“In my opinion, there is a problem that is central to organic chemistry alone and in which biologists cannot help us. We all agree...that the emphasis in synthetic research is the synthesis of properties, and not just compounds.”
Albert Eschenmoser
Research in the Gilmour Lab is focussed on translating fundamental principles of structure and reactivity to applications in catalysis and biomedicine. Physical organic chemistry is at the core of our entire research programme and drives innovation.
Despite the abundance of organic compounds in Nature, only a handful contain fluorine. In contrast, fluorinated organic motifs are found in around 30-40% of all pharmaceuticals and agrochemicals. Fluorination has also played a prominent role in the discovery and development of many of the high-performance materials that are now ubiquitous in everyday life; Teflon® is a prominent example. Closer inspection of the fluorination patterns in these functional molecules reveals striking extremes towards perfluorination (in both 2D and 3D scaffolds) or single site fluorination predominantly in aryl substituents. Consequently, most fluorinated moieties in functional materials lack stereochemical information and are thus achiral. This disparity between the paucity of naturally occurring organofluorine compounds and their venerable history in functional molecule design confirms the enormous potential of fluorinated materials in the discovery of novel properties. That progress has largely been confined to 3 dimensional achiral and 2 dimensional achiral architectures reflects the synthetic challenges associated with preparing stereochemical defined multiply fluorinated systems. Our fluorine programme aims to explore uncharted chemical space to facilitate the discovery of next generation materials for medicinal chemistry, agrochemistry, material sciences and bio-medicine and is generously funded through ERC Starter and ERC Consolidator Grants from the European Commission.
Leveraging fluorine effects to regulate structure and achieve molecular pre-organisation to achieve a specific function is a major interest of the group. Our first independent publication “The Fluorine-Iminium Ion Gauche Effect: Proof of Principle and Application to Asymmetric Organocatalysis” (Angew. Chem. Int. Ed. 2009, 48, 3065) introduced the notion that stereoelectronic control can be harnessed to pre-organise iminium ion intermediates derived from fluorinated pyrroldines. This approach which complements conventional steric strategies has proved to be expansive and has been exploited to interrogate the mode of action and selectivity of the celebrated MacMillan catalysts (Angew. Chem. Int. Ed. 2010, 49, 6520). Furthermore, these principles have since been extended to devise a new strategy for selective chemical glycosylation (Angew. Chem. Int. Ed. 2010, 49, 8724) and to enable the stereoelectronic control of ligand topology of gold based heterocyclic carbenes (Organometallics 2010, 29, 4424; Organometallics 2016, 35, 3040–3044). Several reviews discussing the development of these concepts have since appeared (Angew. Chem. 2011, 123, 12062; Isr. J. Chem. 2017, 57, 92-100; ACS Catalysis 2016, 6, 7167–7173; Acc. Chem. Res. 2018, 51, 1701-1710). Moreover, the effects have been harnessed in reaction design to enable enantioselective, catalysis-based routes to small heterocycles such as arizidines (Chem. Eur. J. 2014, 20, 794). More recently, the Gilmour Lab has extended the impact of successive, synergistic stereoelectronic effects in catalysis (Synlett 2016, 27, 1051–1055; Chem. Eur. J. 2017, 23, 6142-6149) and expanded the gauche effect to elements of the third period, for instance in sulfur-based heterocycles (Chem. Sci. 2015, 6, 3565).
Our interest in the venerable fluorine gauche effect (Acc. Chem. Res. 2018, 51, 1701) has led us to develop a main group I(I)/I(III) catalysis-based platform to enable the formal addition of fluorine across an alkene strategy I(I)/I(III) (J. Am. Chem. Soc. 2016, 138, 5004). This transformation has also been rendered enantioselective (Angew. Chem. Int. Ed. 2018, 57, 16431) and utilised in medicinal chemistry with industrial partners (J. Med. Chem. 2020, 63, 6225-6237; Org. Lett. 2019, 21, 7741-7745). The strategic introduction of fluorine atoms to modulate protein-small molecule interactions has been demonstrated (Angew. Chem. Int. Ed. 2019, 58, 10990). Given the dearth of organofluorine compounds in biology, we envisage that this platform will likely be expansive in designing new (chiral) bioisosteres as drug discovery expands into 3D chemical space.
The renaissance of preparative glycochemistry is largely due to our ever-increasing understanding of biological systems and the ways in which they can be manipulated by natural and non-natural products. Carbohydrates are essential in this regard owing to their natural function in modulating molecular recognition. Driven by the development of chemical biology, synthetic chemists must continually improve and expand upon their existing arsenal of glycosylation methods in order to construct larger, more complex glycostructures in a reliable, stereocontrolled manner. Mild, efficient methods are required not only for the synthesis of complex oligosaccharides, but also to allow the resulting small molecule to be conjugated to larger scaffolds in a manner reminiscent of post-translational modification. In recent years, fluorinated glycostructures have appeared with increasing frequency owing to their ability to function as excellent bioisosteres of 2-deoxy sugars and their often enhanced pharmacokinetic profiles and metabolic stabilities. However, preparative methods for the construction of fluorinated oligosaccharides are underdeveloped. This is partly due to the perceived deactivating nature of the fluorine and lack of anchimeric assistance. In an attempt to reconcile the unfavourable reactivity profiles of F-glycosyl donors with the recent surge of interest in fluoro-oligosaccharide synthesis for biomedical research, a programme to develop highly effective glycosylation protocols has been initiated to meet the clear demand for molecular probes and pharmaceutical candidates.
Consequently, a particular interest in fluorinated carbohydrates has evolved where delineating the role of the fluorine substitution on conferring glycosylation selectivity is a central theme (Angew. Chem. Int. Ed. 2010, 49, 8724; Synlett 2011, 1043; Chem. Eur. J. 2012, 18, 8208; J. Fluorine Chem. 2015, 96; Eur. J. Org. Chem. 2015, 32, 6983; Chem. Eur. J. 2018, 24, 2832-2836). More recently, the development of a “Stereospecific α-Sialylation by Site-Selective Fluorination” has been realized (Angew. Chem. Int. Ed. 2019, 58, 3814-3818) together with structural investigations of oxocarbenium ions (Angew. Chem. Int. Ed. 2019, 58, 13758-13762). These achievements have
significant practical applications and a clinical candidate has now been identified for the non-invasive (PET) imaging of pathogenic bacterial for human medicine in cooperation with the University Hospital Münster (UKM) and the European Institute for Molecular Imaging (EIMI).
Understanding the role of complex gangliosides in neurodegeneration is a crucial aspect of Multiple Sclerosis research. Together with colleagues in the Institute for Neuropathology, we are actively developing tools to study the behavior of myelin-producing oligodendrocyte cells. Cognisant of the fact that myelin contains elevated levels of the sialosylgalactosylceramide gangliosde GM4, we have explored the effect of single site fluorination on oligodendrocyte differentiation, and compare this with the naturally occurring structure (ACS Chem. Neurosci. 2018, 9, 1159-1165; ACS Chem. Neurosci. 2020, 11, 2129-2136). Although no discernible effect on oligodendroglial cell viability is observed with the native epitope found in myelin, the fluorine scaffolds leads to an intriguing upregulation.
Alkene fragments are ubiquitous in complex natural products and small molecule drugs. Despite this importance, strategies to enable simple geometric E → Z isomerisation remain conspicuously underdeveloped. This significantly limits the scope of downstream, stereospecific manipulations. Energy transfer catalysis provides a powerful solution to this challenge (J. Am. Chem. Soc. 2015, 137, 11254-11257; J. Am. Chem. Soc. 2016, 138, 1040–1045). Most recently, taking inspiration from iterative polyketide biosynthesis, we have consolidated the requirements for geometric control, atom economy and efficiency in a simple C3 boro-acrylate unit. Predicated on selective energy transfer from excited state thioxanthone to the conjugated substrate isomer, E → Z directionality results from subtle rotation of the C(sp2)-B bond by 90° in the product. Deconjugation renders re-excitation inefficient by contracting the π-system, thereby providing an unprecedented gating mechanism for alkene isomerization. The reaction is characterized by broad scope and high efficiency. Importantly, the boron substituent renders this component of the chromophore a traceless surrogate of the aryl groups that are synonymous with alkene photo-isomerizations. To demonstrate the synthetic utility of the method, we report the stereocontrolled construction of two polyene therapeutics, namely Aletretinoin (9-cis-retinoic acid) and Isotretinoin (13-cis-retinoic acid) (Science 2020, 369, 302-306).
