Narcissus and Daffodil

306 V.N. Bulavka and O.N. Tolkachev
THE SYNTHESIS OF ALKALOIDS OF THE GALANTHAMINE GROUP
The first synthesis confirming the structure of galanthamine
Galanthamine was isolated for the first time from Galanthus woronowii and its
preliminary structure was proposed from data on the chemical degradation of its
molecule using classical methods (Proskurnina and Yakovleva, 1952, 1955). The
final confirmation of the structures of galanthamine, narwedine and lycoramine
were made by their total synthesis. The first biomimetic route of (±)-2, and after its
resolution, of (+)-1, (–)-1 and (–)-lycoramine synthesis, proposed by Barton and
Kirby (1960, 1962), included the oxidation of diphenolic substrates such as O,Ndimethyl-norbelladine
(6, R = Me), the biogenetic precursor of 1, or its derivatives
(Figure 12.2). The synthesis was carried out starting from 4-hydroxybenzaldehyde
(7) through cyanohydrine (8) and 4-hydroxyphenylacetic acid (9) (34%), which,
after O-benzylation into 10 (67%), was converted into the acid chloride 11 (Figure
12.2). The coupling component was obtained from 3-benzyloxy-4-methoxybenzaldehyde
(12) via the intermediate Schiff base (13), with a subsequent reduction
to 3-benzyloxy-4-methoxy-N-methyl-benzylamine (14) (68% yield). With the
acid chloride 11, the latter yielded the corresponding arylacetamide 15 (85%). The
LiAlH4 reduction of 15 (88%) and Pd/C hydrogenolysis of the intermediate
tertiary amine 16 produced the desired compound 6 in 76% yield. Oxidation with
different agents produced the target ketone (±)-2 in very low yield (0.1–1.4%). The
best results were obtained on K3 [Fe(CN) 6 ] oxidation (0.92–1.4%). The final LiAlH4 reduction afforded a mixture of (±)-1 and (±)-4 in the ratio 3:2 (ca. 100%), from
which the first compound was isolated in crystalline form (39%). Aluminium
isopropoxide reduction produced preferentially the epi-isomer (±)-4 (60%). The
total yield of (±)-2 was 0.18%, and of (±)-1, only 0.07%.
Also proposed was a method of conversion of the ketone (±)-2 into enantiomeric
(–)-1 via a step of dynamic resolution of (±)-2 to (+)-2 in the presence of optically
active additives (–)-1, (–)-4 or (–)-lycoramine, and the LiAlH4 reduction of (+)-2 to
yield a mixture of (+)-1 and (+)-4. The latter were used for seeding during the
conversion of the racemate to (–)-2. A similar LiAlH4 reduction of (–)-2 produced
the target (–)-1 in 58% yield. The subsequent hydrogenation over Pd/C afforded
(–)-lycoramine (Barton and Kirby, 1960, 1962). Recently, a modified version of the
pilot plant method of dynamic resolution of (±)-narwedine has been applied
(Shieh and Carlson, 1994; Czollner et al., 1998).
Synthesis of narwedine via palladium-directed coupling
The synthesis was modified by Holton et al. (1988) as follows (Figure 12.3).
A hydroxy group in 3-hydroxy-4-methoxybenzaldehyde (18) was protected by the
action of NaH in OP(NMe 2 ) 3 , N 2 , then MeSCH 2 Cl; the intermediate O-methylthiomethyl
derivative (19) (Holton and Davis, 1977), on condensation with 4-hydroxyphenethylamine
(17), gave the Schiff base 20, which, after NaBH 4 reduction to
21, hydroxymethylation and NaB(CN)H 3 reduction of 22, gave the N-methylderivative
23 in 90% overall yield. With LiPdCl 4 in MeOH-(i-Pr) 2 NH (–78 °C), 23
produced the palladium derivative (±)-24 as a diastereomeric mixture (95%).
Oxidation with (CF 3 COO) 3 Tl (–10 °C) gave the expected compound (±)-25, which