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

Abstract

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). Lycorine (1) is the most abundant alkaloid in plants of theAmaryllidaceae. It is said that as much as 1% of the dry weight of daffodil bulbs may consist of lycorine. 1 From the time of its initial isolation in 1877 lycorine was recognized as a potent emetic; 2 more recent studies have shown that lycorine inhibits protein and DNA synthesis in murine cells and in ViVo growth of a murine transplantable ascite tumor. 3 Lycorine is a powerful inhibitor of growth and cell division in higher plants, algae, and yeast 4 and has antiviral activity. 5Much of the determination of structure for lycorine was accomplished by Kondo and co-workers 2,6 by utilization of classical chemical studies; proof of structure was provided by X-ray crystallographic analysis of dihydrolycorine hydrobromide. 7 Although several syntheses of racemic lycorine alkaloids have been developed, 8 an asymmetric synthesis had not been reported until we communicated the first asymmetric synthesis of (+)-1-deoxylycorine (2a). 9 Herein we report the details of the synthesis of 2a along with the first asymmetric synthesis of (+)-lycorine (2b), the unnatural enantiomer of 1.

Stereoselectivity of Radical Reactions: Cyclic Systems

“…A similar reaction was used later by Schultz as key step for the synthesis of (+)-lycorine (Scheme 20, Eq. 20.1) [44]. The last stereogenic center is established during the axial reduction of the tetracyclic radical by tin hydride.…”

Modern Developments in Aryl Radical Chemistry

“…Syntheses of various natural products, especially alkaloids, have been successfully completed using this strategy. Cyclizations onto enamides of the 6-endo type led to erysotrine [76] and lycorine alkaloids [77][78][79]. The skeleton of hydroapoerysopines [80] was successfully constructed by a 7-endo cyclization.…”

Tandem Methodology for Heterocyclic Synthesis

“…After hydrolysis and oxidation of 61 to 62, an oxidative decarboxylation reaction was used to provide the C 2 -C 3 -C 12 allylic alcohol unit characteristic of the lycorine alkaloids. The resulting enone was eventually transformed into (±)-1-deoxylycorine (65) via known synthetic intermediates [64].…”