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Concise synthesis of bufogargarizin B by a conformation-controlled skeletal reorganization approach
Peicheng Yang1, Yi Shen1, Jinghan Gui2,3
1State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
Abstract:
Bufogargarizins are a class of unique 19-norbufadienolides isolated from the venom of Bufo bufo gargarizans. Here we report a concise synthesis of bufogargarizin B from inexpensive, commercially available dehydroepiandrosterone by means of a conformation-controlled skeletal reorganization approach. The synthesis features the rapid construction of the 5/7/6/5 tetracyclic core framework by means of a SmI2-mediated ketone-allylic acetate transannular cyclization, and the installation of stereochemically diverse 5,7- and 7,5-fused ring systems through a biomimetic retro-aldol/transannular aldol cascade reaction. In addition, an efficient, scalable synthesis of 2-pyrone-5-boronate, a key building block for the introduction of the side chain of bufadienolides, has been developed, and the highly functionalized all-cis D ring of bufogargarizin B is installed by means of a series of highly chemo- and regioselective redox transformations. This work vividly demonstrates that conformational control plays a critical role in the precise installation of desired stereocenters in transannular cyclization products.
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