Pyrrolidine and piperidine nitrogen heterocycles occur widely in nature as components of pyrrolizidine, indolizidine and quinolizidine alkaloids and are of considerable biochemical, pharmaceutical and agricultural importance because of their diverse biological activities. Their toxicity and halucinatory activities are well known, but probably more important are their antibiotic, antibacterial, antifungal and cytotoxic effects, since they offer the opportunities for the development of novel pharmacological agents. Examples of compounds of interest in my research are pramanicin, preussin, anisomycin, kainic acid, oxazolomycin, lemonomycin, kaitocephalin and the echinocandins. Our current focus is in the development of simple and efficient routes to highly functionalised pyrrolidinones and piperidinones, with substitution at any or all positions around the ring.

We have developed two approaches to access these compounds:

- By modification of a pre-existing ring. This uses heterocyclic templates derived from pyroglutamic 1 and 6-oxopipecolic acids 2 which permit ring modifications, to introduce carbon and heteroatom functionality in a diastereoselective and enantioselective manner. These compounds offer several important advantages as synthetic starting materials: they are fully protected, with a single protecting group, and prepared using cheap reagents; they are of low molecular weight; they have potential for ring functionalisation; and they possess a concave/convex bicyclic system for stereocontrol. All of these compounds have been used to access highly functionalised pyrrolidinones and piperidinones, and work is now underway to apply these compounds in natural product synthesis and for the construction of compounds of well defined molecular architecture.

- By ring formation. The second approach uses highly chemoselective and stereoselective ring closures of a template derived from serine 3; this provides rapid access to highly functionalised tetramic acids and related compounds.

Having demonstrated that approaches to these ring systems are viable, studies to extend their utility in several key areas have been commenced:

- Excitatory Amino Acids. Glutamate is the endogenous neurotransmitter in mammalian systems, and over the last decade there has been substantial interest in the synthesis of analogues of glutamate as selective agonists and antagonists of various CNS receptors, particularly in the context of brain chemistry. This has been important in the development of new treatments for acute brain injury, such as stroke, and for degenerative disorders, such as Alzheimer’s disease. We are interested in the application of some of our published methodology to the synthesis of compounds which would be useful for probing the structure of some of the iGluR and mGluR receptors, in order to understand their function at the molecular level. Current work includes the synthesis of photoaffinity labels suitable for structural studies of the KA and mGluR receptors.

- Antibiotics. The emerging resistance of many organisms to the penicillin and cephalosporin antibiotics is a serious medical problem, and one which will require an ongoing committment from academic and industrial laboratories to ensure that these drugs retain their usefulness. We are interested in the application of some of our published methodology to the synthesis of novel antibiotic compounds which have hitherto remained unexamined.  Oxazolomycin and its analogues are current synthetic targets, to provide compounds suitable for determining details of the biological mode of action of this unusual class of compound. Extensiv work with equisetin has identified new classes of potent antibacterials.  Lemonomycin is also a current target, since this compound has recently been shown to exhibit promising biological activity.

- Molecular Architecture. The value of such pyrrolidine-derived structures has been demonstrated by the development the novel anti-influenza neuraminidase inhibitors A-192558 and A-315675. During the course of our work, we have observed that many pyrrolidinones and piperidinones exhibit well-defined conformation, and that this can be controlled by remote ring substituents. Examples of compounds of interest in this regard are shown, and include conformationally restrained alanine, lysine and ornithine analogues. Current work seeks to use these compounds to develop novel peptidomimetic molecular structures. This work embraces molecular modelling, synthetic chemistry and detailed structural analysis using NMR spectroscopy.