title: Structure determination and total synthesis of (+)-16-hydroxy-16,22-dihydroapparicine.
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.
authors.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.
authors.forename: Tomoyasu
authors.initials: T
authors.lastname: Hirose
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Noguchi
authors.forename: Yujiro
authors.initials: Y
authors.lastname: Furuya
authors.forename: Aki
authors.initials: A
authors.lastname: Ishiyama
authors.forename: Masato
authors.initials: M
authors.lastname: Iwatsuki
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Otoguro
authors.forename: Satoshi
authors.initials: S
authors.lastname: Omura
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Sunazuka
mesh_terms: D000447:Aldehydes / Q000737:chemistry; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001372:Aza Compounds / Q000737:chemistry; D004952:Esters; D026121:Indole Alkaloids / Q000138:chemical synthesis* / Q000737:chemistry; D010084:Oxidation-Reduction; D010963:Plasmodium falciparum / Q000187:drug effects; D013237:Stereoisomerism
chemical_list: C587417:16-hydroxy-16,22-dihydroapparicine; D000447:Aldehydes; D000962:Antimalarials; D001372:Aza Compounds; D004952:Esters; D026121:Indole Alkaloids
keywords: Michael reaction; asymmetric synthesis; cascade reactions; dihydroapparicine; natural products; stereochemistry