Dr Johnathan Wilden
Our research is directed towards the synthesis of small molecule entities with biological activity. Recently we have focussed on the synthesis of molecules containing the sulfonamide functional group as this appears in many compounds of pharmaceutical interest and has recently been shown to be transition state mimetics of peptide hydrolysis and potent irreversible inhibitors of cysteine proteases. Recent work in the group has focused on the preparation of peptidomimetics, particularly aminosulfonic acid analogues of the peptide bond. Our goal is to prepare a-aminosulfonamides (direct analogues of the peptide bond). In the course of this research, we have identified a simple route to β-aminosulfonamide peptidomimetics employing a 1,4-addition strategy.
Given the relative ease in which the vinylsulfonamides undergo 1,4-addition and the stability of the products (neither the amines or amides readily undergo elimination) we are keen to exploit this reaction for other purposes, detailed later in this research proposal. Other work in the group has focused on the preparation of β-lactamase inhibitors based on the penicillin core structure. Our initial studies showed that bromination of pentafluorophenylvinyl sulfonate followed by exposure to a primary amine yielded the β-sultam in good yield.
We are working to extend our methodology to prepare more closely related analogues of the β-lactamase inhibitors, outlined below, along with a proposed mechanistic pathway:
Our ultimate goal is to synthesise α-amino sulfonamide containing peptides which we anticipate will have increased stability to proteases in vivo thereby addressing one of the major difficulties associated with peptide therapeutic agents. We have successfully prepared the aziridines and are looking to convert this species into various functionalised peptide mimetics, either via the dehydro species (biologically interesting in their own right), or via organometallic derivatisation, particularly by the aqueous-compatible organoindium species.
- Trichlorophenol (TCP) sulfonate esters: A selective alternative to pentafluorophenol (PFP) esters and sulfonyl chlorides for the preparation of sulfonamides. Wilden, J. D.; Geldeard, L.; Lee, C, C.; Judd, D. B.; Caddick, S. Chem. Commun. 2007 , 1074-1076.
- A New synthesis of β-Sultams from Pentafluorophenyl Sulfonates. Lewis, A. K. De K.; Mok, B. J.; Tocher, D. A.; Wilden, J. D.; Caddick, S. Org. Lett. 2006 , 8, 5513-5515.
- Inhibition of Dimethylarginine Dimethylaminohydrolase (DDAH) and Arginine Deiminase (ADI) by Pentafluorophenyl (PFP) Sulfonates. Vallance, P.; Bush, H. D.; Mok, B. J.; Hurtado-Guerrero, R.; Gill, H.; Rossiter, S.; Wilden, J. D.; Caddick, S. Chem. Commun. 2005 , 5563-5565.
- Rate Enhancement of PFP Sulfonate Ester Aminolysis by Chloride Salts in Organic and Aqueous Media . Wilden, J. D.; Caddick, S.; Judd, D. B. Tetrahedron Lett. 2005 , 46, 7637-7340.*
- Observations on the Reactivity of Pentafluorophenylsulfonate Esters. Caddick, S.; Wilden, J. D.; Judd, D. B.Chem. Commun. 2005 , 2727-2728.
- Synthesis of Functionalised Sulfonamides via Microwave Assisted Displacement of PFP Sulfonates with Amines . Caddick, S.; Wilden, J. D.; Bush, H. D.; Judd, D. B. QSAR & Combinatorial Sci. 2004 , 23, 902-905.*
- Direct Synthesis of Sulfonamides and Activated Sulfonate Esters From Sulfonic Acids. Caddick, S.; Wilden, J. D.; Judd, D. B. J. Am. Chem. Soc. 2004, 126, 1024-1025.