595.
- M. Czyzewski, J. Bower, M. Box, H. Ottosson and P. G. Steel, 'Silene Equivalents Through the Rhodium Catalysed Reactions of a-Hypersilyl Diazoesters.' Chem. Eur. J., 2011, submitted
- [a] P. Harrisson, J. Morris, P. G. Steel and T. B. Marder, 'A One-Pot, Single-Solvent Process for Tandem, Catalyzed C-H Borylation-Suzuki-Miyaura Cross-Coupling Sequences', Synlett., 2009, 147-150. [b] P. Harrisson, J. Morris, T. B. Marder and P. G. Steel, 'Microwave Accelerated Iridium Catalyzed Borylation of Aromatic C-H Bonds, Orglett., 2009, 11, 3586-3589. [c] H. Tajuddin, L. Shukla, A. Maxwell, T. B. Marder and P. G. Steel, 'A "One-Pot" Tandem C-H Borylation/1,4-Conjugate Addition/Reduction Sequence', Org. Lett., 2010, 12, 5700-5703.
- M. Landrum, A. Smertenko, R. Edwards, P. J. Hussey and P. G. Steel, 'BODIPY Probes to Study Peroxisome Function in Vivo' Plant. J., 2010, 62, 529-538.
- I. Cummins, R. E. Edwards, and P. G. Steel " Methods and means relating to multiple herbicide resistance in plants" Patent Application GB 0717982.3 Filed 14.09.2007
- [a] J. G. Mina, S. Y. Pan, N. K. Wansadhipathi, C. R. Bruce, H. Shams-Eldin, R. T. Schwarz, P. G. Steel, and P. W. Denny, 'The Trypanosoma brucei sphingolipid synthase, an essential enzyme and drug target' Mol. Biochem. Parasitol., 2009, 168, 16-23. [b] J. G. Mina, J. A. Mosely, H. Shams-Eldin, R. T. Schwarz, P. G. Steel and P. W. Denny, 'A plate-based assay system for analyses and screening of the Leishmania major inositol phosphorylceramide synthase.' Int. J. Biochem. Cell. Biol., 2010, 42, 1553-1561. [b] J. G. Mina, J. A. Mosely, H. Z. Ali, P. W. Denny and P. G. Steel, 'Exploring Leishmania major inositol phosphorylceramide synthase (LmjIPCS): Insights into the ceramide binding domain.' Org. Biomol. Chem. 2011, 9, 1823 (Hot Article)