The First Asymmetric Total Syntheses of (+)-Lycorine and (+)-1-Deoxylycorine

The first asymmetric total syntheses of (+)-1-deoxylycorine ( 2a ) and (+)-lycorine ( 2b ), the unnatural enantiomer of lycorine ( 1 ), are described. Construction of lactam 12, a key intermediate in the synthesis of both 2a and 2b, began by Birch reduction-alkylation of the chiral benzamide 3 with 2-bromoethyl acetate followed by ester saponification to give the 6-(2-hydroxyethyl)-1-methoxy-1,4-cyclohexadiene 6a in 96% yield as a single diastereomer. This material was converted to the radical cyclization substrates 11a and 11b . Both 11a and 11b gave 12 and the reduced enamide 11c on treatment with AIBN and Bu 3 SnH in refluxing benzene solution. Lactam 12 also was obtained by photocyclization of enamide 11c . The allylic alcohol unit characteristic of the C ring of the lycorine alkaloids was fashioned by a radical induced decarboxylation-epoxide fragmentation of the N -hydroxy-2-thiazoline ester 21b . The resulting (+)-2- epi -deoxylycorine ( 22 ) was subjected to Mitsunobu inversion followed by LiAlH 4 reduction to give (+)-1-deoxylycorine ( 2a ). The synthesis of (+)-lycorine ( 2b ) involved the conversion of 12 to allylic alcohol 32 followed by a Torssell rearrangement of 32 to give the rearranged allylic acetate 35 . Epoxidation of 35 with dimethyldioxirane gave 36a, which set the stage for a decarboxylation-epoxide fragmentation of carboxylic acid 36b to give 37 by photolysis of 36b in the presence of acridine and tert -BuSH. Reduction of 37 with LiAlH 4 gave (+)-lycorine ( 2b ).