Total Synthesis of (−)‐Batrachotoxin Enabled by a Pd/Ag‐Promoted Suzuki–Miyaura Coupling Reaction.

Watanabe, Yuuki; Morozumi, Hisahiro; Mutoh, Hiroyuki; Hagiwara, Koichi; Inoue, Masayuki

Batrachotoxin is an extremely potent cardio‐ and neurotoxic steroidal alkaloid found in certain species of frogs, birds, and beetles. The steroidal 6/6/6/5‐membered carbocycle (ABCD‐ring) is U‐shaped and functionalized with two double bonds, a six‐membered C3‐hemiacetal across the AB‐ring, a seven‐membered oxazepane on the CD‐ring, and a dimethylpyrrolecarboxy group at the D‐ring carbon chain. These structural features present an unusual and formidable synthetic challenge. Herein we report a total synthesis of batrachotoxin based on a newly devised convergent strategy through a 22‐step sequence. Enantiopure AB‐ring and D‐ring fragments were prepared and subjected to a crucial C(sp2)−C(sp2) coupling reaction. Although both C(sp2) centers were sterically encumbered by proximal tetrasubstituted carbon atoms, Ag2O strongly promoted the Pd(PPh3)4‐catalyzed Suzuki–Miyaura coupling reaction at room temperature, thereby connecting the two fragments without damaging their preexisting functionalities. Subsequent treatment with t‐BuOK induced Dieckmann condensation to cyclize the C‐ring. The judiciously optimized functionalizations realized oxazepane formation, carbon chain extension, and pyrrole carboxylic acid condensation to deliver batrachotoxin.

SUZUKI reaction; STEROIDAL alkaloids; DOUBLE bonds; PYRROLES; CONDENSATION

Angewandte Chemie, 2023, Vol 135, Issue 40, p1

0044-8249

Academic Journal

10.1002/ange.202309688