Research Guides

Department of Chemistry University of Oxford

Professor Michael C. Willis

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

We are interested in developing catalytic processes that activate common functional groups in non-conventional ways; for example, we have developed a series of alkene and alkyne hydroacylation reactions which proceed by activation of an aldehyde’s C-H bond and result in C-C bond-formation. We have developed the first highly enantioselective intermolecular hydroacylation reaction, as well as the first catalyst controlled regioselectivity switch. We have also developed new ligands, have studied the mechanism, and begun to exploit these reactions in synthesis.

Continuing our interest in exploiting non-traditional functional groups in catalysis, we have recently developed simple aryl methyl sulfides as activating groups for arene functionalization, and reported a novel Rh-catalysed carbothiolation process, which we exploited in a new isoquinoline synthesis.

We have recently developed new catalytic methods to introduce sulfur dioxide groups into organic molecules. Despite the similarity between sulfur dioxide and carbon monoxide, the use of sulfur dioxide in catalysis is very limited. We have developed a new sulfur dioxide surrogate, DABSO, which is a stable, solid reagent that is now commercially available. Using DABSO we have developed a series of new reactions, including the palladium-catalysed aminosulfonylation process shown below.

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.

“Well-Defined and Robust Rhodium Catalysts for the Hydroacylation of Terminal and Internal Alkenes”, Amparo Prades, Maitane Fernández, Sebastian D. Pike, Michael C. Willis and Andrew S. Weller, Angew. Chem. int. Ed201554, 8520 –8524.

“Combining Organometallic Reagents, the Sulfur Dioxide Surrogate DABSO and Amines: A One-Pot Preparation of Sulfonamides, Amenable to Array Synthesis”, Alex S. Deeming, Claire J.  Russell and Michael C. Willis, Angew. Chemie. Int. Ed201453, 1168–1171.

“Activating Group Recycling in Action: A Rhodium-Catalyzed Carbothiolation Route to Substituted Isoquinolines”, Milan Arambasic, Joel F. Hooper and Michael C. Willis, Org. Lett. 201315, 5162-5165.

“2-Aminobenzaldehydes as Versatile Substrates for Rhodium-Catalyzed Alkyne Hydroacylation: Application to Dihydroquinolone Synthesis”, Matthias Castaing, Sacha L. Wason, Beatriz Estepa, Joel F. Hooper and Michael C. Willis, Angew. Chemie. Int. Ed201352, 13280–13283.

“Carbon-carbon bond construction using boronic acids and aryl methyl sulfides: Orthogonal reactivity in Suzuki-type couplings”, Joel F. Hooper, Rowan D. Young, Indrek Pernik, Andrew S. Weller and Michael C. Willis, Chem. Sci20134, 1568 – 1572.