Research

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PUZZLE

Our research activities centre on catalysis and synthesis. Current programmes include: (i) the discovery and development of novel catalysis based transformations; (ii) probing control factors and mechanisms of catalytic processes; (iii) the design of new catalyst systems; and (iv) catalysis applications for target-driven synthesis of biologically-relevant materials. 

Overview: The synthesis of organic molecules is of vital importance to society and our standard of life. Alongside enhancing our fundamental understanding, developments in synthesis underpin sustainability and advances in vital areas such as materials, agrochemicals and pharmaceuticals. Natural feedstock’s for synthesis only exist in accessible form in limited quantities and so it is important to make sure we use these effectively. Our programme builds around the principle of using catalysis to enable faster, easier and more efficient synthesis whilst increasing our understanding of these complex processes. Our development of new strategies and novel transformations is aimed at offering more efficient and elegant synthetic routes, thus reducing the time, effort, cost and waste associated with the preparation of complex molecules.

Available Resource: “Diazofree Ynamide Encyclopedia”

An interview with Paul in SYNFORM can be found here.


Transformation Discovery and Strategy Development 

Catalytic methods are ideally suited to the task of imparting novel reactivity and high selectivity under mild conditions and so their use is integral to our work. A major focus is developing and exploiting the idea that an alkyne activated by a π-acid has the potential to show reactivity compatible with an alkylidene carbenoid over the course of a transformation. This means that a simple unit might be employed as a densely reactive intermediate without need for leaving groups or prior pre-activation of the molecule leading to a wide range of potential transformations.

We are exploring a variety of new coupling and cyclisation reactions that start from simple, readily-available materials and lead to significantly more useful and complex products in a low waste reaction, generally with complete atom economy of substrate. Some examples of our work are shown below:

New Approach to Cycloadditions: We recently introduced an alternative strategy to access highly functionalised oxazoles through a formal [3+2]-cycloaddition across a triple bond. Classically this process requires an acyl nitrene to react as a 1,3-N,O-dipole. However the reactions of these are hard to control and no effective application of them has been reported for oxazole formation. Our approach employs robust crystalline and bench stable N-N ylides to act as acyl nitrene equivalents.

The gold catalysed process is proposed to proceed through an unprecedented bis-hetero 4-π cyclisation. Work is underway to explore the potential utility of this cycloaddition strategy in a wider sense.

oxazole formation

Angew. Chem. Int. Ed., 2011, 38, 8931

Alkynes as “Masked” Ylides: One of our major strands of research involves the formation and utility of sulfur ylides directly from alkynes. The ready access to these intermediates from simple, robust functionality under mild reaction conditions contrasts with the longer classical approaches that require several synthetic manipulations and the use of highly reactive and sensitive intermediates and reagents. A range of new transformations have been developed from this programme including intermolecular couplings and cascade processes, as well as intramolecular reactions to prepare sulfur-heterocycles in a cycloisomerisation strategy.

alkynes as masked ylides

Chem. Commun., 2008, 238; Angew. Chem. Int. Ed., 2009, 48, 8372; Pure Appl. Chem., 2010, 82, 1537
and Synlett, 2012, 23, 70

Ynamides as Alternatives to Diazocompounds: Metal carbenes are tremendously useful species for modern synthesis and reaction discovery and are usually accessed in a controlled fashion through the metal promoted decomposition of the diazo-functional group. This approach suffers from a number of drawbacks which limit its uptake in synthesis and other applications, not least the need to preinstall the sacrificial diazo-functionality and the relative instability of that group. One of our major programmes involves the study and development of alternative strategies to access and employ metal carbene systems for the development of efficient synthesis. In this area we recently reported the intermolecular oxidation of ynamides and ynol-ethers as a controlled method for site-selective formation of gold carbenoids and are studying the application of this method for reaction discovery.

Gold catalysed oxidations of ynamides

Chem. Commun., 2011, 47, 379

Silver Catalysis: The use of coinage metals such as silver and gold in metal carbene chemistry is underdeveloped. We recently reported the use of simple silver salts to catalyse a powerful carbon-carbon and carbon-sulfur bond-forming process. Under mild conditions, allyl or propargyl sulfides react with a diazocompound to access functionalised alkene and allene products. The reaction conditions tolerate a range of various functional groups.

Silver catalysed Doyle-Kirmse reaction

Org. Biomol. Chem., 2009, 7, 1276

Novel Molecular Architectures: Our reaction-discovery and strategy-development programmes result in rapid access to unique-, or otherwise difficult to access molecular architectures with potentially unique and/or novel chemical and physical properties. We hope to explore and exploit such systems across diverse areas including chemical imaging, medicinal and bio-chemistry as well as applying them in the development of new synthetic strategies.


Control Factors in Gold Catalysis:

Intertwined with our discovery programmes we seek to probe the mechanisms and control factors in the rapidly developing area of gold catalysis. By understanding the influence of various factors in our reaction systems we gain greater control and predictive ability in this area of catalysis thus furthering its utility to synthesis.

Our recent pyrrole synthesis highlights some of the complexities in this area of catalysis. During the development of this process, careful study showed the formation of two different isomers of the pyrrole from the same starting materials. The reaction conditions could be tuned to favour one isomer over the other depending on the counterion - highlighting the potentially important role of this species in the wider area of catalysis. Depending on the relative basicity of the counterion the intermediate carbocation underwent either deprotonation or 1,2-aryl shift to afford product divergence.

pyrrole synthesis

Org. Lett., 2009, 11, 2293

Further labelling studies showed the situation to be more complex: there are two diverging pathways leading to the formation of the 2,4-disubstituted pyrrole: the 1,2-aryl shift proceeds alongside a regio-divergent ring-opening and ring-expansion pathway.

pyrrole formation: mechanistic studies

J. Organomet. Chem., 2011, 696, 159 and Beilstein J. Org. Chem., 2011, 7, 839

Target synthesis:

With the development of new reactivity modes and transformations we look to exploit and test these chemistries in application to target molecules and their structural analogues.


Catalyst design:

Alongside our reaction discovery programmes, we are exploring the design, realisation and study of new catalysts for organo- and transition-metal based systems. Alongside enhancing catalyst efficacy we look to incorporate alternative activation modes and control-motifs into our active structures.


Funding:

We are grateful for financial support for our research from the University of Birmingham, EPSRC, EU and AstraZeneca.