Professor S.G. Davies

 

Introduction

The SGD group is currently investigating a variety of topics including the development of novel asymmetric transformations and concepts, the total synthesis of natural products of biological significance, the design of unique supramolecular architectures, medicinal chemistry, chemical genomics and enantioselective recognition processes.

Novel Asymmetric Transformations

A range of novel asymmetric methodologies and concepts are currently being developed to complement and enhance the existing arsenal of asymmetric transformations available to the synthetic community.

1.1. Stereoselective N-O rearrangements

To extend the versatility of the [2,3] sigmatropic N-O rearrangement rearrangement discovered within the SGD group, [1] structural diversity within the rearrangement structure to allow for efficient chirality transfer is being evaluated. Application of this rearrangement protocol to cyclic N-benzyl-O-allylhydroxylamines such as 1 will facilitate the synthesis of cyclic N-allyl amines, with the level of diastereocontrol from a peripheral alkyl substituent allowing an extension to asymmetric synthesis. Furthermore, rearrangement of homochiral substrates such as 2-4 containing stereochemical information adjacent to the rearrangement structure, or to both N- and O- atoms is being examined (Figure 1). Elaboration of the product allylic amines will be targeted toward the synthesis of a variety of a- and b-amino acids, amino sugars and other natural products. 

Figure 1 Stereoselective N-O rearrangements

2. Asymmetric Syntheses of Carbohydrates and Amino Sugars

Various approaches utilising a suite of synthetic methodologies largely developed within the SGD group for the asymmetric synthesis of a range of carbohydrates and amino sugars are currently under investigation.  There is no doubt that the total asymmetric synthesis of bespoke carbohydrates and amino sugars or their mimics can successfully compete with syntheses from the chiral pool.

2.1. Iterative Glycolate and Amino Aldol Reactions 

Previous work from within the SGD group has demonstrated a versatile de novo synthesis of a range of hexoses by the employment of an iterative glycolate aldol strategy. [2]   To extend the synthetic versatility of this powerful methodology to the preparation of amino sugars, the incorporation of the amino functionality has to be facilitated. It is envisaged that either enolate or electrophilic components of the reaction may incorporate nitrogen bearing substituents, allowing for the stereoselective introduction of N- at any position along the carbon backbone chain, giving rise sequentially to amino tetroses and hexoses (Figure 2).

Figure 2 Iterative Glycolate and Amino Aldol Reactions

2.2. Novel Cyclisation Reactions

Polyhydroxylated pyrrolidine derivatives can be considered as sugar mimics that exhibit a diverse range of biological activity, including potential as anti-HIV candidates [3] and as glycosidase inhibitors. [4]   We have recently developed a novel ring closing protocol for the asymmetric synthesis of poly-hydroxylated pyrrolidine scaffolds, and are currently pursuing this novel methodology for the asymmetric synthesis of pyrrolidine and piperidine natural product fragments (Figure 3).

Figure 3

3. Total Synthesis

The SGD group is currently actively pursuing the total synthesis of a range of challenging natural product targets including morphine 5, ritalin 6, sphinganine 7, jaspine B 8, aminocyclopentitol 9 and blasticidic acid 10 (Figure 4). 

Figure 4 Total Synthesis

4.  Enantioselective Molecular Recognition

Understanding the complex processes involved in enantioselective molecular recognition is of fundamental importance to the disciplines of chemistry and biology.   The SGD group is actively engaged in this area, through the development of highly efficient synthetic kinetic resolution procedures that allow for the synthesis of desirable homochiral molecules with selectivity factors that compete well with the levels of selectivity usually reserved for enzymes (E>200).

4.1. Kinetic Resolution

We have recently shown that the use of lithium N-benzyl-N-a-methylbenzylamide 11 allows the efficient kinetic resolution of (RS)-tert­-butyl 3-methyl-cyclopentenecarboxylate (E>130), [5] while the use of parallel kinetic resolution upon the related substrate 12 is equivalent to a simple kinetic resolution with an apparent E of up to 1000 (99% e.e. at 50% conversion). [6] To develop this area further, the kinetic and parallel kinetic resolutions of mono- and poly-substituted cyclohexenecarboxylates, and hetereoatom substituted cyclopentenecarboxylates are under investigation for the generation of an array of polyfunctionalised b-amino acid derivatives for secondary structural and biological activity studies (Figure 5).

Figure 5 Kinetic Resolution

5. Promotion of Supramolecular Architectures

While a range of low molecular weight chiral auxiliaries have been used in the SGD group for the preparation of small homochiral molecular fragments, the promotion of highly ordered homochiral frameworks on a supramolecular scale are also of interest.

5.1. Structural Analysis of Mixed a,b-peptides

There has recently been increasing recognition of the ability of oligomeric, non-proteinogenic species to adopt precisely defined three-dimensional structures. [7] While the ability of b-peptides to exhibit secondary structure is well documented, the propensity of 'mixed' peptide sequences prepared from mixtures of a- and b-amino acids to show similar ordered characteristics is essentially unexplored. With synthetic methodologies in hand for the asymmetric synthesis of libraries of structurally diverse a- and b-amino acids, this project aims to identify 'mixed' pseudopeptides most likely to show secondary structural characteristics by combining the power of asymmetric synthesis with molecular graphics techniques and combinatorial chemistry.

5.2. Chiral Gel Phases for Enantioseparations and Asymmetric synthesis.

Diketopiperazines have been shown to form hydrogen bonded ladder type structures in the solid state [8] and the observed capacity of diketopiperazine 13 to form gels with organic solvents [9] strongly suggests that this substance associates as similarly hydrogen bonded ladders, with high levels of macromolecular organisation, in solution (Figure 6). The constitutional requirements of momomer diketopiperazines to generate macromolecular structures are unknown, as is the nature and secondary structure of the parent 13 in organic solvents. Investigations in this area will focus upon the effect of variation of substituents on the diketopiperazine ring in order to determine the monomer properties that direct the macromolecular structures of these molecules. Fine tuning of the homochiral and racemic monomers is now readily accessible from our established diketopiperazine synthesis technology.

Figure 6 Ladders derived from homochiral diketopiperazine monomers.

The nature of the molecular association between homochiral and racemic diketopiperazine monomers is not known, however molecular modelling suggests that macromolecular gel structures derived from racemic monomers should be less stable than the corresponding homochiral structures and therefore the potential for spontaneous resoluton of racemic and scalemic mixtures will be explored. Gels derived from the homochiral diketopiperazines and organic solvents present a novel chiral environment and such self-assembled materials are expected to find application in chiral separation processes. The capacity of diketopiperazines to organise surrounding small molecules may also be exploited to associate reactant and substrate molecules through non-bonded tethering interactions, potentially facilitating novel regiospecific and stereoselective reactions.

6. Medicinal Chemistry and Chemical Genomics

The opportunities for Chemistry to impact on genetics and genomics are unlimited. This area represents the major growth area for organic chemistry in the immediate future and we have already established highly successful projects in the areas of volume-sensitive chloride channels (for the treatment of heart disease; collaboration with Dr. R. Kozlowski, Bristol), arylamine-N-acetyltransferases (for the treatment of tuberculosis and cancer; collaboration with Prof. E. Sim, Oxford), transcriptional upregulation of utrophin (for the treatment of Duchenne muscular dystrophy; collaboration with Prof. K. E. Davies, Oxford) and protein tyrosine phosphatases (for the treatment of cancer and diabetes). All of these projects are ongoing, and in addition we have been recently involved in more fundamental approaches to chemical genomics and the generation of novel drug discovery paradigms.

Recent Publications (2002-2003)

1. Synthesis and utility of the 3,3-dimethyl-5-substituted-2-pyrrolidinone Quat chiral auxiliary.

S. G. Davies, D. J. Dixon, G. J.-M. Doisneau, J. C. Prodger and H. J. Sanganee, Tetrahedron Asymmetry, 2002, 13, 647-658

2. Asymmetric synthesis of homochiral differentially protected bis-b-amino acid scaffolds.

S. G. Davies, S. D. Bull, P. M. Roberts.  E. D. Savory and A. D. Smith, Tetrahedron, 2002, 58, 4629-4642.

3. Ring closing metathesis for the asymmetric synthesis of (S)-homopipecolic acid, (S)-homoproline and (S)-Coniine.

S. G. Davies, K. Iwamoto, C. A. P. Smethurst A. D. Smith, and H. Rodriguez-Solla, Synlett, 2002, 1146-1148.

4. The [2,3] sigmatropic rearrangement of N-benzyl-O-allylhydroxylamines.

S. G. Davies, J. F. Fox, S. Jones, A. J. Price, M. A. Sanz, T. G. R. Sellers, A. D. Smith and F. C. Teixeira, J.C.S. Perkin I, 2002, 1757-1765.

5. Asymmetric synthesis of b-pyridyl-b-amino acid derivatives.

S. G. Davies, S. D. Bull, D. J. Fox, M. Gianotti, P. M. Kelly, C. Pierres, E. D. Savory and A. D. Smith, J.C.S. Perkin I, 2002, 1858-1868.

6. Acyl Quat pyrrolidinone auxiliary as a chiral amide equivalent via direct aminolysis.

S. G. Davies, and D. J. Dixon, J.C.S. Perkin I, 2002, 1869-1876.

7. Asymmetric synthesis of a-amino carbonyl derivatives using lithium (R)-N-benzyl-N-a-methylbenzylamide.

S. G. Davies, S. W. Epstein, A. C. Garner, O. Ichihara and A. D. Smith, Tetrahedron Asymmetry, 2002, 12, 2941-2945.

8. Diastereoselective [2,3]-sigmatropic rearrangements of lithium N-benzyl-O-allylhydroxylamides bearing a stereogenic centre adjacent to the migration terminus.

S. G. Davies, S. D. Bull, S. H. Domingez, S. Jones, A. J. Price, T. G. R. Sellers and A. D. Smith, J.C.S. Perkin I, 2002, 2141-2150.

9. The Asymmetric synthesis of D-Galactose via an iterative syn-glycolate aldol strategy.

S. G. Davies, R. L. Nicholson and A. D. Smith, Synlett. 2002, 1637-1640

10. Chiral glycine cation equivalents: N-acyliminium species derived from diketopiperazines.

S. G. Davies, S. D. Bull, A. C. Garner, M. D. OShea, E. D. Savoury and E. J. Snow, J.C.S. Perkin I, 2002, 2442-2448.

11. Rearrangements and racemisation during the synthesis of L-serine derived oxazolidinones.

S. G. Davies, S. P. Bew, S. D. Bull, E. D.Savoury and D.J.Watkin, Tetrahedron, 2002, 58, 9387-9401.

12.  Asymmetric synthesis of (1R,2S,3R)-g-methyl-cis-pentacin by a kinetic resolution protocol.

S. G. Davies, S. Bailey, A. D. Smith and J. M. Withey, Chem. Comm., 2002, 2910-2911.

13. Phosphine incorporation and exchange in mononuclear h⁵-cyclopentadienyl iron carbonyl complexes.

S. G. Davies,  S. Jones and A. D. Smith, Trends in Organometallic Chemistry, 2002, 4, 59-70.

14.  An approach to identifying novel substrates of bacterial arylamine N-acetyltransferases.

S. G. Davies, E. W. Brooke, A. W. Mulvaney, F. Pompeo, E. Sim and R. J. Vickers, Bioorg. Med. Chem., 2003, 11, 1227-1234.

15. Asymmetric synthesis of cyclic b-amino acids and cyclic amines via sequential diastereoselective conjugate addition and ring closing metathesis.

S. G. Davies, A. M. Chippendale, K. Iwamoto, R. M. Parkin, C. A. P. Smethurst, A. D. Smith and H. Rodriguez-Solla, Tetrahedron, 2003, 59, 3253-3265.

16. Acyl-5,5-dimethyloxazolidin-2-ones as latent aldehyde equivalents.

S. G. Davies,  J. Bach, S. D. Bull, R. L. Nicholson, P. D. Price, H. J. Sanganee and A. D. Smith, Org. Biomol. Chem., 2003, 1, 2001-2010.

17. Synthesis and in vitro evaluation of novel small molecule inhibitors of bacterial arylamine N-acetyltransferases (NATs).

S. G. Davies,  E. W. Brooke, M. Okada, F. Pompeo, E. Sim, R. J. Vickers and I. M. Westwood, Bioorg. Med. Chem. Letters, 2003, 13, 2527-2530.

18. Asymmetric synthesis of substituted 1-aminocyclopropane-1-carboxylic acids via diketopiperazine methodology.

S. G. Davies,  E. Bunuel, S. D. Bull, A. C. Garner, E. D. Savory, A. D. Smith, R. J. Vickers and D. J. Watkin, Org.  Biomol. Chem., 2003, 1, 2531-2542.

19. SuperQuat N-acyl-5,5-dimethyloxazolidin-2-ones for the asymmetric synthesis of a-alkyl and b-alkyl aldehydes.

S. G. Davies, S. D. Bull, R. L. Nicholson, H. J. Sanganee and A. D. Smith, Org. Biomol. Chem., 2003, 1, 2886-2899.

20. Total asymmetric synthesis of sperabillins B and D.

S. G. Davies, R. J. Kelly and A. J. Price-Mortimer, Chem. Comm., 2003, 2132-2133.

21. Double diastereoselective [3,3]-sigmatropic aza-Claisen rearrangements.

S. G. Davies, A. C. Garner, R. L. Nicholson, J. Osborne, E. D. Savory and A. D.  Smith, Chem. Comm., 2003, 2134-2135.

22. Oxidative functionalisation of SuperQuat enamides: Asymmetric synthesis of homochiral 1,2-diols.

S. G. Davies, H. Rodriguez-Solla, H. J. Sanganee, E. D. Savory, A. D. Smith and M-S. Key, Synlett, 2003, 1659-1662.

23. Asymmetric Synthesis of (1R,2S,3R)-3-methylcispentacin and (1S,2S,3R)-3-methyltranspentacin by kinetic resolution of tert-butyl ()-3-methylcyclopentene-1-carboxylate

M. E. Bunnage, A. M. Chippendale, S. G. Davies, R. M. Parkin, A. D. Smith and J. M. Withey, Org. Biomol. Chem., 2003, 3698.

24. The Asymmetric Synthesis of anti-(2S,3S)- and syn-(2R,3S)-diaminobutanoic acid

M. E. Bunnage, A. J. Burke, S. G. Davies, N. L. Millican, R. L. Nicholson, P. M. Roberts and A. D. Smith, Org. Biomol. Chem., 2003, 3708

25. Preparation of (1R,2S,5S)- and (1S,2R,5R)-methyl 2-amino-5-tert-butyl-cyclopentane-1-carboxylate by Parallel Kinetic Resolution of methyl ()-5-tert-butyl-cyclopentene-1-carboxylate

 S. G. Davies, D. D'ez,  M. M. El Hammouni, N. M. Garrido, A. C. Garner, M. J. C. Long, R. M. Morrison, A. D. Smith, M. J. Sweet and J. M. Withey, Chem. Commun., 2003, 2410

References and Notes