Research in the Sheppard Group

We are primarily interested in the development of new synthetic methodology and its application to the synthesis of potentially useful molecules. Our research work is spread across a wide range of different areas including transition-metal catalysis, organoboron chemistry, organocatalysis, multicomponent reactions and sustainable chemistry. A common theme in a lot of the research projects is the development of new methods for activation or formation of carbon-oxygen bonds.

Transition-Metal Catalysis1,3,4-9

We developed a novel approach to aldol chemistry via gold-catalysed formation of boron enolates from alkynes.1 This enables boron enolates to be formed under exceptionally mild conditions in the presence of the aldehyde reaction partner. The resulting aldol products can be elaborated into a variety of potentially useful products including dihydrobenzofurans.2

More recently, we have developed two new approaches to the synthesis of haloalkynes via direct gold-catalysed halogenation of terminal alkynes or Bronsted acid catalysed halogenation of trimethylsilylalkynes.3

A long-running research theme in the group is the development of new transformations of propargylic alcohols.4-6 Our initial work involved the identification of a very general procedure for the Meyer-Schuster rearrangement of propargylic alcohols to enones.4-5 The use of a non-polar reaction solvent (PhMe) in combination with small quantity of protic additive (MeOH or a boronic acid) was found to be the key to ensuring high reactivity of the gold catalyst at room temperature. The method can be applied to a wide range of primary, secondary and tertiary propargylic alcohols. During the course of this work we observed that direct substitution of the propargylic alcohol by methanol was seen in some reactions of propargylic alcohols bearing an electron-rich aryl group. This was subsequently found to be catalysed very efficiently by silver impurities in some batches of the gold catalyst. We were then able to demonstrate the silver-catalysed substitution of propargylic alcohols with a wide range of nucleophiles.5 When the alkyne substituent on a propargylic alcohol is an acetal group, a mild gold-catalysed synthesis of 3-alkoxyfurans can be achieved.6 This highly electron-rich furans show useful reactivity (see ’Scaffolds’ section below), and are otherwise very difficult to synthesise. More recently we developed procedures for the direct dihalohydration of propargylic alcohols to give dihalohydroxyketones7. The diiodohydroxyketones are generated by reaction of the propargylic alcohol with gold catalyst and NIS in an aqueous acetonitrile solvent mixture. These compounds represent a novel class of organic molecules that have never been previously prepared. The corresponding dichlorides were accessed by direct reaction of propargylic alcohols with trichloroisocyanuric acid, without the need for a gold catalyst. In collaboration with researchers at Imperial College London, we have also developed a highly efficient procedure for the acid-catalysed substitution of propargylic alcohols with a range of nucleophiles.8

Organopalladium chemistry is an ongoing area of interest in the group, with previous work including a novel Pd-mediated cyclopropanation reaction.9 More recently, we have used thioacetals to facilitate a mechanistic study of Pd-catalysed alkene oxidation.10 We were able to demonstrate that two divergent oxidation mechanisms were in operation, and that sulfur-stabilised reaction intermediates could be observed and isolated. We have also written a recent review article covering the Pd(II)-catalysed oxidation of alkenes.11

Direct Amidation Reactions13-15

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.13-15 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. Importantly, the methodology is compatible with a wide range of pharmaceutically relevant heterocycles. The B(OCH2CF3)3 reagent16 is now available commercially from Sigma-Aldrich (Product: RNI00014).

Very recently, researchers from Boehringer Ingelheim Pharmaceuticals have shown that our B(OCH2CF3)3 reagent is also very effective for preparing imines, especially those derived from poorly nucleophilic amines.17

Sustainable Synthesis

We have a growing interest in sustainable chemistry, focused in particular on the development of new methods to exploit low-cost biomass as a source of potentially valuable chemicals. Our interest in this area began with a collaborative industry-funded sustainable chemistry project working with Helen Hailes. In an ongoing EPSRC-funded sustainable chemistry project we are working alongside Helen and researchers in a variety of disciplines from UCl, Imperial and Bath to exploit sugar beet pulp as a source of organic molecules for a range of applications. In the development of our new synthetic methodology we are keen to make use of low-cost/low toxicity reagents and solvents in order to make the chemistry as sustainable as possible. We have recently developed an efficient method for the selective dehydration of pentoses to give tetrahydrofurans.

Synthesis of Novel Molecular Scaffolds18-24

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 work in this area has included the development of new multicomponent reactions to access medium ring compounds,19-20 and the synthesis of polysubstituted cyclopropanes via an unusual cis-selective aminocyclopropanation reaction.21 More recent work has involved the development of short synthetic routes to spirocyclic indolines from readily available indoles,22 and the efficient synthesis of the previously unknown endo-cantharimide scaffold24 via efficient cycloaddition reactions of 3-alkoxyfurans.6 Further recent work, as part of our sustainable chemistry interests, has focused on the development of new methods for conversion of readily available sugars into useful chiral heterocyclic scaffolds.24

Medicinal Chemistry25-27

In an ongoing collaboration with Professor Neil Millar’s group (UCL Pharmacology), we have developed a series of novel allosteric ligands for α-7 nicotinic acetyl choline receptors with diverse pharmacological properties.25 In recent work we have extended this to the discovery of a set of structurally similar compounds that exert five different pharmacological effects on the receptor,26 as well as the identification of a novel series of triazole-containing allosteric modulators.27


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

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

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

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

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

6. M. N. Pennell, R. W. Foster, P. G. Turner, C. J. Tame, H. C. Hailes, T. D. Sheppard, Chem. Commun. 2014, 50, 1032. doi: 10.1055/s-0033-1340302

7. J. M. D'Oyley, A. E. Aliev, T. D. Sheppard, Angew. Chem. Int. Ed. 2014, 53, 10747. doi: 10.1002/anie.201405348

8. E. Barreiro, A. Sanz-Vidal, E. Tan, S. -H. Lau, T. D. Sheppard, S. Díez-González, Eur. J. Org. Chem. 2015 in press. doi: 10.1002/ejoc.201501249.

9. 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

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

11. S. E. Mann, L. Benhamou, T. D. Sheppard, Synthesis 2015, 47, 3079. doi: 10.1055/s-0035-1560465

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

13. P. Starkov, T. D. Sheppard, Org. Biomol. Chem. 2011, 9, 1320. doi:10.1039/C0OB1069C

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

15. V. Karaluka, R. M. Lanigan, P. M. Murray, M. Badland, T. D. Sheppard, Org. Biomol. Chem. 2015, 13, 10888. doi: 10.1039/c5ob01801c.

16. T. D. Sheppard, Tris(2,2,2-trifluoroethoxy)boron, e-EROS Encyclopedia of Reagents for Organic Synthesis, 2014. doi: 10.1002/047084289X.rn01754

17. J. T. Reeves, M. D. Visco, M. A. Marsini, N. Grinberg, C. A. Busacca, A. E. Mattson, C. H. Senanayake, Org. Lett. 2015, 17, 2442, doi: 10.1021/acs.orglett.5b00949

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

19. 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

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

21. 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

22. P. Dhankher, L. Benhamou, T. D. Sheppard, Chem. Eur. J. 2014, 20, 13375. doi: 10.1002/chem.201403940

23. R. W. Foster, L. Benhamou, M. J. Porter, D. -K. Bucar, H. C. Hailes, C. J. Tame, T. D. Sheppard, Chem. Eur. J. 2015, 21, 6107. doi: 10.1002/chem.201406286

24. R. W. Foster, C. J. Tame, D -K. Bucar, H. C. Hailes, T. D. Sheppard, Chem. Eur. J. 2015, 21, 15947. doi: 10.1002/chem.201503510

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

26. J. K. Gill-Thind, P. Dhankher, J. M. D'Oyley, T. D. Sheppard, N. S. Millar, J. Biol. Chem. 2015, 290, 3552. doi: 10.1074/jbc.M114.619221

27. A. Chatzidaki, J. M. D'Oyley, J. K. Gill-Thind, T. D. Sheppard, N. S. Millar, Neuropharmacology 2015, 97, 75. doi: 10.1016/j.neuropharm.2015.05.006

site by orang-utan productions