Compounds Related to Podophyllotoxin. XIV. Isopodophyllotoxin and Epiisopodophyllotoxin

Lactonization of 1-(trimethoxyphenyl)-3-hydroxymethyl-4-hydroxy-6,7-methylenedioxy-1,2,3,4-tetrahydro-2-naphthoic acid with dicyclohexylcarbodiimide gave isopodophyllotoxin. Lactonization with acetic anhydride gave the corresponding acetate. Hydrolysis of this acetate lactone not only removed the acetate group but also opened the lactone ring to regenerate unchanged acidic starting material. Aromatization of the acetate with palladium at elevated temperatures produced dehydroanhydropicropodophyllin, which was prepared for comparison from α-apopicropodophyllin as well as from desoxypicropodophyllin. The nature of the lactone system and the hydroxyl group in isopodophyllotoxin is proved by its oxidation with manganese dioxide to isopodophyllotoxone, a tetralone lactone. The stereochemistry at three of the four centers of asymmetry is established by hydrogenolysis of the hydroxyl group and identification of the resulting desoxy compound as (trans,trans) desoxyisopodophyllotoxin. The configurations of the hydroxyl group in isopodophyllotoxin and in the stereoisomeric epiisopodophyllotoxin derived from isopodophyllotoxone by reduction have been assigned by Schreier on the basis of n.m.r. studies.