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Organic Chemistry Highlights

Total Synthesis

Monday, May 6, 2024
Douglass F. Taber
University of Delaware

The Inoue Synthesis of Batrachotoxin

Batrachotoxin (4) is one of the toxic principles isolated from the skin of the poison dart frog Phyollobates of the Choco rain forest of Colombia. Masayuki Inoue of the University of Tokyo devised a practical route to 4 based on the convergent coupling of the iodo alkene 1 and the alkenyl boronate 2, leading to the pentacyclic lactone 3 (Angew. Chem. Int. Ed. 2023, 62, e202309688, DOI: 10.1002/anie.202309688; for an alternative approach, see J. Org. Chem. 2023, 88, 17479, DOI: 10.1021/acs.joc.3c02290).

The preparation of 2 began with the prochiral cyclopentanedione 5. Combination with paraformaldehyde led to the acetate 6. Enantio- and diastereoselective hydrogenation dissolved the symmetry, leading after protection to the silyl ether 7. The lactone was constructed by ozonolysis and transesterification followed by oxidation, to give, after alkenyl boronate construction, the bicyclic 2.

The starting material for 1 was the commercial Wieland-Miescher ketone 8, available in high enantiomeric purity. Hydrogenation followed by selective ketalization delivered the ketone 9, that was oxidized to the bromo enone 10. Addition of the lithiated enol ether 11 followed by mixed ketal formation and oxidative cleavage led initially to the alkenyl bromide corresponding to 1. The iodide 1 proved to be a more efficient coupling partner.

Although the reactive centers both of 1 and of 2 are adjacent to quaternary centers, efficient conditions for the coupling were developed. On exposure to base, subsequent Dieckmann cyclization via the lactone enolate 12 led to the ketone 3.

Desilylation of 3 followed by saponification and decarboxylation delivered the diol 13. After some exploration, a reagent combination was found to reduce the ketone to the desired equatorial alcohol, via intramolecular hydride delivery. Protection and deprotection then gave the diol 14. Hydroxyl-directed epoxidation followed by oxidation led to the keto aldehyde, which via reductive amination, β-elimination of the epoxide and acylation was carried on to the amide 15. Cyclization led to 16, setting the stage for the assembly of batrachotoxin 4.

It is instructive to compare and contrast the two Inoue approaches to batrachotoxin 4, as well as alternative approaches previously discussed in these pages (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; The Du Bois Synthesis of Batrachotoxin 2017, June 5; The Luo Synthesis of Batrachotoxinin A 2020, October 5.)

D. F. Taber, Org. Chem. Highlights 2024, May 6.