One-Step Synthesis of the 1-Azaspiro[5.5]undecane Skeleton Characteristic of Histrionicotoxin Alkaloids from Linear Substrates via Hg(OTf)2-Catalyzed Cycloisomerization |
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Authors: | Dr. Kunihiro Matsumura Dr. Keisuke Nishikawa Hiroaki Yoshida Toshiki Niwa Yuichiro Fushii Dr. Matsumi Doe Prof. Dr. Yoshiki Morimoto |
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Affiliation: | Department of Chemistry, Graduate School of Science, Osaka City University, Sumiyoshi-ku, Osaka, 558-8585 Japan |
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Abstract: | Histrionicotoxin (HTX) alkaloids isolated from the poison arrow frogs possess a unique structure characterized by a 1-azaspiro[5.5]undecane skeleton common to the HTX family. The unique molecular architecture of HTXs and the interest as potential target drugs have prompted synthetic chemists to promote the total synthesis so far. However, all of the synthetic strategies to access the 1-azaspiro[5.5]undecane framework of HTXs take a multistep approach from linear starting materials due to stepwise construction of either six-membered carbo- or azacycle. Herein, we report the direct one-step construction of the 1-azaspiro[5.5]undecane skeleton from linear amino ynone substrates bearing an N-methoxycarbonyl group utilizing our mercuric triflate (Hg(OTf)2)-catalyzed cycloisomerization reaction. The utility of this novel methodology was demonstrated by the total and formal syntheses of HTX-235A and HTX-283A, respectively, from the azaspirocycle. |
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Keywords: | Alkaloids cyclization diastereoselectivity spiro compounds total synthesis |
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