Structure Determination and Total Synthesis of (+)‐16‐Hydroxy‐16,22‐dihydroapparicine |
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Authors: | Dr. Tomoyasu Hirose Dr. Yoshihiko Noguchi Yujiro Furuya Dr. Aki Ishiyama Dr. Masato Iwatsuki Dr. Kazuhiko Otoguro Prof. Dr. Satoshi Ōmura Prof. Dr. Toshiaki Sunazuka |
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Affiliation: | Kitasato Institute for Life Sciences and Graduate School of Infection Control Sciences, Kitasato University, 5‐9‐1 Shirokane, Minato‐ku, Tokyo 108‐8641 (Japan), Fax: (+81)?3‐5791‐6340 |
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Abstract: | Herein, we describe the first asymmetric total synthesis and determination of the relative and absolute stereochemistry of naturally occurring 16‐hydroxy‐16,22‐dihydroapparicine. The key steps include 1) a novel phosphinimine‐mediated cascade reaction to construct the unique 1‐azabicyclo[4.2.2]decane core, including a pseudo‐aminal‐type moiety; 2) a highly stereospecific 1,2‐addition of 2‐acylindole or a methylketone through a Felkin–Anh transition state for the construction of a tetrasubstituted carbon center; and 3) an intramolecular chirality‐transferring Michael reaction of the ketoester, with neighboring‐group participation, to introduce a chiral center at C15 in the target molecule. In addition, we evaluated the antimalarial activity of synthetic (+)‐(15S,16R)‐16‐hydroxy‐16,22‐dihydroapparicine and its intermediate against chloroquine‐resistant Plasmodium falciparum (K1 strain) parasites. |
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Keywords: | asymmetric synthesis cascade reactions dihydroapparicine Michael reaction natural products stereochemistry |
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