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Dr Tom Sheppard

Research Overview

Our research is focussed on the development of new synthetic methods for organic chemistry, via the design of new chemical reactions and tandem reaction sequences or the development of novel catalysts. Our current areas of interest include:

Catalysis 1-7

We have interests in both organocatalysis and metal catalysis (and combinations thereof), with ongoing projects in the group in both areas. Current interests include the application of gold,1-4 copper,1 palladium,5-6 platinum and silver3 catalysts. We also have an interest in the development and application of new boron-centred reagents and catalysts.1,8-9

Recently, we have reported a new method for the generation of boron enolates via the gold-catalysed addition of boronic acids to alkynes.1 The intramolecular cyclisation of ortho-alkynylbenzeneboronic acids (A) gives cyclic boron enolates that can be trapped via aldol reaction with an aldehyde present in the reaction mixture. The resulting products are useful for further elaboration into biaryls, phenols or dihydrobenzofurans.

Reaction scheme to generate boron enolates via gold-catalysed addition of boronic acids to alkynes


Further work on metal-catalysed reactions of propargylic alcohols led to the development of a highly efficient and widely applicable method for the Meyer-Schuster rearrangement to give a variety of enones.2-3 The Meyer-Schuster rearrangement of primary alcohols can readily be combined with addition of nulceophiles to the resulting enones. A silver-catalysed substitution reaction of propargylic alcohols, applicable to a wide range of nulceophiles, was also discovered.3 More recently, we have developed a gold-catalysed method for the halogenation of terminal alkynes and an acid-catalysed method for direct halogenations of trimethylsilylalkynes.4

Catalysis-2


Organopalladium chemistry is an ongoing area of interest in the group, with previous work including the discovery of a novel Pd-mediated cyclopropanation reaction.5 More recently, we have used thioacetals to facilitate a mechanistic study of Pd-catalysed alkene oxidation.6 We were able to demonstrate that two divergent oxidation mechanisms were, and that sulfur-stabilised reaction intermediates could be observed and isolated. 

Catalysis-3

Very recent work has involved the development of a ruthenium-catalysed synthesis of isoindolinones via alkyne cyclotrimerisation in a sustainable green solvent.7

Strategically Important Hydration & Dehydration Reactions

The study of hydration and dehydration reactions is a major theme running through our research. In the former case, the addition of water to carbon-carbon triple bonds has been the main area of interest (see catalysis section above).1-3 Dehydration reactions are amongst the most important processes used in the synthesis of pharmaceuticals and other industrially important molecules. Despite this fact, the removal of a water molecule with concomitant formation of a new bond between two reactants often requires hazardous reagents which often suffer from poor levels of efficiency.

The direct formation of amides from carboxylic acids and amines is perhaps the most commonly used transformation in pharmaceutical synthesis. As a consequence, there is considerable interest in the development of more efficient and convenient methods for achieving this condensation.12 Our group has developed the use of simple borate esters such as B(OCH2CF3)3 as convenient reagents for direct amidation.8-9 The reagent is applicable to amidation reactions with a wide range of acids and amines, and the amide products can be purified using a simple and convenient solid-phase work-up procedure with commercially available resins. The B(OCH2CF3)3 reagent is now available commercially from Sigma-Aldrich (Product: RNI00014).

SIHDR-1


The direct displacement of alcohols with nucleophiles is also a strategically important process in synthetic chemistry. This direct substitution avoids the use of hazardous alkylating agents such as alkyl halides or sulfonates, and the only stoichiometric by-product is water. During our study of the gold-catalysed Meyer-Schuster rearrangement of propargylic alcohols, we discovered a novel silver-catalysed substitution reaction that enables direct substitution of the alcohol group with oxygen, carbon and nitrogen nucleophiles.3

SIHDR-2

Multicomponent Reactions10-11

Multicomponent reactions are inherently atom-economical processes in which most of the atoms in three or more reactants are incorporated into the final reaction product. This enables the straightforward variation of functional groups/substituents at a number of different sites within the reaction product which can be highly effective in library synthesis. We are interested in designing and developing new multicomponent reaction processes which provide access to usefully functionalised molecules in an efficient manner.

We have previously reported a novel multicomponent reaction employing
N-alkyloxazolidines10 which has been applied to the synthesis of a diverse array of products. Further work led to the development of a multicomponent approach to medium-ring lactones and lactams – structurally complex functionalised molecules which are assembled in a single step from commercially available starting materials.11

Multicomponent Reactions

Novel Functionalised Ring Systems for Medicinal Chemistry

We are keen to apply our novel synthetic methodology to the construction of new molecular scaffolds for medicinal chemistry. The development of effective routes to structurally novel small molecules with appropriate physical properties can serve to make new areas of chemical space readily accessible to medicinal chemists for the first time. Notably, there is considerable interest in the generation of small molecule scaffolds with a well-defined three-dimensional shape which can readily be functionalised at several different positions. Our interests in this area include medium-ring scaffolds (via multicomponent reactions),8-9 benzo-fused heterocycles1,7,14-15 and the design of new synthetic methods to prepare functionalised small-ring systems such as cyclopropanes,13 oxetanes and azetidines.

Novel Functional Ring Systems for Mediacl Chemistry

Medicinal Chemistry14

In an ongoing collaboration with Professor Neil Millar’s group (UCL Pharmacology), we have developed a series of novel allosteric ligands for nicotinic acetyl choline receptors with diverse pharmacological properties.14 Ongoing work on this project is focused on the application of novel synthetic methodology to the construction of structurally novel ligands for these important targets, which are of potential interest for the treatment of both pain and neurodegenerative disease.

Medicinal Chemistry

References

1. C. Körner, P. Starkov, T. D. Sheppard, J. Am. Chem. Soc. 2010, 132, 5968. doi:10.1021/ja102129c

2. M. N. Pennell, M. G. Unthank, P. Turner, T. D. Sheppard, J. Org. Chem. 2011, 76, 1479. doi:10.1021/jo102263t

3. M. N. Pennell, P. G. Turner, T. D. Sheppard, Chem. Eur. J. 2012, 18, 4748. doi:10.1002/chem.201102830

4. P. Starkov, F. Rota, J. M. D'Oyley, T. D. Sheppard, Adv. Synth. Catal. 2012, 354, 3217. doi:10.1002/adsc.201200491

5. S. S. Ramos, W. B. Motherwell, P. Almeida, L. Santos, T. D. Sheppard, M. C. Costa, Tetrahedron 2007, 63, 12608. doi:10.1016/j.tet.2007.10.016

6. S. E. Mann, A. E. Aliev, G. J. Tizzard, T. D. Sheppard, Organometallics 2011, 30, 1772. doi:10.1021/om2000585

7. R. W. Foster, C. J. Tame, H. C. Hailes, T. D. Sheppard, Adv. Synth. Catal. 2013, 355, 2353. doi:10.1002/adsc.201300055

8. P. Starkov, T. D. Sheppard, Org. Biomol. Chem. 2011, 9, 1320. doi:10.1039/C0OB01069C

9. R. M. Lanigan, P. Starkov, T. D. Sheppard, J. Org. Chem. 2013, 78, 4512. doi:10.1021/jo400509n

10. R. Waller, L. J. Diorazio, B. A. Taylor, W. B. Motherwell, T. D. Sheppard, Tetrahedron 2010, 66, 6496 doi:10.1016/j.tet.2010.05.083.

11. M. Bachman, S. E. Mann, T. D. Sheppard, Org. Biomol. Chem. 2012, 10, 162. doi:10.1039/C1OB06534C

12. R. M. Lanigan, T. D. Sheppard, Eur. J. Org. Chem. 2013, 7453. doi:10.1002/ejoc.201300573

13. S. Ishikawa, T. D. Sheppard, J. M. D'Oyley, A. Kamimura, W. B. Motherwell, Angew. Chem. Int. Ed. 2013, 52, 10060. doi:10.1002/anie.201304720

14. J. K. Gill, P. Kumar, T. D. Sheppard, E. Sher, N. S. Millar, Mol. Pharm. 2012, 81, 710. doi:10.1124/mol.111.076026

15. T. D. Sheppard, J. Chem. Res. 2011, 377. doi:10.3184/174751911X13096980701749