Picrotoxanes isolation

Aduncin, a picrotoxane sesquiterpenoid isolated from Dendrobium aduncum, has been assigned structure (147) on the basis of its spectroscopic properties and their similarity to those of a- and /3-dihydropicrotoxinin (148). A full paper dealing with the previously reported synthesis of 4-epidendrobine (149) has been published (cf. Vol. 7, p. 74). 

The first picrotoxanes discovered were isolated from the dried seeds of Menispermum cocculus (Anamirta cocculus) (1). Their characteristic features are two y-lactones and an oxrrane. M. cocculus belongs to the Menispermaceae ( moon seed family), which is in the order Ranunculales, and thus part of the primitive eudicots. So far, M. cocculus is the only species of the primitive eudicots recorded to contain picrotoxanes, and this species can be found in India, Sri Lanka, and southeast Asia. 

Guo et al. reported the isolation of picrotoxanes from Cuscuta japonica (Japanese dodder), a parasitic vine of many shrubs, growing in China, Korea, and Japan (41). This was the first report of a picrotoxane detected within the Asterid subclass of the core eudicots. The picrotoxanes of this member of the Convolvulaceae are also found as constituents of Coriaria species. As this plant is a parasite, it is possible that the picrotoxanes present were received from the sap of its host. 

Unfortunately, the next isolation of a picrotoxane from a sap-sucking insect, Asterococcus muratae (Homoptera), has only been presented at two scientific... 

The isolation procedures for the picrotoxanes have been mostly quite conventional. Plant material has been extracted with alcohols, and in few cases with chloroform. On concentration, water was added in many cases with subsequent... 

Isolation from Toxic Honey and Quantitative Analysis of its Main Picrotoxanes... 

Via a plant hopper and honeybees, partly metabolized picrotoxanes from Coriaria spp. growing in New Zealand are found in toxic honey. The rather difficult isolation of picrotoxanes from honey has been described several times 2,3,10,99,100) and even now the procedure seems not entirely satisfactory (700). Originally, the isolation of picrotoxanes was achieved by extraction of honey with acetone. Later, ethyl acetate was the preferred solvent. In the late 1960s, the two main picrotoxanes were identified as tutin (11) and hyenanchin (15). Originally, the detection was governed by the physical properties of crystals obtained, color reactions, and bromoether formation. Palmer—Jones then developed a method... 

The most thorough examination of a species in the Picrodendraceae was conducted by Koike, Ohmoto, and coworkers on P. baccatum (36,46,53-56,77,78). This tree is endemic to the West Indies. The plants investigated by the authors were harvested in the Botanical Garden of Bogor, Indonesia in 1986. In the next 15-20 years this Japanese group isolated 9 monolactone sesquiterpenes and 19 norditerpene picrotoxanes from this plant material. At first, these researchers examined a relatively small sample of the bark of the tree to determine the structural type of the toxins. Thus, 1.2 kg of dried bark were extracted successively with n-hexane. 

Comparison with the structure and chemistry of picrotoxinin (1) facilitated the structure elucidations of all the other picrotoxanes. Thus, Riban who isolated coriamyrtin from C. myrtifolia (tanner s brush) in 1864 18a), concluded that its structure had to be similar to that of picrotoxin due to its analogous reversible halogenation reaction 18b). Okuda and Yoshida proposed the correct formula of coriamyrtin (9) 125, 126). This was confirmed by correlation with the structure of mtin (11) (57), which had been determined by X-ray analysis of its derivatives, O i-bromotutin (= a-bromoisotutin) (105) (25,127) and a-bromoisotutinone (106) (26) (Scheme 3). 

A-Methyldendrobinium chloride (84) was the first quaternary picrotoxane alkaloid isolated and characterized by Inubushi 114). The next dendrobinium salt isolated was A-isopentenyldendrobinium chloride (85) 81). Its structure was determined by pyrolysis to dendrobine (82). The configuration of its quaternary nitrogen was determined by synthesis 81). 

To demonstrate the versatility of his S3mthesis strategy Yamada used ketoester 151 as relais substance to S3mthesize two further picrotoxane alkaloids isolated from Dendrobium species, nobilonine (90) and 2-hydroxydendrobine (87) (Scheme 14) (84). Monobromination of 151 with bromine in dioxane and subsequent treatment with water resulted in hydroxy-y-lactam 152, whereas attempts to hydroxylate 151 by Barton oxidation led to rearrangements. Chemo- and stereoselective reduction with zinc borohydride converted 152 into the en fo-alcohol. To counterbalance the unfavorable conformational equilibrium this alcohol had to be converted into the alcoholate to achieve lactonization. Chemoselective reduction of the hydroxylac-tam moiety of lactone 153 again followed Borch s protocol, which led in this case to boron complexed amino compounds necessitating successive acid treatment to obtain racemic 2-hydroxydendrobine (87) in low yield accompanied by dendrobine (82). 2-Hydroxydendrobine (87) was converted into nobilonine (90) by Eschweiler-Clark methylation. 

Asteromurin A (22), a compound isolated from a scale insect was the next target of Yamada , picrotoxane synthesis project. An intermediate of the synthesis of tutin (11), the unsaturated epoxide 395, was the relais substance. 

The first report of the incorporation of radioactively labelled mevalonic acid into dendrobine (82) was by Yamazaki et al. (224). Sodium [2— CJmevalonate [( )-463 ] was administered to stems of D. nobile by the cotton-wick method. After 12 days, the plants were extracted and radioactive dendrobine (82) was isolated by column chromatography. The total incorporation was 0.012%. Subsequent Kuhn-Roth oxidation led to acetic acid that showed the expected activity assuming the biosynthesis pathway a leading to the picrotoxanes via a cadalene as precursor (Scheme 55, pathway c). 

Although investigations of biosynthesis have become considerably more convenient by shifting to stable isotopes and nondestructive spectroscopic methods, the pioneering work was never continued. Thus, the pathway from copabomeol (474) to dendrobine (82), mono- and dilactone picrotoxanes, and norditerpene picrotox-anes is stiU unknown and no enzymes of this biosynthetic pathway have been defined or isolated. There is mention of genes of the dendrobine bios3mthesis isolated and expressed in Escherichia coli (233). 

Ref. 4 in Wakamatsu K, Kigoshi H, Niiyama K, Niwa H, Yamada K (1984) Stereocontrolled Total Synthesis of (+)-Asteromurin A, a Picrotoxane Sesquiterpene Isolated from the Scale Insect Asterococcus muratae Kuwana. Chem Lett 1763... 

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