SCI Scotland Group PhD Student Competition Winner - Katherine Geoghehan

14 December 2017

14 December 2017

Bridging the gap between academia and industry - Suzuki-Miyaura

Katherine Geogheghan, University of Edinburgh - Lloyd-Jones group

Mechanistic chemistry can bridge the gap between academia and industry, allowing the rational design, optimisation and scale up of new chemical reactions. Cross-coupling has become an essential tool for organic synthesis. The ability to form a new carbon-carbon bond is used extensively throughout discovery chemistry in the pharmaceutical, materials and agrochemical sectors. The pioneer chemists who developed cross-coupling into the key reaction it is today are Heck, Negishi and Suzuki. The impact of their research in "palladium-catalysed cross couplings in organic synthesis" has become so significant that they became Nobel Prize laureates in 2010, giving chemists the ability to form more new and complex molecules than ever before. Many “blockbuster” drugs contain biaryl moieties, including Lipitor from Pfizer, which made a record $130 billion over 15 years.

The Suzuki-Miyaura reaction was originally reported in 1979 and since then the use of this reaction has continued to grow, leading it to become the most widely utilised tool for catalytic carbon-carbon bond formation. The palladium catalysed coupling of a boronic acid and an organohalide compound is used greatly throughout the pharmaceutical industry, and three decades later we are still working to further improve and understand this complex reaction. The need to improve is obvious. It allows higher yields, milder conditions, and more diverse products. Recent developments now allow the coupling of previously challenging substrates, reactions can be performed at lower temperatures and with lower catalyst loadings, all reducing the cost and increasing the scope of this powerful reaction. But without a full understanding of the mechanism, improvements can only take us so far.

The mechanism of the Suzuki-Miyaura reaction continues to be an area of controversy. While the use of boronic acids has been widely studied there are still problems left unsolved. Boronic acid derivatives are used as replacements for unstable boronic acids in order to mitigate undesired side reactions, but very little is known about the mechanism by which these species react. Whether they can cross-couple directly or need to undergo pre-activation remains unknown. My research aims to elucidate the mechanism of this cross-coupling process. This in-depth understanding could be directly implemented industrially to improve the scale up process for chemical synthesis and has two major advantages, not only producing more desired product but giving a reduction in waste side products, which cost time, money and energy to separate and dispose of. This insight would also aid discovery chemistry, in which carbon-carbon bond construction is frequently carried out using cross-coupling reactions.

A key example of where this knowledge would be beneficial is in the synthesis of a treatment for advanced lung cancer, crizotinib, a tyrosine kinase inhibitor. Tyrosine kinases are enzymes that can stimulate cancer cells to grow. Pfizer achieved large scale synthesis of this complex molecule using the Suzuki-Miyaura coupling of a boronic acid derivative, but we still don’t fully understand the mechanism. This missing information could help to minimise unwanted side products and increase conversion to the desired product, which could go on to save lives.

My research directly undertakes this challenge, to fill this void in knowledge which bridges the gap between academia and industry.

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