C6c3 Compounds

A very large number of compounds exhibit a characteristic C6-aromatic-C3-side chain compounds; for example, aromatic amino acids, hydroxycinnamic acids, phenylpropenes, coumarins, isocou-marins, chromones, and so forth. The biosynthesis of these compounds follows the shikimic acid pathway. Shikimic acid was isolated as early as 1885 by Eijkman from the Japanese plant I. anisatum. Its name originally derives from the Japanese Shikimi, but shikimic acid was later found to be widespread in nature. Therefore, C6-C3 compounds, which are biosynthesized from shikimic acid, are most likely to be characteristic components of Illicium species.

Volatile simple phenylpropanoids (Figure 4.1) have been found in leaf oil of most Illicium species. £-Anethol (compound 1), safrole (7), and eugenol (11) were isolated from the leaf oil of I. anisatum by J.F. Eijkman a long time ago. £-Anethol was then isolated again, as an insecticide (Miyazawa et al., 1993) and as a sweetening substance, from the fruits of I. verum (Hussain et al., 1990). In fact, £-anethol has been used as a flavoring agent in beverages, candy, baked goods, and chewing gum (Furita and Bellanca, 1975). It is worth noting that the oil of Chinese star anise usually contains over 70% E-anethol. E-anethol, however, is a present in small amounts or is absent in the oil of other Illicium plants (Liu and Yang, 1989; Yang et al., 1992). The analogues of E-anethol, 2-6, were also found in the leaves of Illicium verum (Sy and Brown, 1998). However, safrole (7) and novel 1,2-methylenedioxy-4-(propane-1,2-diol)benzene (10) were found in the fresh leaves of I. dunnianum (Sy et al., 1997), and more oxygenated C6-C3 compounds, myrsticin (8) (Yakushijin et al., 1983), and sarisan (9) and methoxyeugenol (12) (Shibuya et al., 1978; Sy et al., 1997) were isolated from I. anisatum and I. dunnianum. Another phenylpropanoid bearing more substituents (13-20) (Figure 4.2) was isolated from the bark of I. difengpi (Kouno et al., 1992) and the leaves of I. verum (Sy and Brown, 1998). Compounds 13-18 appear to be biogenetically derived from threo-anethol glycol (5), which was also present as a significant component of the methylene chloride extract of the leaves of I. verum. Moreover, phenylpropanoid glycosides (21-28) (Figure 4.3) were present in I. difengpi and I. anisatum (Kouno et al., 1992; Tanaka et al., 1998; Jiang et al., 1999). Glycoside 21 was 6-p-coumaroyl glucoside of 19.

Phenylpropanoids bearing an additional prenyl group (Figure 4.4) are also characteristic phenols in Illicium plants. O-Prenylated chavicol (29), O-prenylated eugenol (30), and 32 occur in the fresh leaves of I. dunnianum (Sy et al., 1997), whereas the leaves of I. anisatum contain O-prenylmeth-oxyeugenol (31) in addition to 30 (Shibuya et al., 1978). Illicinol (33) was the only phenolic component isolated from the dried leaves of I. arborescens (Yakushijin et al., 1983). The structure of 33 was confirmed by direct comparison of illicinol with an authentic sample obtained by the reaction of 2-allyl-4,5-methylenedioxyphenol and prenylbromide in the presence of base. In addition, Yakusuijin et al. (1983) reported the presence of compounds 34 and 35 in the wood of I. anisatum. Anisoxide (36) was first isolated by Jackson and Short (1937) from star anise oil obtained from the seeds of I. verum. The structure of 36 was established by Barton et al. (1958) by degradation as well as by synthesis from 1-(2-hydroxyl-4-methylphenyl)-3-methylbutan-2-one. Although anisoxide contains a chiral carbon, it was obtained as a racemate, and thereby might be an artifact formed during the isolation procedure. Okely and Grundon (1971, 1981), who asked this question, proved that anisoxide could originate from an abnormal Claisen rearrangements of feniculin (36a), a main component in star anise oil, at 185°C, followed by cyclization of the resultant 1,2-dimethylallylphenol (36b) (Scheme 4.1). Later, anisoxide was confirmed to be absent in the star anise oil and the seeds of I. verum, using GC analysis. Okely and Grundon concluded that anisoxide had been previously obtained as a result of prolonged distillation of anise oil (Okely and Grundon, 1971, 1981).

Another group of C6-C3 compounds bearing an additional prenyl group occurs in I. tashiroi and I. arborescens (Figure 4.5). Illicinone A (37) is a typical example of these compounds, which feature a structure consisting of the units of both lignans [C6 + C3] and terpene [C5] (Yakushijin et al., 1980). (45)-Illicinone A (37a), its dihydro-derivative (2R, 45)-illicinone B (38a), and (45)-illicinone C (39a) and (2R, 45)-illicinone D (40a), having an epoxide ring on a prenyl group, were found in I. tashiroi (Yakushijin et al., 1980, 1984; Fukuyama et al., 1992). It is interesting that each isomer, with regard to the C-4 chirality, (4R)-illicinone A (37b), (25, 4R)-illicinone B (38b), (2R, 4R)-illicinone B (38c), (4R)-illicinone C (39b), (25, 4R)-illicinone D (40b), and (2R, 4R)-illicinone D (40c), was isolated from the leaves of I. arborescens (Yakushijin et al., 1984). In addition, a number of illicinone-type compounds having a variety of the modified prenyl units, illicinone G (41), (2R, 45)-illicinone F (42a), and (25, 45)-illicinone F (42b), were isolated from I. tashiroi (Fukuyama et al., 1994). Illicinone H (43) and its methyl derivatives 44 and 45, which lacked a methylenedioxy group, existed in usual illicinones A-F and were found in I. tashiroi (Fukuyama et al., 1994) and I. anisatum (Hano et al., 1992; Kaku et al., 1993), as shown in Figure 4.6.

The C-4 chirality of illicinone A was determined by the CD spectra of both a-hydroxycyclo-hexanones 48 and 49, derived from 37b as shown in Scheme 4.2. Two chair conformations a and b for 48 and 49 seem to be possible. In fact, the CD spectra of 48 and 49 exhibited a positive Cotton effect in a nonpolar solvent; therefore, 48a and 49a configurations should dominate. However, och3

och3

och3

CH3O'

OH

OCH3

OCH3

OCH3

OCH3

FIGURE 4.2 Phenylpropanoids (compounds 13-20)

the CD spectrum of 48 still showed only a positive Cotton effect in polar solvents, but inversion of the sign of the Cotton effect in the CD spectrum of 49 was observed on changing the polarity of the solvent. These results indicate that 48 predominantly takes the conformer 48a in both nonpolar and polar solvents, whereas 49 adopts conformer 49a in nonpolar solvents and there is an equilibrium between 49a and 49b in polar solvents. On the basis of the CD spectra, the absolute configuration of 37b and 37a isolated from I. arborescens and I. tashiroi could be established as 4R and 4S, respectively (Yakushijin et al., 1984).

Yakushijin et al. (1984) reported interesting thermal and photochemical transformations of illicinone A (37) (Scheme 4.3 and Scheme 4.4). (4R)-Illicinone A (37b) was heated in a sealed

OCH3

OCH3

0 0

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