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
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).