Dr Paul J Stevenson

Research

Nitrogen containing compounds, particularly heterocycles, are prevalent in many biologically interesting molecules. Current research effort is focussed on developing new synthetic methods and applying these methods to the synthesis of biologically active alkaloids. The pumiliotoxin alkaloids, isolated from the defensive skin secretions of dendrobates frogs are current targets. Figure 1 lists some targets that have recently been synthesised in our laboratory.

 

Indolizidines are present in the defensive skin secretions of dendrobates frogs in micro gram quantities. Most of the structural studies on these compounds are based on a combination of glc/ms and glc/FT IR. Many structures are tentative until synthetic material becomes available. A recent synthesis of the putative structure of homopumiliotoxin 235C revealed that the original proposed tentative structure was incorrect and a new revised structure has been put forward. Work is currently in progress to synthesise the revised structure for 235C. We have also synthesised the postulated tentative structure of the unusual 5, 9 E-indolizidine 259B using newly developed diastereoselective chemistry of chiral N,O-acetals. The FT-IR spectrum of synthetic indolizidine 259B is different to natural 259B so again a structural modification is required. The IR-spectrum strongly suggests that that there is branching in the side chain. There is currently not enough natural sample of sufficient purity for nmr analysis. Attempts are currently being made to locate the branch point by matching theoretical IR-spectra, generated using DFT calculations, to the spectrum of the natural product.

Extension of Povarov cyclisation to include enamides has led to efficient synthesis of the heterocyclic core of the natural product Bradykinin inhibitor martinellic acid. Tandem reactions based on Povarov chemistry of four membered ring cyclic enamides has led to a short synthesis of the topical cytotoxic agent Luotonin A.

Current synthetic targets include the allopumilotoxins 339B and deoxypumiliotoxin 251H. We have recently demonstrated that alkene reacts from the unexpectedly from concave face which gives rise to key deoxypumilio and allopumiliotoxin precursors from a common intermediate.

 

 

The biocatalysis facility within the School of Chemistry has furnished kilogram quantities of bromo and iodo benzene cis-diol. The synthetic potential of these versatile intermediates are currently under investigation and synthetic targets include both enantiomers of epibatidine, and all possible stereoisomers of the anti-tumour alkaloid pancratistatin.