Picrotoxane, synthesis

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. 

Natural lactams having carbon skeleton of picrotoxane, synthesis of ... 

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 picrotoxane sesquiterpenes are a family of natural products from a poisonous berry Menispermum cocculus which were documented as early as the 1600s by Indian natives who used them to stun fish and kill body lice. Trost and coworkers reported an approach to total synthesis of this family based on Pd-catalyzed cycloisomerization [68, 69]. Several synthesis recipes were tested and it was found that a combination of dbpp with a ligand capable of internal proton delivery (dpba) gave the best result and provided a key intermediate 27 for total syntheses of corianin, picrotoxinin, picrotin, and picrotoxate (Scheme 10). 

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). 

When Porter and Coscia published their reviews (2, 3) no total synthesis of a picrotoxane had come forth. Even the partial syntheses were not well developed, as mubironine A (97), an oxidation product of dendrobine (82), was not known as natural product at that time. The same is true for nordendrobine, the demethylation product of dendrobine (82), now known as mubironine B (98). Partial syntheses in the 1970s were made to determine the structure or absolute configuration of new picrotoxanes and are described earlier in this chapter. 

Due to the more complex structures of most sesquiterpene picrotoxanes compared with the dendrobines, fewer syntheses have been reported. Their structures with up to nine stereogenic centers were too complex to be used as test molecules for newly developed reactions. Three of the syntheses reported beginning with 1979 followed new strategies (two picrotoxinin syntheses and one coriamyrtin synthesis). The other syntheses of picrotoxinin (1), picrotin (2), coriamyrtin (9), tutin (11), corianin (21), methyl picrotoxate (42), and asteromurin A (22) were extensions either of successful dendrobine syntheses or partial syntheses. Remarkably, with one exception, all the syntheses are EPC-syntheses. 

EPC-synthesis of methyl picrotoxate (42). Trost s syntheses were the last attempts toward sesquiterpene picrotoxanes. No efforts to s)mthesize C-18-or C-19-picrotox-anes ( norditerpene picrotoxanes) have been reported so far. 

An intermediate of the coriamyrtin synthesis 119) was chosen to synthesize a further main picrotoxane sesquiterpene of Coriaria species, (+)-tutin (11). 

The possible therapeutic use of corianin (21) in the treatment of schizophrenia and the general influence of picrotoxanes on the central nervous system make more economic pathways desirable. Trost and Krische have shown that relais substance 431 can be easily prepared from commercially available picrotoxin 131). This constimtes a partial synthesis of corianin (21) in nine steps (Scheme 51). 

To date, the last total synthesis of a sesquiterpene picrotoxane (132) is a variant of the above-described picrotoxinin/corianin synthesis by Trost et al. Again, the synthesis started with (—)-carvone and the introduction of the C-1 unit corresponds with the earlier syntheses. The choice of the protective group was governed by the discovery that the oxygen(s) of alkoxymethyl ethers had a directing effect in the following addition of (cyanomethyl)lithium. 

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... 

Tanaka K, Uchiyama F, Sakamoto K, Inubushi Y (1983) Synthetic Studies on a Picrotoxane Sesquiterpene, Coriamyrtin III. Completion of the Stereocontrolled Total Synthesis of Coriamyrtin. Chem Pharm Bull 31 1972... 

Trost BM, Haffner CD, Jebaratnam DJ, Krische MJ, Thomas AP (1999) The Palladium-Catalyzed Enyne Cycloisomerization Reaction in a General Approach to the Asymmetric Syntheses of the Picrotoxane Sesquiterpenes. Part. I. First-Generation Total Synthesis of Corianin and Formal Syntheses of Picrotoxinin and Picrotin. J Am Chem Soc 121 6183... 

Niwa H, Yamada K (1986) Stereocontrolled Total Synthesis of Picrotoxane Sesquiterpe-noids. J Syn Org Chem (Japan) 44 180... 

Two new sesquiterpenoids of the picrotoxane group are amotin (208) and amoenin (209). In the course of an investigation of the toxic substances of the honeydew honey excreted by a sap-sucking insect which feeds on Coriaria arborea Lindsey, the two dihydro-derivatives of tutin (210) and hyenanchin (211) have been identified.Included in this paper are the n.m.r. spectral assignments of a number of compounds belonging to the picrotoxane series. Another milestone in sesquiterpenoid chemistry has been passed by the successful synthesis of (-)-picrotoxinin (212) starting from (-)-carvone (Scheme 33).One of the crucial steps in this fairly long synthesis was the double lactonization towards the end of the route. 

Coriamycin (30) is a member of the picrotoxane sesquiterpenes it stimulates the central nervous system, similar to the activity of the better known picro-toxinin. In a general route for the construction of the picrotoxane carbon skeleton, Tanaka et al have described a stereocontrolled synthesis of (30), starting from the product (26) resulting from l,6>addition of 2-methylcyclopentane-l,3-dione to protoanemonin (25). Methanolysis of (26) led to (27), which was converted into (28) by addition of isopropenylmagnesium bromide. The latter was then converted into coriamycin (30) via the intermediate lactone (29). 

Pioneering the field of metal-catalyzed cycloisomerizations, Trost and his group was also the first to discover the power of cycloisomerizations in the total synthesis of complex natural structures. In 1999, he reported the first-and second-generation strategy for the synthesis of picrotoxane core structure through a palladium-catalyzed cycloisomerization [71]. 

Trost, B. and Krische, M.J. (1999) Palladium-catalyzed enyne cydoisomerization reaction in an asymmetric approach to the picrotoxane sesquiterpemes. 2. Second-generation total synthesis of corianin, picrotoxinin, picrotin, and methylpicrotoxate. J. Am. Chem. Soc., 121,6131-6141. 

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