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Organic Chemistry Highlights

Total Synthesis

Monday, June 5, 2017
Douglass F. Taber
University of Delaware

The Du Bois Synthesis of Batrachotoxin

(-)-Batrachotoxin (3), an extremely potent (1-2 mg/kg subcutaneous) neurotoxin isolated from the skin of the Colombian golden poison frog Phyllobates terribilis, binds to Na+ ion channels. Justin Du Bois of Stanford University envisoned (Science 2016, 354, 865. DOI: 10.1126/science.aag2981) coupling an AB component with a D ring precursor to give 1, with the C ring to be completed by the free radical conversion of 1 to 2.

The assembly of the D-ring precursor 7 began with 5, prepared by lipase-mediated resolution of the racemate following the procedure of Takano. Silylation followed by reduction delivered 5, that was epoxidized, then converted to the iodide 6. Reductive elimination followed by oxidation then completed the preparation of the enone 7.

The construction of 12 began with the commercially-available Hajos-Parrish ketone (8), following the route previously described by Parsons. Hydrogenation and ketalization led to the cyclopentanone 9. Dibromocarbene addition to the derived silyl enol ether followed by hydrolysis gave the bromoenone 10. Addition of silyl acetylene 11 followed by acid-mediated cyclization furnished 12, that was coupled with 7. Desilylation of the alkyne followed by silylation of the tertiary alcohol with 13 completed the assembly of 1.

The cyclization of 1 to 2 by Bu3SnH began with addition to the non-silylated alkyne to give an alkenyl radical, that added to the exo methylene to give a new radical. That added to the other alkyne, leading to 14. H atom abstraction followed by H atom transfer from Bu3SnH then led to 2.

On exposure to TBAF, two of the three silyl groups of 2 were removed, leading to 15. This was carried on via oxidative cleavage and reductive amination to (-)-batrachotoxin (3). Remarkably, the enantiomer of 3, (+)-batrachotoxin, also prepared by total synthesis, showed similar but not identical physiological activity.

It is informative to compare this synthesis to the complementary approach to 3 reported previously (C-O Ring-Containing Natural Products: Cyanolide A (Krische), Bisabosqual A (Parker), Iso-Eriobrucinol A (Hsung), Trichodermolide A (Hiroya), Batrachotoxin Core (Du Bois) 2014, January 20) by Professor Du Bois.

D. F. Taber, Org. Chem. Highlights 2017, June 5.