Csp3-H Zincation: Functional Group Tolerant Modifications of Pharmaceutical Moieties

Selective C-H functionalisation is a gold-standard reaction in synthetic chemistry for pharmaceutical and natural product synthesis, adding complexity and value to simple starting materials while generating the minimum possible waste. Medicinal chemistry prefers molecules with a high degree of 3-dimensional structure, equating to a high proportion of sp³ (compared to sp² or sp) carbons[1,2]. C-H functionalisation of sp³ centres is typically carried out in research and scale-up labs using organo-lithium or organo-magnesium reagents. However, these highly reactive species are incompatible with the delicate functional groups often found in pharmaceutical synthesis late-stage intermediates. Organo-zinc reagents are well understood to be tolerant of a wide variety of functional groups which would be destroyed by organo-lithiums or -magnesiums, and zinc-mediated C-H functionalisations have been reported for sp² positions, though Csp³-H zincations are almost unknown[3].

Recently, we have been developed the first example of a Csp³-H functionalisation of a key pharmaceutical motif, alkylthiadiazole, enabled by a zinc complex[4]. During this project, you will explore applying this strategy to a range of other common drug moieties – in each case, this will involve optimisation of Csp³-H zincation/functionalisation conditions to the new substrate before exploring the substrate scope as well as electrophilic trapping and Pd-catalysed Negishi couplings in both batch (flask) and continuous flow conditions as well as determining reaction mechanisms. The project will equip you with a range of highly desirable skills in practical organic synthesis, advanced synthetic technologies including flow chemistry and reaction monitoring instrumentation and mechanistic studies. Zinc-mediated Csp³-H functionalisation is an underexplored area, and as such this project will afford you significant freedom to guide the direction of research according to your interests. Research will take place in the Heriot-Watt Institute of Chemical Sciences (ICS) which provides a vibrant, supportive and inclusive environment for chemistry research across a wide range of fields. Flow chemistry and reaction monitoring will be facilitated by the presence of the Continuum Flow Lab (https://analysisforindustry.site.hw.ac.uk/about/cf/), a cutting-edge facility dedicated to these vital enabling technologies, experience with which is in high demand from the pharmaceutical industry.

For details of our previous research, please visit the Barker group website: https://barkergroup.wordpress.com/. Applicants should contact Dr Graeme Barker directly for informal enquiries.