Narcissus and Daffodil

Synthesis of galanthamine 311
mercially available compound) these authors obtained a 23% yield in three stages,
the yield of (±)-1 from 7 (which is commercially available) is 2.14% (30 times higher).
Kametani et al. (1969a,b) used the following route for the synthesis of 4-benzyloxyphenylacetic
acid (10) (Figure 12.5). 10 was obtained from 7 through the
aldehyde 36 and the intermediate imino-propionitrile of structure 37 (Vaghani and
Merchant, 1961). However, in this scheme, the total yield of 10 was not indicated,
and only half of the starting material was inserted into the target compound.
Another component, 2-bromo-4-methoxy-5-benzyloxy-benzaldehyde (29), was
obtained in three steps starting from 3,4-dimethoxybenzaldehyde (38) by 3-monodemethylation
with concentrated H 2 SO 4 to isovanilline (18) (61%) (Brossi et al.,
1967), and bromination with bromine in acetic acid to give the expected compound
39 in 67% yield (Henry and Sharp, 1930; Raiford and Ravely, 1940). The
total yield of 29 after O-benzylation was about 33% (Jackson and Martin, 1966),
which after total conversion should exceed 54%. Recently, a more advanced route
(Figure 12.5) was proposed from isovanilline (18), which after O-benzylation to 12
(98%) and bromination in acetic acid in the presence of NaOAc produced 29 in
79% yield (Bolton et al., 1987), or a total 47% yield (77% taking into consideration
a complete conversion of products on the hydrolysis reaction step).
Similarly, Kametani et al. (1973) synthesised (±)-1 via (±)-N-norgalanthamine
((±)-44) (Figure 12.6). The substrate for oxidation was obtained in three steps from
the acid 30 via the acylchloride 31, coupled with the amine 40 to produce the amide
41, which was debenzylated to 42 in 72% total yield. On K 3 [Fe(CN) 6 ] oxidation, the
key compound (±)-43 was obtained in only 0.7% yield. The latter was reduced with
LiAlH 4 to (±)-44 in 32% yield. The final formaldehyde-formic acid methylation of
(±)-44 produced the desired (±)-1 in 70% yield, corresponding to 0.11% total yield.
In another synthesis of (±)-1, Kametani et al. (1971a) used the intermediate
isomeric amide 48 (a positional carbonyl isomer of 33). Starting from 4-benzyloxyphenylacetic
acid (10) converted to acyl chloride (11), and the bromoamine 46
obtained from bromoaldehyde (29) in two steps without isolation of the intermediate
45 (75%), the desired amide 47 was produced in 72.3% yield (Figure 12.6).
After elimination of protective benzyl groups with hydrobromic acid, the resulting
dihydroxy-amide 48 was oxidised with K 3 [Fe(CN) 6 ] to afford a tetracyclic amide of
structure (±)-49 in low yield (1.9%). A subsequent LiAlH 4 reduction afforded
12.3% of (±)-1 and 4.9% of (±)-4. Thus, the total yield of the title compound
according to this scheme was 0.095%, which was 99 times lower than that according
to the alternative route via the intermediate 33.
The oxidation of unprotected amide 52 (obtained from 28 and 50 via 51) with
VOCl 3 produced the expected cyclic compound (±)-53 in 2% yield (Figure 12.7),
which was reduced to (±)-1 and (±)-4, with (±)-1 isolated in 61% yield. The 0.77%
total yield of the latter is 12 times lower than that shown according to the route in
Figure 12.4 with the application of bromo amide (Kametani et al., 1971b; Kametani,
1972b).
In another modification of (±)-1 synthesis, Kametani et al. (1972) used the
isomeric 2-bromo derivative 54 as a starting material (Figure 12.8). The latter was
transformed via 55 (63%) and 56 (86%) into the acid chloride 57, and coupled with
the methylamine derivative 28 to give the amide 58 (37%). Hydrochloric acid
debenzylation produced diphenol 59 (77%), which on irradiation with a mercury
lamp afforded the key compound (±)-53 in only 1% yield. LiAlH 4 reduction as