Narcissus and Daffodil

12 Synthesis of galanthamine and
related compounds
V.N. Bulavka and O.N. Tolkachev
INTRODUCTION
(–)-Galanthamine is the principal representative alkaloid from the Amaryllidaceae
family, possessing a characteristic benzofuro[3a,3,2-ef ][2]benzazepine skeleton.
It is an anticholinesterase agent of low toxicity used in medicine for the treatment
of a number of conditions (Mashkovsky and Kruglova-L’vova, 1951; Mashkovsky,
1955). It is under evaluation for the treatment of Alzheimer’s disease (Fulton and
Benfield, 1996; Moraes-Cerdeira et al., 1997).
Galanthamine hydrobromide was produced commercially as ‘Nivalin’ in Bulgaria
from Galanthus nivalis L. and later from Leucojum aestivum cultivars, and in the
former USSR from leaves of Ungernia victoris L. collected in the mid-Asia regions.
The limited plant sources available in the Russian flora for commercial exploitation,
the low concentration of the alkaloid in plant material and the labourconsuming
character of the chemical processes, led to a need for alternative routes
of galanthamine production. At present, synthetic methods seem to have assumed
practical significance.
The chemistry of Amaryllidaceae alkaloids has been extensively reviewed
(Abduazimov, 1993; Cook and Loudon, 1952; Fuganti, 1975; Grundon, 1984,
1985, 1987; Jeffs, 1990; Lewis, 1990, 1997; Polt, 1996). Today about 20 natural
alkaloids of the galanthamine type, isolated from species of Amaryllidaceae, are
known. Up to now, five alkaloids – galanthamine, narwedine, lycoramine, sanguinine
and N-norgalanthamine – have been obtained by total synthesis.
CHEMICAL PROPERTIES OF GALANTHAMINE
(–)-Galanthamine ((–)-1) is a strong base, which on interaction with alkylhalogenides
produces quaternary ammonium salts. The oxidation of (–)-1 with MnO 2
in mild condition leads to the ketone 2, isolated in optically inactive form (Barton
and Kirby, 1962; Combes and Lefebvre, 1962). Its (–)-enantiomer is the natural
alkaloid known as narwedine (Figure 12.1). Narwedine readily undergoes racemisation
in alcoholic solutions, especially in the presence of organic bases and acids,
or spontaneously without any additives (Barton and Kirby, 1960, 1962). The
mechanism of this process has been explained by the formation of tautomeric
dihydrofuranoic and hydroxyspirodienone (3) forms, which are converted in a