Picrotoxane sesquiterpenes

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]. 

Further elaboration on the oxidation states of diene bicycle 75 provided the divergent total synthesis of corianin (78), picrotoxinin (79), and picrotin (80) in less than half the number of steps previously reported. 

---

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). 

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

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... 

Ayafor JF, Tane P, Ngadjui BT, Connolly JD, Rycroft DS, Tillequin F (1993) Picrotoxi-maesin, a New Picrotoxane Sesquiterpene from Maesa kamerunensis Mez. Planta Med 59 ... 

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... 

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). 

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. 

So far, Dendrobium species have yielded 21 pseudoalkaloids of the picrotoxane type and 27 sesquiterpene picrotoxanes (5 dilactones, 20 monolactones. 

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. 

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. 

Like H. globosa the Jamaica walnut or blackwood or bitter plum (P. baccatum) contains sesquiterpenes as well as norditerpenes of the picrotoxane type. Picro-dendrin Q (74), the most toxic picrotoxane for mammals, is found in the bark of this tree. In the Dominican Republic, the tree is also called mata becerro (calf killer) and its bark is used to kill lice and bed bugs (239). 

Dahmen J, Leander K (1978) Amotin and Amoenin, two Sesquiterpenes of the Picrotoxane Group from Dendrobium amoenum. Phytochemistry 17 1949... 

Tang J, Liu QF, Dai JQ, Zhao WM (2004) A New Picrotoxane Type Sesquiterpene from Dendrobium densifiorum. Chin Chem Lett 15 63... 

Zhao CS, Liu QF, Halaweish F, Shao BP, Ye YQ, Zhao WM (2003) Copacamphane, Picrotoxane, and Alloaromadendrane Sesquiterpene Glycosides and Phenolic Glycosides from Dendrobium moniliforme. J Nat Prod 66 1140... 

---