Synthesis of Dihydrolycorine

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Abstract
Dihydrolycorine, the sole product from the hydrogenation of the alkaloid lycorine of the Amaryllidaceae, was synthesized by the following sequence of reactions. Methanolysis of the tetrahydrophthalic anhydride yielded a mixture of a pair of half-esters (4a and 4b). This mixture was subjected to the Friedel-Crafts cyclization to give the tetrahydrofluorenone (5) and the tetralone. The keto-alcohol, derived from 5 by treatment with LiAlH4 followed by MnO2, underwent the Schmidt rearrangement, giving, after hydrolysis, 2 lactams (11 and 14), one (11) of which was found to be an abnormal rearrangement product. The lactam (14) was prepared alternatively in a better yield. The mixture of the half-esters (4a and 4b) was treated with ethyl chloroformate followed by NaN3 to give the azide, which, after heating, gave the lactam-ester (16) as a sole isolable product by treatment with trifluoroacetic acid. Hydrolysis of 16, conversion of the resulting acid into the mixed anhydride, and its reduction with NaBH4 yielded the lactam-alcohol (14) which was converted to the lactam-homoacid (21) through the cyanide. The stereochemistry of 21 was established by its conversion into .gamma.-lycorane. Halolactonization of 21 gave the iodo-lactone which was transformed into the iodo-acetoxy-imide (38) with acetic anhydride and acetic acid. Treatment of 38 with LiCl in dimethylformamide gave the olefin which was oxidized to the epoxide (42) with m-chloroperbenzoic acid. Reductive cleavage of 42 with LiAlH4 in the presence of ZnCl2 gave dl-dihydrolycorine identical with that from natural sources.

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