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, Ag2 O 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.
Keywords: Cross-Coupling; Cyclization; Natural Products; Terpenoids; Total Synthesis.
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