Narcissus and Daffodil

Synthesis of galanthamine 325
ethanol or BBr3 , 119 underwent elimination of the trimethylsilanyl group and
dienone-phenolic rearrangement, with the formation of apogalanthamine-type
compound 128. On alkaline hydrolysis with K2CO3 in aqueous methanol, deacylation
of 119 accompanied cyclisation to crinine-type Amaryllidaceae alkaloids
129.
A number of norbelladine-type amides (118) and similar compounds of the
structure 130–133 were synthesised, and their oxidation process with phenyliodine
(III) bis(trifluoroacetate) was thoroughly studied (Figures 12.14 and 12.16).
The main products were found to be trialkylsilanylsubstituted dienones 134 (32%),
135 (46%), 136 (37%) and 137 (28%). In the case of 118 and 131, the oxidation was
accompanied by the formation of by-products, dienones 138 (9%) and 139 (12%),
respectively. The amide 140 on oxidation under similar conditions produced only
the trimethylsilanyl substituted compound 141, in 26% yield.
Thus, the most easily removable group for catechol hydroxyls was the diphenylmethylene
group, and the transformation of dienone to narwedine-type enone
was successfully achieved only in the case of 119. The enone 120 formed was a
suitable intermediate for galanthamine type synthesis.
Synthesis of galanthamine and lycoramine analogues
By means of photochemical cyclisation of substituted enamidobenzamides spirocyclohexyl-isoquinolines,
analogues of (±)-galanthamine and (±)-lycoramine have
been produced (Missoum et al., 1997). Various chemically modified galanthamine
derivatives (N-C 1 -C 12 -alkylene substituted analogues) have been obtained recently
as cholinesterase inhibitors (Thal et al., 1997).
Classical approaches to lycoramine synthesis
Several multi-step syntheses of (±)-lycoramine have been also published. They are
not actually biomimetic, and do not include galanthamine or narwedine intermediates.
Two main strategic approaches were used. The first strategy was based
on step-by-step construction of a lycoramine system, containing the properly substituted
benzene nucleus. Thus, Hazama et al. (1968) offered the 23-step synthesis
from 3-ethoxy-2-hydroxybenzaldehyde in 0.027% total yield. Misaka et al. (1967,
1968), in a 20-step synthesis from 2,3-dimethoxybenzaldehyde, reached a 0.39%
total yield. Martin and Garrison (1981, 1982) published the 15-step synthesis from
2-hydroxy-3-methoxybenzaldehyde, with a 17.35% total yield. A successful 13-step
synthesis from 3,4-dimethoxycinnamonitrile, in the scheme of Sanchez et al.
(1984), was realised with over 22.64% total yield.
In the second strategic approach, the substituted aromatic and cycloaliphatic
moieties underwent simultaneous modification. Thus, Schultz et al. (1977) have
used methyl 3-hydroxy-4-methoxybenzoate and 3-ethoxy-2-cyclohexenone as synthones
in a 16-step synthesis with 8% total yield. Ackland and Pinhey (1987a) used
cycloaliphatic synthones, 4-ethoxycarbonyl-cyclohexadienones mixture, prepared
in two stages from 2-trimethylsilyloxy-1,3-butadiene and methylpropiolate, and
tributyl-(2,3-dimethoxyphenyl)stannane, in a 14-step synthesis with 8% total yield
(Ackland and Pinhey, 1987b). Parker and Kim (1992) carried out an eight-step
synthesis starting from cycloaliphatic synthone trans-2-bromo-4-(tert-butyldimeth-