Sesquiterpenes

Shikimi (I. anisatum L.) has been known as a toxic plant since ancient times. It has been documented that people in Japan often were killed by unintentionally eating the fruits of the Japanese star anise (I. anisatum L.). Although the convulsive activity of the fruits of I. anisatum had been known for several centuries, it was only in 1952 that Lane et al. (1952) succeeded in the first isolation of a pure convulsive principle, which was named anisatin (Figure 4.16).

This result was reconfirmed in 1958 by Kawano and Matsuo (1958). In 1968, the structures of anisatin (107) and another convulsive principle, neoanisatin (108), were determined to be unique cage-shaped sesquiterpenes having a rare spiro P-lactone ring by Yamada and Hirata (Yamada et al., 1968). The structure of 107 was fully assigned on the basis of the both structures of the oxidatively degraded products, noranisatin (107a) and noranisatinone (107b), which had been already established by the spectral data (Yamada et al., 1965) and x-ray crystallographic analysis of bromono-ranisatinone (107c) (Sakabe et al., 1965) (Scheme 4.8). Later, the structure of anisatin was confirmed by x-ray crystallographic analysis (Wong et al., 1988). The total syntheses of (-)-anisatin (107) and (-)-noranisatin (107a) were first accomplished by Niwa et al. (1990, 1991), although several groups challenged synthesis of its complex molecule (Linder et al., 1982; Kende and Chen, 1985).

Anisatin causes picrotoxin-like convulsions in mice and dogs (Kajimoto et al., 1955), and the toxicity of anisatin and neoanisatin is much stronger than that of picrotoxin in the estimation of their LD50: 1 mg/kg for anisatin, in mice (i.p.). The neuropharmacological study of anisatin demonstrates that it is a potent noncompetitive GABA antagonist like picrotoxin (Kudo et al., 1981).

Kouno, one member of Kawano's group who had continued to investigate the toxic substance in I. anisatum (Kawano et al., 1958), succeeded in systematic studies on chemical components in Illicium plants. A number of anisatin-related sesquiterpenes, which have been reported by his group,

OH

och3

OH O

OH O

och3

ch3o

ch3o

och3

FIGURE 4.9 Tetrahydrofuran-type prenylated C6-C3 compounds 58-67 and chemical shift values (SH) for H-11 in illifunones can be classified into some subgroups as follows: anisatin (Figure 4.17), pseudoanisatin (Figure 4.18 and Figure 4.19), minwanensin (Figure 4.20), majucin (Figure 4.21), pseudomajucin (Figure 4.22), and cycloparvifloralone types (Figure 4.23), and some rare carbon skeletons (Figure 4.24).

The presence of very toxic anisatin is notified in many Illicium plants, such as I. anisatum, I. majus, I. floridanum, I. minwanense, and I. merrillianum (Lane et al., 1952; Kouno et al., 1989; Shimidt et al., 1998; Wang et al., 1994; Huang et al., 1999). The examples of anisatin-type sesquiterpenes are shown in Figure 4.17. All of them except for 114 belong to neoanisatin derivatives lacking the hydroxyl group at the C-3 position. 1-Hydroxyneoanisatin (109), 6-deoxy-1-hydroxy-neoanisatin (110), 2-oxo-6-deoxyneoanisatin (115), and an epimeric mixture of 116 and 117 were isolated from I. majus (Yang et al., 1990; Kouno et al., 1991), whereas 2 a-hydroxyneoanisatin (111) was isolated from the pericarps of I. anisatum (Kouno et al., 1991). It should be noted that veranisatins A (112), B (113), and C (114) were isolated as new convulsants in little amounts from nontoxic Chinese star anise (I. verum Hook. f.), which has been used as a basic spice and in traditional Chinese and Japanese medicines. They caused severe convulsions and death at 3 mg/kg

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