Studies towards the biomimetic synthesis of pyridomacrolidin Nageswara Rao Irlapati, a Jack E. Baldwin, a Robert M. Adlington, a, * Gareth J. Pritchard b and Andrew R. Cowley a a Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK b Department of Chemistry, Loughborough University, Loughborough, Leicestershire LE11 3TU, UK Received 16 December 2005; revised 11 January 2006; accepted 26 January 2006 Available online 28 February 2006 Abstract—A possible biomimetic synthesis of pyridomacrolidin has been proposed and experimentally supported by carrying out a model study. Regio and stereospecific [3C2] cycloaddition of an in situ generated unusual di-tert-butylated acyl nitrone with Z-2-cyclodecenone and subsequent aromatisation was the key step in our proposed biomimetic synthesis. Finally a pyridomacrolidin analogue was prepared via Friedel–Crafts di-de-t-butylation of the cycloadduct. q 2006 Elsevier Ltd. All rights reserved. 1. Introduction As part of our ongoing program towards the biomimetic synthesis of pyridone natural products we became particularly interested in a biomimetic synthesis of pyridomacrolidin 2. Pyridovericin 1 and pyridomacrolidin 2 are novel metabolites isolated in 1998 by Nakagawa and co-workers from the entomopathogenic fungus Beauveria bassiana (Fig. 1). 1 Structurally 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 H 5. 4 Chemically this class of compounds has elicited a significant amount of interest as demonstrated by the significant synthetic work already published. 5,6 Biologically, pyridovericin 1 and pyridomacrolidin 2 have been shown to inhibit the protein tyrosine kinase (PTK) activity at concentrations of 100 mg/mL. PTK inhibitors are of potential use as therapeutic agents against a variety of proliferative and inflammatory diseases. 7 In common with several compounds found to inhibit PTKs, pyridovericin 1 and pyridomacrolidin 2 contain a p-hydroxyphenyl moiety, which presumably mimics tyrosine. Interest in these type of compounds has largely focused on the determination of the biosynthetic pathway for the generation of tenellin 3, bassianin 4, and ilicicolin H 5. 8–10 Biosynthetically, it has been shown through a series feeding experiments that tenellin 3, originates from a polyketide chain 6 and the aromatic amino acid L-phenylalanine 7. Mechanistically, it has been proposed that L-phenylalanine 7 combines with the polyketide 6 unit to generate the acyltetramic acid intermediate 8. Oxidation of acid 8 could then generates the transient p-quinonemethide intermediate 9, which could undergo a ring expansion to generate the 2-pyridone 10. Finally, oxidation of the newly formed pyridone unit 10 could generate tenellin 3 (Scheme 1). 7,9 Although it is believed that the biosynthesis of pyridovericin 1 presumably follows a similar pathway as that of tenellin 3, the biosynthesis of pyridomacrolidin 2 has not yet been 0040–4020/$ - see front matter q 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2006.01.090 Tetrahedron 62 (2006) 4603–4614 HO N H OH O O OH HO N OH O O OH O O O O OH HO N OH O O HO N OH O O OH HO N H OH O O H H OH 1 2 4 5 3 Figure 1. Pyridovericin 1, pyridomacrolidin 2, and related fungal metabolites. Keywords: [3C2] Cycloaddition; Pyridovericin; Pyridomacrolidin; Cepha- losporolide B; Regio- and stereospecific; Friedel–Crafts dealkylation. * Corresponding author. Tel.: C44 1865 275 626; fax: C44 1865 275 632; e-mail: robert.adlington@chem.ox.ac.uk