Narcissus and Daffodil

320 V.N. Bulavka and O.N. Tolkachev
was optimised to produce the key compound in 80% yield (92% conversion)
(Bulavka et al., 1990). Isomeric 2-bromo-3-hydroxy-4-methoxy-benzaldehyde (54),
suitable for photochemical cyclisation (as on Figure 12.8), was also obtained by
highly regioselective bromination of isovanilline with N-bromosuccinimide (Bulavka
et al., 1991).
Synthesis of 2-bromo-O-methylnorbelladine (95) was carried out according to
the scheme shown on Figure 12.12 via the Schiff base 94, preferably without its isolation.
The reductive amination of 39 with 17 (molecular sieves 4 Å, then NaBH4 in
MeOH) yielded the secondary amine 95 (85–96%), which after N-formylation
(89%, or 99% conversion) to 82 (Bulavka et al., 1994b) was oxidised with Mn(III)
acetylacetonate in acetonitrile to 83 (25%) (Bulavka and Tolkachev, 1995), and
then converted to (±)-1 and (±)-2 (53% and 31%). The total yield of (±)-1 was 9.5%,
higher than in the previous scheme.
Industrial synthesis of galanthamine – recent modifications
Czollner et al. (1997, 1998) recently modified the method of oxidation, optimising
the phenol coupling process to 45–50%. The final product was obtained as the
optically active compound. Phenolic oxidation of the formyl-tyramine derivative
82 in a two-phase liquid system was proposed, while (±)-8-bromo-N-formylnornarwedine
(83) was obtained in 26% yield (Henshilwood and Johnson, 1996).
A similar route was described in a patent of Tiffin et al. (1997). Compound 83 was
asymmetrically reduced to enantio-enriched (–)-galanthamine in 36% yield and
50% enantiomeric excess with a hydride agent formed in situ from LiAlH 4 , (–)-Nmethyl-ephedrine
and 2-(ethylamino)pyridine (Dyer et al., 1996; Czollner et al.,
1996). Using complex hydrides (NaBH 4 /CeCl 3 , LiAlH 4 /AlCl 3 , etc., –78 °C in
tetrahydrofuran), narwedine was recently reduced to (–)-galanthamine in high
yield (99.5%) (Shieh and Carlson, 1995). Carrying out an oxidative cyclisation of
the biogenetic precursor O-methyl-norbelladine in the presence of extract from
Narcissus bulbs produced (–)-galanthamine in yields 3 times higher than that
obtained in the absence of precursor (Bannister and McCague, 1997). In a similar
route, Chaplin et al. (1997a) used N-methylation of compound 95 before a phenolic
coupling reaction (30%). Palladium-catalysed debromination produced
racemic narwedine in 84% yield. Chaplin et al. (1997b) have also patented a
resolution of racemic bromo-narwedine as dibenzoyltartrate and reduction to
(–)-galanthamine with L-selectride.
Galanthamine synthesis by electrochemical oxidation
of belladine-type amides
Vlahov et al. (1980a,b) undertook a broad experimental study of the electrochemical
oxidative transformation of bis-alkoxy- or benzyloxy-substituted bromo-amides
into derivatives of narwedine and cyclodienones, intermediates in the synthesis of
1 (Figure 12.13). They synthesised a series of substituted bromoamides 96–98 (R′,
R″ = Me, PhCH 2 ) and 102. Anodic oxidation of these compounds (+1.30 V in
MeCN, ≤ 0°C) gave only trace amounts of the desired enones (34 or 49). The
main compounds isolated were dienones (99–100 or 103) (25–60%), together with