Narcissus and Daffodil

MeO
COCI
OCH Ph
2
28
50 51 52
MeO
O
53
O
NMe
O
MeN
Synthesis of galanthamine 313
above produced a mixture of (±)-1 and (±)-4. A total yield of 0.093% was obtained
using this scheme, which was 40 times lower than in the case of (±)-1 synthesis via
isomeric bromoamide. Thus Kametani’s group demonstrated the necessity of
blocking the para-position to the hydroxy group by bromination in the benzyl
moiety in the phenolic coupling process.
Subsequently, Bulgarian and German scientists tried to improve the synthesis of 1.
Vlahov et al. (1978), in a modified route of the synthesis, used 4-methoxybenzylation
for hydroxyl group protection and subsequent de-protection in mild conditions.
Thus, intermediate amides 60 and 61 were transformed to 33 and 48,
respectively (Figure 12.9). However, the final cyclocondensation of 48 to 49 (as in
figure 12.6) proceeded with low yields. In another variation of the synthesis by the
same authors, in order to avoid the use of LiAlH 4 reduction of the amide 62, the
following succession was applied: a transformation of 62 to thioamide 63 by P 2 S 5 -
pyridine treatment (58% yield) with subsequent NaBH 4 -CoCl 2 reduction to the
substituted N-methyl-phenethylamine (64) in 80% yield. The oxidative cyclocondensation
of the amide 33 produced the desired racemic bromo-ketone (±)-34 in a
O
OCH Ph
2
MeO OCH2Ph MeO
1 + 4
Figure 12.7 Synthesis of galanthamine (1) via non-brominated belladine-type benzamide
(52) (Kametani, 1972b; Kametani et al., 1971b).
MeN
OH
O
OH