Histrionicotoxin synthesis

A retro-l,3-dipolar cycloaddition followed by an 1,3-dipolar cycloaddition was used for a highly efficient total synthesis of (-)-histrionicotoxin (4-354) (HTX) by Holmes and coworkers [123]. HTX is a spiropiperidine-containing alkaloid which was isolated by Doly, Witkop and coworkers [124] from the brightly colored poison-arrow frog Dendrobates histrionicus. It is of great pharmacological interest as a noncompetitive inhibitor of acetylcholine receptors. 

Other routes to piperidines involving 1,4-addition reactions include the incorporation of a Michael addition reaction as the piperidine ring formation step in the total synthesis of Histrionicotoxin <06JA12656> and the use of an intramolecular 1,4-addition, 6-endo-dig ring... 

Scheme 23. Synthesis of (-)-histrionicotoxine by a peri cyclic domino process...

The active principle of dart frog poisons is alkaloids. The study of the den-drobatid poisons led to the discovery of over 200 new alkaloids, including batrachotoxins Pig. 10.5), pumiliotoxins, histrionicotoxins, gephyrotoxins, and decahydroquinolines (Daly et al., 1994). The most common compounds have the basic structure of piperidine and include histrionotoxin. In Phyllobates, the synthesis of other alkaloids is suppressed in favor of batrachotoxins. These are... 

Since the migrating group retains its configuration, the use of enantiomerically enriched oximes provides a direct entry to enantiomerically pure lactams. These lactams may be used as a key building block for the synthesis of diverse compounds. Westermann and Gedrath applied this strategy to the stereoselective synthesis of enantiomerically pure o-.a-disubstituted a-amino acids (equation 135), bicyclic lactams and the spirocyclic framework of Histrionicotoxins (equation 136). 

Both enantiomers of the oximes 353, R = (CH2)2CH=CH2, n = 1, 2 could be obtained in a pure form by lipase-catalysed kinetic resolution of its racemic oxime esters. Applying the previous sequence, both isomers of compounds 354 could be easily obtained. The synthesis of the framework of Histrionicotoxin 356 was obtained from 355 and is shown in equation 136. ... 

The skin of neotropical frogs of the Dendrobatidae family has been a rich source of bioactive compounds [42] such as the alkaloids epibatidine, batrachotoxins, histrionicotoxin, and indolizidines. The latter have been investigated due to their activity as noncompetitive blockers of the nicotinic receptor channels [43]. Because only small amounts are available and due to their pronounced physiological activity, these alkaloids are important targets for organic synthesis [44]. Since... 

Perhydropyridol[2,l-h][l,3]oxazines are used in the synthesis of in-dolizidines (gephyrotoxins and monomorine-I) [88H(27)1575 91SL44, 91SL878] and histrionicotoxin (91SL44) alkaloids. 

One of the first examples of high asymmetric induction in the intramolecular [2 + 2] photocycloaddition in which the chiral center located at the side chain found in Winkler and coworkers113 approach to the synthesis of (—)-histrionicotoxin alkaloid 240. Irradiation of 237 is the key step in the synthetic strategy. The isomer 238 was formed in... 

The product 40 was used in a synthesis of the Columbian frog venom perhydro-histrionicotoxin 49 and that also used the Beckmann rearrangement of the oxime 47. Note that only the group anti to the N-0 bond migrates and that it does so with retention. You can see that each ring was expanded in this synthesis. 

The intramolecular nitrogen-trapping protocol used by Banwell has also been successfully exploited in the assembly of spirocyclic frameworks relating to the aromatic erythrina alkaloids.24 However, when it was applied to the synthesis of nonaromatic spirocycles, as found in histrionicotoxin, the flexible alkyl tether proved to be problematic.25 In this study, gem-dichlorocyclopropane substrate 37 was initially subjected to silver(I) salts under a variety of conditions only to provide solvolysis and elimination products without any indication of trapping by the pendent... 

Comins, D.L., Zhang, Y., and Zheng, X. (1998) Photochemical reactions of the chiral 2,3-dihydro-4(lH)-pyridones asymmetric synthesis of (—)-perhydro-histrionicotoxin. Chemical Communications, 2509-2510. 

The nitrone protection strategy has also been used in the total synthesis of (-)-histrionicotoxin (84) and some related alkaloids. The bicyclic isoxazolidine 82 underwent the cycloreversion-cycloaddition reaction at 190 °C to give the key intermediate 83 in high yield (82%) <02JCS(P1)1494>. 

Anodic oxidation in the synthesis of piperidine alkaloids 90YGK814. Antitumor sesbanimides, total synthesis of 87YGK983. l-Azaspiro[5.5]undecane system of histrionicotoxines, syntheses of 89BSF370. 

An S 2 copper-catalyzed nucleophilic substitution of the chloride in a cyclic chloroacetate by butylmagnesium bromide was employed in a synthesis toward perhydrohistrionicotoxin [Eq.(47)] [79]. Histrionicotoxins are found in South American dart-poison frogs of the Dendrobatid family. Palladium-catalyzed chloroacetoxylation of 2-substituted diene 68 gave a highly regio- and stereoselective 1,4-addition product where the chloride ends up in the 1-position. Copper-catalyzed reaction of the chloroacetate 69 with butylmagnesium... 

The structures, synthesis, and biological activity of the histrionicotoxins were reviewed in Volume 4 of this series [715], Work described below was published subsequent to this review. 

Histrionicotoxin (340) and (-)-histrionicotoxin 235A (341) were synthesized from (S)-6-hydroxy-8-nonenoate, using an allylic epoxide cyclization to generate three of the required chiral centers [717]. A recent synthesis of the histrionicotoxin ring system employed a tandem Michael addition-nitrone cyclization [718]. GC-MS, GC-FT1R, and revised i3C NMR spectral data have been reported for a number of histrionicotoxins [719],... 

The first total synthesis of racemic histrionicotoxin (58), the parent structure in a family of related spirocyclic alkaloids isolated from the skins of Dendrobates histrionicus, utilized the Eschenmoser reaction to generate the anchor of what would become the enyne group extending from the a-position of the piperidine nucleus. The spirothiolactam intemiediate (77) was condensed with ethyl 2-bromoace-toacetate in the presence of sodium bicarbonate to produce (78) in good yield (Scheme 18). Prior to further reaction on the vinylogous carbamate, the pendent allylic acetate was elalx>rated to the enyne (79). Subsequent deacylation and enyne protection yielded spirobicycle (80), which gave a 1 1 mixture of isomers upon reduction. The desired diastereomer (81) was isolated and subsequently converted to racemic histrionicotoxin (58). 

Addition of Grignard reagents to five- and six-membered systems (11) and (12) also leads to V-acyl-iminium ion precursors. The products, being tertiary alcohols, are rather susceptible, however, to ringopening and dehydration, so that their isolation may be problematic. Nevertheless, this methodology has proven highly useful for the synthesis of the amphibian alkaloid histrionicotoxin. ... 

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