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

Abstract

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.