Tom Hunta, Andrew F. Parsonsa and Robert Prattb a Department of Chemistry, University of York, Heslington, York, YO10 5DD, UK b Vernalis Research Limited. Oakdene Court, 613 Reading Road, Winnersh, Wokingham, Berkshire, RG41 5UA.

Isolated from the Cinchona tree, (-)-quinine is well known for its antimalarial properties and has been used for over three centuries as the principal treatment for malaria. Only recently have new compounds been developed among which chloroquine has been the most effective, but chloroquine resistant parasites are appearing and the search for new potent antimalarial compounds is of current interest.

Another area of interest surrounding (-)-quinine and the other Cinchona alkaloids is in the development of asymmetric phase-transfer catalysts ¹ and for use as chiral ligands in catalytic processes such as the Sharpless asymmetric dihydroxylation. ²

The first stereoselective total synthesis of (-)-quinine was recently reported ³ by Stork et al. which followed an 18 step synthesis but doesn't easily allow functionalisation at the biologically important C-3 position. This project aims to develop a more efficient synthetic route that builds in functionalisation at the C-3 position that could later be derivatised to form many (-)-quinine analogues.

Previous work within our group ^4,5 has looked at phosphonyl radicals and it is hoped to further this work by developing 6-exo-trig phosphonyl radical cyclisations of 1,7-diene precursors as the key step toward the stereoselective synthesis of (-)-quinine. See figure 1 for a general example.

The advantage of this route is the incorporation of a versatile phosphonate group that would allow a number of (-)-quinine C-3 analogues to be quickly and easily synthesised.

It is hoped that this methodology could then be extended to using solid supported phosphonyl radicals, then a combinatorial approach could be adopted.

References:

1. A. Nelson, Angew. Chem. Int. Ed. , 1999, 38 , 1583.
2. For an overview see J. Clayden, N. Greeves, S. Warren and P. Wothers, Organic Chemistry, Oxford University Press, 2001, pp 1241.
3. G. Stork, D. Niu, A. Fujimoto, E. R. Koft, J. M. Balkovec, J. R. Tata and G. R. Dake, J. Am. Chem. Soc., 2001, 123, 3239.
4. J. M. Barks, B. C. Gilbert, A. F. Parsons and B. Upeandran, Synlett, 2001, 1719.
5. J. M. Barks, B. C. Gilbert, A. F. Parsons, and B. Upeandran, Tetrahedron Lett., 2001, 42 , 3137.

© Department of Chemistry, University of York.