Synthesis of (s)-(+)-dihydrokavain from l-malic acid

Synthesis of (S)-(+)-Dihydrokavain from L-Malic AcidTropical kava plant (Piper Methysticum) grown in Pacific Islands posesses a series of lactones with ? -pyrones such as dihydrokavain, kavain and methysticin. These compounds display sedative, anti-convulsive, anaesthetic and biological properties. Recent studies showed that dihydrokavain could be used for treatment of TNF-? related diaseses. There are many routes for the synthesis of racemic dihydrokavain, one of the main constitutents of the kava extract, but only six methods for asymmetric synthesis. Five of these syntheses are based on catalytic asymmetric synthesis, only one chiral pool approach. The aim of this study is to develop an alternative route for asymmetric synthesis of (S)-dihydrokavain from L-malic acid as naturally cheap chiral pool material. The key reaction of this approach is based on the regioselective ring opening reaction of cyclic sulfate with lithium triethylorthopropiolate.Selective Friedel-Crafts acylation of anhydride derivatives of L-malic acid with benzene afforded the corresponding ? -hydroxy-keto-acid. Palladium catalyzed hydrogenation of carbonyl group of keto-acid furnished ? -hydroxy acid. Reduction of ? -hydroxy acid with LiAlH4 produced 1,2-diol in which primary hydroxyl group was activated toward nucleophilic substitution through formation of the corresponding cyclic sulfate. Regioselective ring opening reaction of cyclic sulfate with triethyl orthopropiolate smoothly proceeded to form hydroxy ? , ? -unsaturated ester after acidic hydrolysis that was converted under basic conditions to free acid derivative. In the final step, free acid derivative was cyclized to (S)-(+)-dihydrokavain by the treatment with catalytic HgO and H2SO4 in methanol. Using tha same reactions (R)-enantiomer of dihydrokavain was also synthesized from D-malic acid. Using our strategy the asymmetric synthesis of both enantiomers of dihydrokavain from malic acids was accomplished in six steps in % 30-35 overall yields.Structural characterization of the known compounds synthesized in this study was verified by comparing physical constants and spectroscopic results with literature data. Characterization of the compounds prepared in this work was carried out with FT-IR, 1H, 13C NMR and mass spectroscopic technics.