Research Guides

The general theme of our research is Organic Synthesis. More specifically we are interested in developing and utilising modern organic chemistry techniques to provide innovative solutions to many of the long-standing challenges of organic synthesis. One area we are particularly interested in is increasing levels of selectivity in synthetic transformations; this can be regio- chemo- or stereoselectivity. To address these aims we have chosen to focus on the development of new reactions, reagents and strategies for asymmetric synthesis, often employing catalytic techniques. The interrelated fields of reaction development, asymmetric catalysis and target oriented synthesis thus form the cornerstone of our research program. The current group comprises a mix of postdoctoral researchers, DPhil and Part II students.

New Reaction Development

The design and development of new bond constructions, i.e., new reactions, is a key activity within our group. For a new chemical reaction to be competitive with existing methodology it must offer clear advantages, for example a new reaction might improve upon reaction efficiency or operational simplicity. Our approach to reaction discovery focuses on the use of transition metal complexes to effect catalytic transformations. The scheme below illustrates how we are using Rh(I) catalysis develop the hydroacylation of alkenes and alkynes as a synthetically useful process.

Asymmetric Processes and Catalysis

The control of absolute stereochemistry remains a formidable challenge in organic chemistry. In combination with our efforts to develop new bond connections we are also pursuing new enantioseletive reactions. We have adopted two distinct approaches to this problem; the first is to develop a new reaction from first principles through the simple bond formation moving on to a diastereoselective reaction and ultimately an enantioselective process. Our studies on Rh-catalysed hydroacylation are a good example of this approach. The second approach relies on designing new strategies for asymmetric synthesis. These may not feature a new reaction but will rely on applying known reactions in novel potentially enantioselective ways. One area where we have adopted this approach is the development of an enantioselective Suzuki coupling using a desymmetrisation stragety.

Transition Metal Catalysed Heterocycle Synthesis

In the majority of heterocycle syntheses the key heteroatom is usually incorporated into an acyclic precursor which is then cyclised to deliver the required product. This has limitations if variation of the heteroatom, or in the case of nitrogen, the heteroatom substituent, is required without recourse to the synthesis of separate cyclisation precursors. We are developing a general strategy based on the preparation of an activated carbon backbone into which the required heteroatom or heteroatom group can then be inserted in a single step using transition metal catalysis. The scheme below illustrates the application of this concept to the synthesis of N-functionalised indoles, including the natural product demethylasterriquinone A1.

Target Synthesis

The synthesis of complex target molecules, be they natural or non-natural products, provides a superb testing-ground for our methodology. We are interested in the preparation of a range of architecturally challenging biologically relevant targets.

“Cascade Palladium-Catalyzed Direct Intramolecular Arylation/Alkene Isomerization Sequences: Application to Indole and Benzofuran Synthesis”, Myriam Yagoubi, Ana C. F. Cruz, Paula L. Nichols, Richard L. Elliott and Michael C. Willis, Angew. Chem. Int. Ed. 2010, 49, 7958 - 7962.

“Rhodium-Catalyzed Intermolecular Alkyne Hydroacylation: The Enantioselective Synthesis of α- and β-Substituted Ketones via Kinetic Resolution”, Carlos González-Rodríguez, Scott R. Parsons, Amber L. Thompson and Michael C. Willis, Chem. Eur. J. 2010, 16, 10950 – 10954.

“Cascade Palladium-Catalyzed Alkenyl Aminocarbonylation/Intramolecular Aryl Amidation: An Annulative Synthesis of 2-Quinolones”, A. C. Tadd, A. Matsuno, M. R. Fielding and M. C. Willis, Org. Lett. 2009, 11, 583–586.

“Catalytic Enantioselective Intermolecular Hydroacylation: Rhodium-Catalyzed Combination of β-S-Aldehydes and 1,3-Disubstituted Allenes”, J. D. Osborne, H. E. Randell-Sly, G. S. Currie, A. R. Cowley M. C. Willis, J. Am. Chem. Soc. 2008, 130, 17232–17233.