Total Synthesis of Pyridovericin: Studies toward the Biomimetic Synthesis of Pyridomacrolidin Jack E. Baldwin,* ,† Robert M. Adlington, † Aurelia Conte, † Nageswara Rao Irlapati, † Rodolfo Marquez, † and Gareth J. Pritchard ‡ Dyson Perrins Laboratory, Oxford UniVersity, South Parks Road, Oxford OX1 3QY, U.K., and Department of Chemistry, Loughborough UniVersity, Loughborough, Leicester LE11 3TU, U.K. jack.baldwin@chem.ox.ac.uk Received March 5, 2002 ABSTRACT The total synthesis of the novel metabolite pyridovericin 1 is reported. The synthesis of this key intermediate in our proposed biomimetic synthesis of pyridomacrolidin 2 has been accomplished in good yield from readily available 2,4-dihydroxypyridine. Pyridovericin 1 and pyridomacrolidin 2 are novel metabolites isolated in 1998 by Nakagawa and co-workers from the entomopathogenic fungus BeauVeria bassiana (Figure 1). 1 Both pyridovericin 1 and pyridomacrolidin 2 contain the same p-hydroxyphenyl pyridone unit present in the related fungal metabolites tenellin 3, 2 bassianin 4, 3 and ilicicolin 5. 4 The biological activity of both pyridovericin 1 and pyridomacrolidin 2 has been shown to include the inhibition of protein tyrosine kinase (PTK) activity at concentrations of 100μg/mL. 1 PTK inhibitors are of potential use as therapeutic agents against a variety of proliferative and inflammatory diseases. 5 In common with several compounds found to inhibit PTKs, pyridovericin 1 and pyridomacrolidin 2 contain a p-hydroxy phenyl moiety, which presumably mimics tyrosine. The combination of the structural novelty and complexity coupled with the promising biological activity prompted us to design a biomimetic synthesis of pyridomacrolidin 2. The † Oxford University. ‡ Loughborough University. (1) (a) Takahashi, S.; Kakinuma, N.; Uchida, K.; Hashimoto, R.; Yanagishima, T.; Nakagawa, A. J. Antibiot. 1998, 51, 596. (b) Takahashi, S.; Kakinuma, N.; Uchida, K.; Hashimoto, R.; Yanagishima, T.; Nakagawa, A. J. Antibiot. 1998, 51, 1051. (2) ElBayouni, S. H.; Brewer, D.; Vining, L. C. Can. J. Bot. 1968, 46, 441. (3) Wat, C.-K.; McInnes, A. G.; Smith, D. G.; Wright, J. C. L.; Vining, L. C. Can. J. Chem. 1977, 55, 4090. (4) Matsumoto, M.; Minato, H. Tetrahedron Lett. 1976, 3827. (5) Levitzki, A.; Gazit, A. Science 1995, 267, 1782. Figure 1. Pyridovericin 1, pyridomacrolidin 2, and related metabolites. ORGANIC LETTERS 2002 Vol. 4, No. 13 2125-2127 10.1021/ol0200504 CCC: $22.00 © 2002 American Chemical Society Published on Web 05/29/2002