Lecturer in Organic Chemistry

B.A., Ph.D. (Cambridge).

Tel: 0116 2522128

email: sh78@le.ac.uk

Research Interests

Current research projects are in the area of organic synthesis and its application to Chemical Biology and Green Chemistry. These projects cover many areas including the synthesis of biologically active molecules and the development of new synthetic methods.  Projects are multi-disciplinary involving contemporary organic synthetic and spectroscopic techniques as well as mechanistic chemistry.

Glycosidase Enzyme Inhibitors

We are interested in the synthesis and biological activity of novel glycosidase inhibitors based on azasugars and have recently reported the first asymmetric synthesis of 3-aminopyrollidines such as 1.¹  We are currently exploring the attachment of  a second aglycone-mimicking unit to compounds such as 1 to generate aza-disaccharides. These compounds are often more potent and/or selective inhibitors than the parent azasugar due to increased interactions with the aglycone binding region within the active site of glycosidase enzymes. In related studies we have already synthesised a number of novel O - and N -linked aza-disaccharides (e.g. 2) employing complementary pinacol and ring closing metathesis (RCM) – dihydroxylation strategies. Our interest in glycosidase inhibitors also extends into the synthesis of novel calystegines such as 3.²

Novel CNS agonists – Epibatidine Analogues

Novel CNS agonists are potential drugs for the relief of pain and the treatment of neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease.  In this regard we are interested in the synthesis and biological activity of novel analogues of the natural product epibatidine that are potent and subtype selective N-acetylcholine receptor (nAChR) agonists.  We have recently reported our results with one such compound - isoepibatidine 4^3,4 and current studies are investigating the synthesis of fluorinated analogues such as 5.

Mechanistic Chemistry

During the course of our synthetic projects we sometimes discover unusual or unexpected results that can lead to an intriguing insight into the mechanism of a particular reaction.  We are always keen to fully investigate these findings to shed some light on our observations.  Thus we have recently reported the use of cyclopropyl ketones to investigate the mechanism and rate of SmI₂-mediated pinacol reactions.^5,6 

Current mechanistic studies are investigating skeletal rearrangements of the 2-azanorbornane system present in our epibatidine analogues. 

Recent Publications

1.  Asymmetric synthesis of 3-amino-4-hydroxy-2-(hydroxymethyl) pyrrolidines as potential glycosidase inhibitors’ Curtis K.L.;  Evinson E.L.; Handa S.; Singh K. Org. Biomol. Chem., 2007, 5, 3544 - 3553.
2. ‘The first syntheses of 6,7-dihydroxylated calystegines and homocalystegines' Groetzl, B.; Handa, S.; Malpass, J.R. Tetrahedron Lett. 2006, 47, 9147-9150.
3. ‘Approaches to syn-7-substituted 2-azanorbornanes as potential nicotinic agonists; Synthesis of syn- and ant-isoepibatidine’ Malpass, J.R.; Handa S.; White R. Org. Lett., 2005, 7, 2759-2762.
4. ‘Epibatidine isomers and analogues: Structure-activity relationships’ White R.; Malpass J.R.; Handa S.; Baker, S.R.; Broad, L.M.; Folly, L.; Mogg A. Bioorg. & Med. Chem. Lett., 2006, 16, 5493-5497.
5.  ‘Samarium(II)iodide-mediated intramolecular pinacol coupling reactions with cyclopropyl ketones’ Foster S.L.; Handa S.; Krafft M.; Rowling D. Chem. Commun. 2007, 4791-4793.
6.  ‘Synthesis of N-heterocyclic diols by diastereoselective pinacol coupling reactions' Handa, S.; Kachala, M. S.; Lowe, S. R. Tetrahedron Lett. 2004, 45, 253-256.