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Abstract
The tricyclic skeleton of the gephyrotoxin amphibian alkaloids was synthesized via an enantioselective serial sequence involving nine discrete steps that furnished Kishi’s intermediate 5 in 22% overall yield. This efficient and expeditious synthetic approach exploits the inherent stereochemistry of a (1R)-2-tropinone derivative for the construction of the core cis-2,5disubstituted pyrrolidine ring system and constitutes a formal synthesis of gephyrotoxin 287C.
Highlights
Alkaloids isolated from amphibian skin have aroused tremendous academic and pharmaceutical interest due to their structural diversity and biological activity
As part of an ongoing study in our laboratory aimed at developing new molecular scaffolds for neurological therapeutic agents,[5,6,7,8] the gephyrotoxin skeleton was an attractive target for synthesis
We envisaged utilization of an enantiopure cis-2,5-disubstituted pyrrolidine 6 derived from the (1R)-2-tropinone derivative 7.7 The ketone 7 is readily available from the degradation of cocaine 8 and can be obtained on a multigram scale in isolated yields ranging from 65–80%
Summary
Alkaloids isolated from amphibian skin have aroused tremendous academic and pharmaceutical interest due to their structural diversity and biological activity. Reduction of the intermediate ozonide with NaBH4 and subsequent treatment of the reaction mixture with CH2N2 furnished the new cis-2,5-disubstituted pyrrolidine building block 6 in 67% yield over three steps. A solution of ketone 7 (130 mg, 0.5 mmol) in dry THF (2 mL) was added dropwise. After stirring for 2 h, TBSCl (1.0 M in THF, 1 mL, 1.0 mmol) was added dropwise at 0 °C.
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