Histrionicotoxin, perhydro

The application of multistrategic retrosynthetic analysis to the target perhydro-histrionicotoxin is outlined in Section 6.3 of Part One. 

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. 

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. 

Spiropiperidine Alkaloids.—new synthetic pathway to ( )-perhydro-histrionicotoxin (27) (Scheme 5) has been elaborated. The final product is the intermediate (28), convertible to (27) as described earlier. A further synthetic entry into this ring system uses a Mannich-type spiro cyclization as key step and leads ultimately to racemic 2,7-epiperhydrohistrionicotoxin (29) (Scheme 6). The structure and stereochemistry of the urethane intermediate (30) were ascertained by X-ray diffraction analysis. ... 

Members of the histrionicotoxin family of alkaloids have attracted considerable interest because of their nnique structural features and their important properties as cholnolytics and modifiers of specific ion channels in nerves. Syntheses of perhydro-histrionicotoxin, a nonnatural alkaloid with comparable activity, were described in the literature. Recent reports showed that a variety of simpler analogs of perhydrohistrion-icotoxin also possess significant neurological activity. Godleski et selected... 

A formal synthesis of ( )-perhydrohistrionicotoxin has been described.The important aspects of the synthesis are detailed in Scheme 87. Although cycliza-tion to the spirolactam gave two products in almost equal amounts, the desired ring closure to the 6,6-azaspirane system proceeded with high stereoselectivity, thus establishing three of the four requisite stereocentres for perhydro-histrionicotoxin (54) in a single step. 

The ene reaction can also be appHed for spirocydizations. In the synthesis of the alkaloid perhydro-histrionicotoxin the spirocychc intermediates 413 and 417 have been prepared, of which only diastereomer 413 has the correct configuration of the... 

A synthesis of the azaspiro-[5.5]-undecan-8-ol ring system characteristic of the histrionicotoxins was first reported in 1975 in 30% overall yield by Gossinger etal. (SchemeXXI) (11. The carbon-13 magnetic resonance spectral peaks for azaspiro-[5.5]-undecan-8-ol were as follows 67.5 (C-8), 52.0 (C-6), 40.8 (C-2), 40.0,38.5,37.4,33.7,27.5,20.0,15.9. The base peak in the mass spectra was at m/z 126. No major ion at m/z 96 was included in the mass spectral tabulation. Infrared and proton magnetic resonance data were reported. The synthetic approach was not successful for the synthesis of 7-n-butylazaspiro-[5.5]-undecan-8-ol, a desamyl-analog of perhydro-histrionicotoxin. This compound has now been synthesized by Takahashi etal. (246). 

A number of laboratories have conducted studies on the synthesis of perhydro-(dodecahydro)-histrionicotoxin. A spiroketolactam intermediate has figured prominently in such efforts. Various synthetic routes to this compound are presented in Scheme XXII. A number of syntheses of perhydrohistrionicotoxin and other analogs of histrionicotoxin have now been reported These are summarized in Schemes XXIII— XXX. 

Scheme XXIX. Synthesis of a 6-epimer of the spirohydroxylactam intermediate for perhydro-histrionicotoxins I4I). Reaction B was found to result in an inversion. The structure of the final lactam was confirmed by X-ray analysis. An alternative route afforded the spirohydroxylactam precursor of dl-perhydrohistrionicotoxin. A i) (CH3)2t-BuSiCl, ii) n-ButylCu, AICI3, hi) OH", iv) AC2O, V) NaOBr, vi) CH2N2. B i) Dihydrofuran, ii) CH2 = CHCH2Br, base. C i) OSO4, ii) triethylphosphonoacetate, hi) Pt02, H2. Di) KH, ii) OH", heat, hi) NH2OH, iv)...

A radioactive perhydro-derivative of histrionicotoxin (pH]H,2-HTX (10, 92) has proved a very useful tool for investigation of the binding sites for histrionicotoxin in membranes and microsacs from Torpedo electroplax preparations (see Table 12 for references). Its use has not been extended to muscle preparations where the density of nicotinic receptor channel complexes are many fold lower than in Torpedo electroplax. Indeed, no specific binding could be detected in the electroplax of the Egyptian electric fish (Malapterurus electricus) where the density of nicotinic receptors also appear very low (97). In membranes from Torpedo electroplax pH]Hi2-HTX binds to a site with an affinity constant (Kd) of about 0.4 pM. The density of the binding sites for pH]Hi2 HTX is apparently about twice that of the acetylcholine-binding sites in electroplax membranes. The rate of... 

Corey, E. J., M. Petrzilka, and Y. Ueda A new synthetic route to (i)-perhydro-histrionicotoxin. Tetrahedron Letters 1975, 4343—4346. 

ScHOEMAKER, H. E., and W. N. Speckamp A novel synthetic approach to perhydro-histrionicotoxin. Stereoselective synthesis of 1-aza-spiranes. Tetrahedron Letters 1978, 1515—1518. 

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