Corianin synthesis

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. 

Mitsunobu reaction as well as by mesylation and subsequent base treatment failed, the secondary alcohol was inverted by oxidation with pyridinium dichromate and successive reduction with sodium borohydride. The inverted alcohol 454 was protected as an acetate and the acetonide was removed by acid treatment to enable conformational flexibility. Persilylation of triol 455 was succeeded by acetate cleavage with guanidine. Alcohol 456 was deprotonated to assist lactonization. Mild and short treatment with aqueous hydrogen fluoride allowed selective cleavage of the secondary silyl ether. Dehydration of the alcohol 457 was achieved by Tshugaejf vesLCtion. The final steps toward corianin (21) were deprotection of the tertiary alcohols of 458 and epoxidation with peracid. This alternative corianin synthesis needed 34 steps in 0.13% overall yield. 

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). 

MS IR H-NMR C-NMR ORD [ ]d X-ray calculations (AMI, MacroModel) synthesis forms together with corianin (21) the molecular compound pseudotutin... 

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. 

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). 

Wakamatsu K, Kigoshi H, Niiyama K, Niwa H, Yamada K (1984) Stereocontrolled Total Synthesisof (-l-)-Tutin, AToxic Sesquiterpene of Picrotoxane-Type. Tetrahedron Lett 25 3873 Krische MJ, Trost BM (1998) Transformation of the Picrotoxanes The Synthesis of Corianin and Structural Analogs from Picrotoxinin. Tetrahedron 54 7109... 

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... 

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. 

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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