Synthesis of dihydrolycorine

Abstract

Dihydrolycorine, which is the sole product from the hydrogenation of the alkaloid lycorine of the Amaryllidaceae, has now been synthesized by the following sequence of reactions. Methanolysis of the tetrahydrophthalic anhydride (3) yie1ded 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 (6). The keto-alcohol, derived from 5 by treatment with LiAlH4 followed by MnO2, underwent the Schmidt rearrangement, giving, after hydrolysis, two lactams (11 and 14), one (11) of which was found to be an abnormal rearrangement product. The lactam (14) has been 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 (17) into the mixed anhydride (18), and its reduction with NaBH4 yielded the lactam-alcohol (14) which was converted to the lactam-homoacid (21) through the cyanide (20). The stereochemistry of 21 was established by its conversion into γ-lycorane. Halolactonization if 21 gave the iodo-lactone (36) 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 (41) 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.