Organic Chemistry Portal
Organic Chemistry Highlights

Total Synthesis

Monday, January 1, 2018
Douglass F. Taber
University of Delaware

The Tokuyama Synthesis of (-)-Histrionicotoxin

Histrionicotoxin (3) is one of the more complex of the alkaloids isolated from the skins of the brightly-colored "poison dart" frogs of Central America, in this case Oophaga histrionica (formerly Dendrobates histrionicus), native to Colombia. Hidetoshi Tokuyama of Tohoku University assembled (Angew. Chem. Int. Ed. 2017, 56, 1087. DOI: 10.1002/anie.201609941) 3 by the remarkable free-radical cyclization of 1 to 2.

The preparation of 1 began with 4, the adduct between cyclohexane-1,3-dione and methyl acrylate. Exposure to strong acid followed by acid-catalyzed esterification gave 5, that underwent reductive amination with 6 to give 7. Selective reduction of the ester to the alcohol followed by oxidation gave an aldehyde, to which vinyl magnesium bromide 8 was added, leading to 9. Cross metathesis with methyl acrylate 10 followed by oxidation gave 11, that was ketalized with the enantiomerically-pure 12 to give the cyclization precursor 1.

The reduction of the bromide of 1 led to an aryl radical that abstracted the H atom adjacent to the N to give a new radical, that in turn added to the unsaturated ester to give 13. There are four possible diastereomers of 13, that may well be in equilibrium one with another under the reaction conditions. The diastereomer 13 is favorably disposed to abstract the H atom adjacent to the O, leading, after final H atom transfer, to 2.

Deketalization of 2 gave 14, that was reduced, then selectively coupled with 15 to give the selenide 16. Acid-mediated removal of the N protecting group followed by alcohol protection and oxidation delivered the alkene 17. Reduction followed by diastereoselective addition of allyl magnesium chloride 18 gave 19, that was temporarily protected with thionyl chloride before the Z-enyne sidechains of (-)-histrionicotoxin (3) were installed following established procedures.

D. F. Taber, Org. Chem. Highlights 2018, January 1.