The Synthesis of Picrotoxinin

Abstracted with permission from J. Am. Chem. Soc., 1996,118, 233 1996 American Chemical Society 

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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. 

Of particular note in comparison with the Wittig procedure is Boeckman s total synthesis of gascardic acid (equation 11). It was found that direct Wittig methylenation was low yielding in the reaction with (36). It was hypothesized that this was because of interference with the two-carbon side chain. The problem was solved by hydrolyzing the esters, followed by addition and elimination of the sulfoximine and reesterification to obtain the desired adduct (37) in 70% overall yield. The Johnson method was also utilized to selectively methylenate the less-hindered ketone (38) in the synthesis of (-)-picrotoxinin (equation 12). ... 

The past year has seen so many announcements of syntheses of complex carbocyclic natural products that the task of highlighting a few of them has been especially difficult. Clearly the stereocontrolled synthesis of the sesquiterpene hirsutic acid (1) by Trost and his co-workers merits special attention, as does the ingenious synthesis of its close relative hirsutene (2) by a group led by Tatsuta. No less meritorious is the synthesis of picrotoxinin (3) by Corey and Pearce or the syntheses of aphidicolin (4) by groups led by Trost and McMurry. Finally, mention must be made of the splendid single-handed effort by Still which resulted in the total synthesis of periplanone-B (5), the cockroach sex excitant pheromone. ... 

The bislactonization procedure adapted by Corey from the earlier work of Alder for the synthesis of picrotoxinin (4, 79) has been shown to be applicable to several simple substrates e.g. (69) -> (70). The rra 5-isomer of (69) gives largely the ( )-isomer of (70) under suitable conditions. 

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. 

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). 

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. 

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... 

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. 

Enyne cycloisomerizations can also be exploited to annulate a cyclopentane onto an existing ring system. An example drawn from Trost and co-workers asymmetric total synthesis of picrotoxinin (119) is the conversion of bridged bicyclic intermediate 117 into tricycle 118 (Scheme 6-20) [46]. The optimal cyclization conditions in this case were unusual, requiring an internal proton delivery and a bidentate phosphine. A related example is the conversion of 120 to 121, which was the pivotal step in Trost s synthesis of (—)-dendrobine (122) [47]. An all-carbon tether is not required, as is exemplified by the conversion of 123 to 124 in the total synthesis of ( )-phyllanthocin (125) [48]. Note that in-situ reduction of the o-palladium species prior to /5-hydride elimination has occuined in this latter-example. The enyne disconnection in the synthesis of ( )-phyllanthocin was... 

S)-(+)-Carvone (17) has itself served as the starting material in the synthesis of the tricyclic lactone, eucannabinolide (18)(ref.17) and in that of the wheat plant fungal toxin helminthospoal (19) (ref.18). By contrast,(R)-(-)-carvone has been engaged as the intermediate for the formation of the epoxydilactone, picrotoxinin (20) (ref.19). 

Regiospecific alkylation of dimethylhydrazone anions with the masked acrolein equivalent, 3-bromo-propionaldehyde dimethyl acetal, has brcn used as an alternative to a conventional Michael reaction in Corey s total synthesis of picrotoxinin (c/. equation 13). Azaallyllithium reagents derived from aldehyde and ketone hydrazones, unlike enolates, yield monoalkylation products with control of both regio-chemistry and stereochemistry. In appropriate cases, alkylation followed by deprotection to form a dicarbonyl product can be a very effective synthetic strategy. 

The same annulation method has been used in a stereocontrolled synthesis of picrotoxinin (3), a natural product with the hydrindane skeleton33,48. 

Hydridopalladative entry into the reaction cycle is also practical, hi a total synthesis of picrotoxinin 197, enyne 195 was converted into tricycle 196 in the presence of palladium acetate, dbpp, and dpba (Scheme The unusual catalyst system was necessary to... 

This enzyme-like reactivity enables the synthesis of highly complex molecules from substrates containing carboxylic acids, such as picrotoxinin derivatives which, when exposed to the same oxidizing conditions, yield lactone and hydroxylactone products (Scheme 38). 

Conditions have been reported for the stereoselective halogenolactonization of E-2-methylpent-3-enoic acid to give butyrolactones (35). A somewhat different lactonization procedure has been used in a total synthesis of Picrotoxinin the key intermediate (37) was formed (in 99% yield ) from the diacid (36) using Pb(OAc)4 (6 equivs.) in acetonitrile (25 °C, 1.5 h). ... 

Dendrobine, a congener of the powerful convulsant picrotoxinin, was first isolated from the Chinese tonic Chin Shih Hu in 1932, but its complete structure was not unravelled until 1964. Three groups of workers have reported the synthesis of dedrobine since that time. The synthesis outlined below was developed by Kende and his group at Rochester, and is based on the c/s-hydroindan nucleus (B) derived from the Diels-Alder adduct (A) by cleavage and aldol cyclization. The hydroindan derivative (B) already carrying the isopropyl unit, bears appropriate functionality for elaboration of the N-methylpyrrolidine ring and the 7-lactone moiety. 

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). 

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. 

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. 

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