Development of a General sp2-sp3 Coupling Methodology

2010 saw the award of the Nobel Prize for Chemistry to Negishi, Suzuki and Heck for the palladium-catalysed cross coupling between aryl halides and other aryl / alkene systems. Over the past 20 years, sp2-sp2 couplings have changed the way in which the Pharmaceutical industry builds molecules, and thus are rightly deserving of this highest award. Furthermore, these couplings have proven to be tolerant of a wide range of functional groups, solvents, and substrates, making them a general solution to the synthesis of biaryls and aryl-alkenes. Currently, the desire for inclusion of more sp3 atoms within lead compounds has never been higher, with a number of studies confirming that compounds which have more three-dimensionality have a lower attrition rate on the long journey to become a new chemical entity. With current attrition rates around the 97% level, any small lowering of this could have a huge economic impact on the Pharmaceutical sector. Thus attention has turned to adaptation of the existing palladium-catalysed coupling technologies to the formation of sp2-sp3 coupled products. Whilst there are some notable methodologies within this relatively young field of research, there has yet to emerge a general and reliable method to couple aryl and alkyl groups.

This programme of research will take a number of preliminary findings and transform these into a general and flexible methodology for the synthesis of aryl and heteroaryl rings coupled to stereogenic sp3 alkyl groups. Unlike the majority of research in this area, this new methodology will not rely on palladium or other expensive / toxic metals as catalysts, but rather delineate a method which exploits the underdeveloped chemistry of sulfoxides. This will therefore be complementary to other methodologies being investigated around the world.

The development of a general and reliable methodology for the coupling of sp2 and stereogenic sp3 carbons would have a very significant impact on the synthetic community both in academe, and (most significantly) in the pharmaceutical arena. The ability to reliably synthesise molecules with stereogenic sp3 carbons attached to aryl or heteroaryl rings, with complete regio and stereocontrol would give synthetic chemists easy access to a vast new collection of compounds suitable for screening for potential lead compounds for future therapeutics. As compounds with a higher proportion of sp3 atoms seem to have a lower attrition rate on the long road to becoming an approved drug, this could have a huge potential economic impact on the pharmaceutical industry (attrition rates are currently 97%, and thus any small improvement here can make a massive economic impact), and also obviously open the door to new therapeutic reagent discoveries.

Smaller, but still significant impacts from the successful outcome of this work will be the addition to the literature of a method for the cross-metathesis of vinyl sulfoxides, which is not currently known, development of the relatively small number of reports on the conjugate addition to vinyl sulfoxides, and of course the training of a PhD student, giving them the skills and competencies needed for a successful career in scientific research.