Synthesis: Synthesis of Natural Products and Biological Probe Molecules, New Synthetic Methodology, Biomimetic Synthesis, Metal-Mediated Catalysis, Organocatalysis, Supramolecular Chemistry, Physical Organic Chemistry Head of Section: Prof Stephen Clark

Research Group Leaders

Dr Götz Bucher, Prof Stephen Clark, Dr Graeme Cooke, Dr Richard Hartley, Prof Pavel Kočovský, Dr Rudi Marquez, Dr Andrew Sutherland

Research Areas

Synthesis of Bioactive Natural Products
This area of research concerns the total synthesis of natural product targets of high structural complexity which possess potent bioactivities such as alkaloids, terpenoids, polycyclic ethers, macrocycles and heteroaromatic compounds. Natural products currently undergoing total synthesis include the marine polyethers hemibrevetoxin B, CTX-3C and gambieric acid A, which possess either neurotoxic or anti-fungal activity. Syntheses of the marine alkaloids manzamine A and nakadomarin A are also under investigation; the former compound possesses a wide range of biological activities including anti-cancer, anti-malarial and anti-HIV activity. Other marine natural product targets include the complex polycyclic diterpenes ophirin B and litophynin E and the anti-leukaemic alkaloid convolutamydine A.
The biomimetic synthesis of complex bioactive natural products is also an area of current interest. The synthesis of polycyclic indole mycotoxins from simple precursors using biosynthetically inspired polyene cascade reactions, in which several bonds and stereogenic centres are created in a single reaction with a high degree of control, is currently under investigation.

Development of New Synthetic Methodology
New synthetic methodology development is fundamental to the evolution of molecular synthesis, and a diverse range of new synthetic methods is currently under investigation in the Synthesis Section at Glasgow. This work includes the stereoselective construction of highly functionalised synthetic intermediates by rearrangement of catalytically generated ammonium and oxonium ylides and the synthesis of allylic amides by palladium-mediated aza-Claisen rearrangement reactions. Rearrangement reactions are also being used to prepare complex spiro-fused systems that are found in some bioactive natural products.
Several catalytic and stoichiometric metal-mediated reactions are also under investigation. The use of organotitanium reagents for the alkylidenation of carbonyl compounds has been explored extensively and this work is being applied to the solid-phase synthesis of diverse chemical libraries of piperidines, quinolines, benzofurans and indoles. There are also important innovations in the application of new catalytic asymmetric reactions to synthetic problems; novel chiral metal complexes have been developed for the asymmetric allylic oxidation and amination of alkenes and for alkene cyclopropanation and epoxidation. Chiral palladium complexes are being used to perform enantioselective catalytic aza-Claisen rearrangement reactions.
Organocatalysis is an area of research that is currently of huge interest to both industrial and academic researchers. The Synthesis Section at Glasgow is making several important and highly original contributions to this area, most notably by developing new generations of organocatalysts for the highly asymmetric hydrosilation of ketones and ketimines and for the asymmetric addition of allylic silanes to aldehydes and ketones.

Supramolecular Chemistry and the Synthesis of Molecular Devices
The synthesis of supramolecular systems as the basis of new devices and ‘smart’ materials is a burgeoning area of research. Research at Glasgow is focussed on the synthesis of self-assembling structures that have the propensity to undergo electrochemically controllable molecular recognition. These supramolecular systems are being exploited as model systems for flavoenzymes and as the basis of electrochemically-driven molecular machines and devices. This work is also being applied to the construction of molecular polymers and surfaces with electronically tuneable recognition properties.

Physical Organic Chemistry
Much of the research in this area involves the preparation of molecular probes as tools for the detailed study of reaction mechanisms. This work frequently relies on the detection and study of highly reactive intermediates (e.g. radicals, carbenes and nitrenes) that are found in many chemical and some biochemical reactions. The synthesis of molecules possessing unusual physical and chemical properties by virtue of their unusual three-dimensional architectures is also an important area of investigation.
Physical organic chemistry in the Department of Chemistry at Glasgow has recently received substantial funding in the form of the £4.4M Science and Innovation Award given to WestCHEM in partnership with Strathclyde Institute for Pharmacy and Biomedical Sciences. This funding is being used to support appointments in both the Departments of Chemistry that comprise WestCHEM.

Biological Chemistry and the Synthesis of Probe Molecules and Therapeutic Agents
Several non-natural product targets are being synthesised as possible probe molecules and potential therapeutic agents. Current synthetic targets include peptidomimetics as potential would-healing agents, protein phosphatase inhibitors and novel imaging agents to study noradrenaline transport and indentify benzodiazepine receptors. The synthesis of spin trap agents to explore oxidative stress at the cellular level is also under active investigation.