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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 1-2

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, Copper, Palladium, Platinum, Magnesium and Iron catalysts2. We also have an interest in the development and application of new boron-centred reagents and catalysts.

Recently, we have reported a new method for the generation of boron enolates via the gold-catalysed addition of boronic acids to alkynes1. 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

Three and Four Membered Rings 3-7

Small ring systems (three and four membered rings) provide well defined control of molecular shape and can be extremely useful in drug design. Cyclopropane rings are commonly used, for example, to impart rigidity into a drug structure and to prevent quick metabolism of the drug by blocking activated positions. In addition, the inherent strain of small ring systems can be effectively harnessed in a range of controlled ring opening processes. We are interested both in developing new methods for the synthesis of small rings, and in designing and exploring new reactions which exploit the strain of these systems.

Structures of various 3 and 4 membered rings

Past work has focussed on the development of methods for accessing aminocyclopropane derivatives using organozinc carbenoids3-6, and a novel palladium-mediated cyclopropanation reaction7. Current efforts are directed towards developing new methods for the stereoselective synthesis of oxetanes, cyclobutanes and azetidines.

Synthetic Approaches to Medium Ring Systems

Medium ring systems (eight to twelve membered rings) are often found in biologically active natural products, and as a consequence, methods for their synthesis are of considerable interest. An effective strategy involves the fragmentation of a bicyclic system containing two smaller rings. We are interested in developing tandem reaction sequences which proceed directly from an open chain system to a bicyclic intermediate (B), which can subsequently undergo fragmentation to give a functionalised medium ring system. In our current work, we are investigating efficient routes to the natural products Antimycin A3b and Cephalosporolide D.

General reaction scheme for synthesising a medium ring system
Structures of antimycin A3b and cephalosporolide D

Multicomponent Reactions 8-9

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 products in an efficient manner.

General reaction scheme for a multicomponent reaction

We have previously reported a novel multicomponent reaction employing N-alkyloxazolidines8-9 and current efforts are focussed on extending this work to other related systems.

Multicomponent reaction scheme involving N-alkyloxazolidines

Bio-orthogonal Reactions

The ability to carry out chemical reactions either on the surface of a protein, or in the presence of proteins and/or biological systems is extremely useful for the study of a wide range of biological processes. We have an ongoing interest in both the development of new bio-orthogonal reactions, and the modification of existing chemical reactions to enable them to be efficiently carried out in aqueous systems and in the presence of proteins.

Selected Publications

  1. An Alternative Approach to Aldol Reactions: Gold-Catalyzed Formation of Boron Enolates from Alkynes , C. Körner, P. Starkov, T. D. Sheppard, Journal of the American Chemical Society 2010, 132, 5968.doi:10.1021/ja102129c
  2. Metal-catalysed halogen exchange reactions of aryl halides , T. D. Sheppard, Organic and Biomolecular Chemistry 2009, 7, 1043. doi:10.1039/b818155a
  3. Intramolecular amidocyclopropanation reactions using diethoxymethyl-functionalised lactams as organozinc carbenoid precursors , L. Jerome, T. D. Sheppard, A. E. Aliev, W. B. Motherwell, Tetrahedron Letters 2009, 50, 3709. doi:10.1016/j.tetlet.2009.03.224
  4. Asymmetric synthesis of aminocyclopropanes and N-cyclopropylamino alcohols via direct amidocyclopropanation of alkenes using chiral organozinc carbenoids , G Bégis, D. Cladingboel, L. Jerome, W. B. Motherwell and T. D. Sheppard, European Journal of Organic Chemistry 2009, 1532.doi:10.1002/ejoc.200801033
  5. Observations on the direct amidocyclopropanation of alkenes using organozinc carbenoids , W. B. Motherwell, G Bégis, D. Cladingboel, L. Jerome and T. D. Sheppard, Tetrahedron 2007, 63, 6462.doi:10.1016/j.tet.2007.03.027
  6. Synthesis of enantiopure aminocyclopropanes by diastereoselective addition of a chiral amino substituted organozinc carbenoid to alkenes , G Bégis, T. D. Sheppard, D. Cladingboel, W. B. Motherwell, and D. A. Tocher, Synthesis, special issue commemorating the 60 th birthday of Professor SV Ley, 2005, 3186.doi:10.1055/s-2005-918469
  7. Functionalisation of terpenoids at C-4 using organopalladium dimers – unusual participation of an adjacent alkene during the oxidation of the palladium-carbon bond, leading to cyclopropane formation , S. S. Ramos, W. B. Motherwell, P. Almeida, L. Santos, T. D. Sheppard and M. C. Costa, Tetrahedron 2007, 63, 12608. doi:10.1016/j.tet.2007.10.016
  8. Isocyanide Based Multicomponent Reactions of Oxazolidines and Related Systems, R. Waller, L. J. Diorazio, B. A. Taylor, W. B. Motherwell and T. D. Sheppard, Tetrahedron 2010, submitted.
  9. Observations on the reaction of N-alkyloxazolidines, isocyanides and carboxylic acids: A novel three-component reaction leading to N-acyloxyethylamino acid amides , L. J. Diorazio, W. B. Motherwell, T. D. Sheppard and R. W. Waller, Synlett 2006, 2281. doi:10.1055/s-2006-950413