Efficient synthesis of natural products with a 3,6-disubstituted 4-hydroxy-2H-pyran-2-one framework

3,6-disubstituted 4-hydroxy-2H-pyran-2-ones have generated a lot of interest in medicinal chemistry since this structural scaffold is found in many biologically active natural products. Sch-419560 (1) has recently been isolated from the fermentation culture of Pseudomonas fluorescens and exhibited remarkable antibiotic properties. [1] 3,3-Dimethylallylconrauanalactone (2) was isolated from the bark of Garcinia conrauana Engl. (Guttiferae), [2] Aurantiacone (3) from the leaf resin of Diplacus aurantiacus. [3] Here we report on the total synthesis of these natural products: [4–5] The 2-alkylated 5-hydroxy-3-oxopent-4-enoic acid esters 6 were prepared according to Lygo's method [6] by reacting the dianions of 2-alkylated ethyl acetoacetates 5 under selective γ-acylation with N-acyl-2-methyl-aziridines 4. The 5-hydroxy-3-oxopent-4-enoic acid ethyl esters 6 were transformed to produce the bispotassium salts 7. The free 5-hydroxy-3-oxopent-4-enoic acids 8 were released with aqueous tartaric acid solution and lactonized under mild conditions with TFAA or Ac₂O-pyridine. The primarily formed O-acetyl derivatives were finally hydrolyzed with potassium carbonate to give the 4-hydroxy-2H-pyran-2-ones 9.

References: [1] Chan, T. A. et al. (2002) J. Antibiot. 55: 215. [2] Waterman, P. G. et al. (1982) Phytochemistry 21: 1393. [3] Wollenweber E. et al. (1989) Phytochemistry 28: 3493. [4] Schmidt, D. et al. (2006) Chem. Commun. 4732. [5] Schmidt, D. et al. (2007) Synlett 333. [6] Lygo, B. (1995) Tetrahedron 51: 128591.