Of picrotoxinin

Some naturally occurring analeptics have been known for centuries. Two of the best known and most thoroughly studied are strychnine [57-24-9] (1) and picrotoxin [124-87-8] a 1 1 combination of picrotoxinin [17617-45-7] (2) and picrotin [21416-53-5] (3). These continue to be of interest in the study of mammalian neurotransmission. 

The example given above of the selection of deoxycholic acid as a SM for the synthesis of cortisol also illustrates the use of a chiral natural substance as synthetic precursor of a chiral TGT. Here the matching process involves a mapping of individual stereocenters as well as rings, functional groups, etc. The synthesis of helminthosporal (105) from (-i-)-carvone (106)21 and the synthesis of picrotoxinin (107) from (-)-carvone (108)22 amply demonstrate this approach employing terpenes as chiral SM s. 

In one example (Lawrence and Casida 1984, Abalis et al. 1985) rat brain microsacs were used to test the action of cyclodiene insecticides such as dieldrin and endrin on the GABA receptors contained therein. The influx of radiolabeled CL into the microsacs via the pore channel of the receptor was inhibited by these chemicals. A similar assay was developed using microsacs from cockroach nerve. Assays with this preparation showed again the inhibitory effect of a cyclodiene (this time heptachlor epoxide) on CL influx. Also, that microsacs from cyclodiene resistant cockroaches were insensitive to the inhibitory effect of picrotoxinin, which binds to the same site on the GABA receptor (Kadous et al. 1983). 

Matsumura F. 1985. Involvement of picrotoxinin receptor in the action of cyclodiene insecticides. Neurotoxicology 6(2) 139-164. 

Carvone is used as a starting material in the preparation of picrotoxinin. The (7 5) form is present in gingergrass, Listea guatemaleusis, lavender and Artemisia ferganensis ... 

One of the anchimeric effects that hampered the stmcture elucidation of picrotoxinin (1) considerably was the high stability of its oxirane (Scheme 1). When combined with the fact that this functionality seemed highly unusual for a naturally occurring compound at the time, tests to confirm the presence of this funcionality failed. For example, even gaseous hydrochloric acid in acetic acid did not cleave this epoxide, but led to anhydropicrotoxinin (103) by intramolecular ether formation (Scheme 2). Under strongly basic condition the many functionalities of the... 

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). 

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 first synthesis of this group of sesquiterpenes was Corey s and Pearce s EPC-synthesis of picrotoxinin (1), which, due to the originality of its steps and relative shortness, has become a classic 118, 200, 201). To form the quaternary center they used a method partly developed for this synthesis. 

Barton oxidation was the key to form the 1,2-diketone 341 in surprisingly high yield, in order to close the five-membered ring (Scheme 38). The conditions chosen for the deprotection of the aldehyde, mercuric oxide and boron trifluoride etherate, at room temperature, immediately led to aldol 342. After protection of the newly formed secondary alcohol as a benzoate, the diketone was fragmented quantitatively with excess sodium hypochlorite. Cyclization of the generated diacid 343 to the desired dilactone 344 proved very difficult. After a variety of methods failed, the use of lead tetraacetate (203), precedented by work performed within the stmcmre determination of picrotoxinin (1), was spectacularly successful (204). In 99% yield, the simultaneous formation of both lactones was achieved. EIcb reaction with an excess of tertiary amine removed the benzoate of 344 and the double bond formed was epoxidized with peracid affording p-oxirane 104 stereoselectively. Treatment of... 

Conversion of synthetic picrotoxinin (1) to picrotin (2) was achieved by Corey and Pearce in four steps and 30% overall yield 124). To prevent intramolecular oxymercuration, the tertiary alcohol of picrotoxinin (1) was protected as trifluor-oacetate 346 prior to addition of mercury trifluoroacetate in a benzene/THF mixture as solvent. Demercuration with sodium borohydride failed, thus the covalent C-Hg bond was cleaved by tributylstannane in ethanol. Mild hydrolysis of the bistrifluor-oacetate 347 afforded picrotin (2) in 30% overall yield (75% corrected for recovered 1) from picrotoxinin (1). 

The third new strategy for the construction of picrotoxinin (1) was presented by Yoshikoshi et al. (120). The chiral starting material, 399, of the EPC-synthesis of picrotoxinin (1) and picrotin (2), was derived from (—)-carvone in four steps (214). 

Starting with picrotoxinin (1) Yoshikoshi developed an improved synthesis of ( )-picrotin (2). Epoxidation of picrotoxinin (1) with peracid at room temperature led to a 5 2 mixture of the epimeric epoxides. Regioselective cleavage of the epoxide was achieved with sodium phenylselenyl triethoxy boronate. Radical reduction of the phenyl selenides 414 with stannane completed this three-step sequence to picrotin (2) in 87% overall yield. 

A further intermediate of the above-described synthesis of picrotoxinin (1), diester 423, inspired the authors to attempt the first EPC-synthesis of methyl picrotoxate (42) (63). Originally, this compound was found as a degradation product of picrotoxinin (1) (2, 3). It was reported later as a minor constituent in both the plant M. cocculus and in the sponge S. inconstans. 

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