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

• Published in: Journal of the American Chemical Society Vol. 118; no. 26; pp. 6210 - 6219
• Main Authors: Schultz, Arthur G, Holoboski, Mark A, Smyth, Mark S
• Format: Journal Article
• Language: English
• Published: American Chemical Society 03-07-1996
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja9606440

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 Bu3SnH 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 LiAlH4 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 LiAlH4 gave (+)-lycorine (2b).