The Sutherland Research Group

Group2011

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Research Interests

Our research focuses on the development and understanding of new organic reactions with particular emphasis on using transition metal catalysis to create new chiral molecules. Once developed, we then apply our new chemistry to the synthesis of biologically active and medicinally important compounds. In collaboration with biologists and clinical physicists we also test the biological properties and study the potential applications of our new compounds.

Current projects involve:

1. Development of Palladium-Catalysed Aza-Claisen Rearrangements for the Synthesis of Natural Products: Early studies on the use of the Overman rearrangement for the synthesis of (2S,3S,4R)-γ-hydroxyisoleucine,1 the amino acid component of the natural product, funebrine have led to the development of a palladium(II)-catalysed, ether-directed aza-Claisen rearrangement. Extensive experimentation has allowed the identification of the methoxymethyl (MOM) ether as the most effective at directing the metal catalyst to one face of the allylic trichloroacetimidate resulting in a stereoselective rearrangement giving the major erythro-product in ratios of up to 16:1.2,3 Further studies have shown the involvement of both oxygen atoms of the MOM-group in coordinating the catalyst and that other metals such as Pt(II), Au(I) and Au(III) can also be used to catalyse the reaction.4-6 We have shown that the products of this reaction, allylic trichloroamides can be easily oxidised to give after deprotection, the corresponding β-hydroxy-α-amino acid.7 Alternatively, used in conjunction with ring closing metathesis reactions has led to the preparation of simple pyrrolidine and piperidine natural products such as α-conhydrine.3

Rearrangement Scheme

We have also shown that linear allylic trichloracetimidates with a side chain containing a terminal alkene can undergo a tandem, one-pot aza-Claisen rearrangement/ring closing metathesis resulting in the direct and highly efficient synthesis of cyclic allylic amides.8 Using side chains of different lengths has allowed the preparation of 5-, 6-, 7- and 8-membered analogues in excellent yields and the use of chiral Pd(II)-catalysts such as (S)-COP-Cl results in the asymmetric synthesis of these compounds. The products of this highly efficient one-pot tandem process, cyclic allylic trichloracetamides, are excellent synthetic intermediates and can be easily manipulated to introduce a range of diverse functional groups. These are currently being used for the total synthesis of piperidine and amaryllidaceae alkaloids, such as (+)-γ-lycorane and (+)-2-deoxylycoricidine.

Tandem Process

1. A. G. Jamieson, A. Sutherland and C. L. Willis, Org. Biomol. Chem., 2004, 2, 808. 
2. A. G. Jamieson and A. Sutherland, Org. Biomol. Chem., 2005, 3, 735. 
3. A. G. Jamieson and A. Sutherland, Org. Lett., 2007, 9, 1609. 
4. A. G. Jamieson and A. Sutherland, Tetrahedron, 2007, 63, 2123. 
5. A. G. Jamieson and A. Sutherland, Org. Biomol. Chem., 2006, 4, 3889. 
6. M. D. Swift and A. Sutherland, Tetrahedron Lett., 2007, 48, 3771. 
7. K. N. Fanning, A. G. Jamieson and A. Sutherland, Org. Biomol. Chem., 2005, 3, 3749. 
8. M. D. Swift and A. Sutherland, Org. Lett., 2007, 9, 5239.

2. New Tracer Agents For The SPECT Imaging Of The Noradrenaline And Peripheral Benzodiazepine Receptors: In collaboration with Dr Sally Pimlott (Western Infirmary) and Dr Deborah Dewar (Dept. of Clinical Medicine), we have initiated a programme for the development of radioiodinated compounds for the Single Photon Emission Computerised Tomography (SPECT) imaging of neurological receptors that are implicated in a range of neurological disorders such as clinical depression, Parkinson’s disease, Alzheimer’s disease, anxiety and stroke. For example, iodinated stereoisomers and derivatives of reboxetine have been prepared for the SPECT imaging of the noradrenaline receptor.1,2 These compounds have been prepared using the Sharpless asymmetric epoxidation to introduce the stereogenic centres. Construction of the morpholine ring was then followed by a copper catalysed aromatic halogen exchange reaction to introduce the iodine label. In vitro testing of these compounds using a [3H]nisoxetine displacement assay with homogenised rat brain show these compounds to have nanomolar affinity with the noradrenaline receptor.2

Reboxetine Synthesis

A short, flexible synthesis of PK11195, a potent ligand for the peripheral benzodiazepine receptor has also been developed.3 This new approach involves a Heck type reaction for the synthesis of the isoquinoline ring, introduction of the chlorophenyl group using a Suzuki reaction and finally formation of the side-chain amide using an acylation/alkylation two-step strategy. The flexibility of this approach has been demonstrated by the synthesis of a bromo-analogue which has been used to prepare the corresponding iodide and an organostannane for SPECT imaging.4 Use of these derivatives show that radioiodination is most efficient using an electrophilic iododestannylation reaction giving radiolabeled [123I]-PK11195 with excellent specific activity. Work is currently underway on the design and synthesis of new structural analogues of PK11195 that may lead to imaging agents with greater selectivity for the peripheral benzodiazepine receptor.

PK11195


1. N. K. Jobson, R. Spike, A. R. Crawford, D. Dewar, S. L. Pimlott and A. Sutherland, Org. Biomol. Chem., 2008, 6, 2369.
2. N. K. Jobson, A. R. Crawford, D. Dewar, S. L. Pimlott and A. Sutherland, Bioorg. Med. Chem. Lett., 2008, 18, 4940.
3. L. Stevenson, S. L. Pimlott and A. Sutherland, Tetrahedron Lett., 2007, 48, 7137.
4. S. L. Pimlott, L. Stevenson, D. J. Wyper and A. Sutherland, Nucl. Med. Biol., 2008, 35, 537.

3. Synthesis and Design of Substituted Polyazamacrocyles, New Anti-Parasitic Agents: In collaboration with Dr Michael Barrett (Division of Infection and Immunity), we have initiated a research programme to develop new compounds to treat human African trypanosomiasis and malaria. The aim in this programme was to develop compounds which might interfere with polyamine biosynthesis in parasites and thus, a number of novel polyazamacrocycles were developed with reactive functional side-chains and shown to have significant in vivo activity (e.g. 1).1 More recently work has begun to probe the structure activity relationship of these compounds and it has been found that these compounds are toxic to both trypanosomes and malaria without the need for reactive side chains. Moreover, by incorporating alkyl or aryl groups into the back bone of the macrocycle has allowed the generation of a series of compounds which are more stable and thus have more potential as anti-parasitic agents (e.g. 2).2 Current work is now studying the functionalisation of these compounds with moieties such as guanidine and benzamidine groups which are recognised by specific parasite receptors (e.g. 3).3 The aim is to develop compounds that are not only potent but also parasite specific.

Polyazamacrocyles


1. J. M. Wilson, F. Giordani, L. J. Farugia, M. P. Barrett, D. J. Robins and A. Sutherland, Org. Biomol. Chem., 2007, 5, 3651.
2. C. M. Reid, C. Ebikeme, M. P. Barrett, E.-M. Patzewitz, S. Muller, D. J. Robins and A. Sutherland, Bioorg. Med. Chem. Lett., 2008, 18, 2455.
3. C. M. Reid, C. Ebikeme, M. P. Barrett, E.-M. Patzewitz, S. Muller, D. J. Robins and A. Sutherland, Bioorg. Med. Chem. Lett., 2008, 18, 5399.

4. New Approaches for the Synthesis of Amino Acids: We have a general interest in the novel and efficient synthesis of amino acids of particular biological importance. For example, a chiral pool approach from L-aspartic acid has been developed for the rapid synthesis of isotopically labelled L-arginine.1 These types of isotopically labelled amino acids have application in protein structure determination and in elucidating natural product biosynthesis. Similarly, a chiral pool approach from L-aspartic acid has been utilised for the preparation of (S)-gizzerosine.2 This amino acid causes gizzard erosion and is a potent agonist of the histamine H2-receptor. Using a different strategy, (+)-blastidic acid, the β-amino acid component of the peptidyl-nucleoside antibiotic, (+)-blasticidin S has been prepared using β-alanine as the starting material and an asymmetric conjugate addition reaction to effect the key step.3

Amino Acids

1. D. J. Hamilton and A. Sutherland, Tetrahedron Lett., 2004, 45, 5739.
2. K. N. Fanning and A. Sutherland, Tetrahedron Lett., 2007, 48, 8479.
3. R. Bischoff, N. McDonald and A. Sutherland, Tetrahedron Lett., 2005, 46, 7147.

Acknowledgements: We are grateful to the following organisations for their financial support of our work.

Funders