Picrotoxanes total syntheses

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). 

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. 

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... 

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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