Synthesis of the amaryllidaceae alkaloids clivonine and clividine

Abstract

(±)-Clivonine (I) and (±)-clividine (II), lactone alkaloids isolated from Amaryllidaceae plants, have been synthesisef from c-2-methoxycarbonyl-t-6-(3,4-methylenedioxyphenyl)cyclohex-4-ene-r-carboxylic acid (III). Curtius rearrangement of (III) followed by treatment with methanol gave methyl c-6-(N-methoxycarbonylamino)-t-5-(3,4-methylenedioxyphenyl)cyclohex-3-ene-r-carboxylate (VI), which was converted into methyl c-6-(N-methoxycarbonylamino)-t-5-(3,4-methylenedioxyphenyl)cyclohex-3-enyl-r-acetate (IX) by an Arndt–Eistert reaction. Compound (IX) was, after hydrolysis, cyclised to 1-methoxycarbonyl-r-7-(3,4-methylenedioxyphenyl)-2,3,t-3a,4,7,t-7a-hexahydro-2-oxindole (XI). Chloromethylation followed by acetylation of (XI) gave r-7-(6-acetoxymethyl-3,4-methylenedioxyphenyl)-1-methoxycarbonyl-2,3,t-3a,4,7,t-7a-hexahydro-2-oxindole (XII). Lithium aluminium hydride reduction of (XII) furnished the corresponding amino-alcohol, which gave (±)-tetrahydroclividine (XV) and (±)-tetrahydroclivonine (XVI) in 1 : 1 ratio upon oxidation with osmium tetraoxide. Oxidation of (XV) and (XVI) with manganese dioxide yielded (±)-clividine and (±)-Clivonine, respectively.