Structure Determination and Total Synthesis of (+)-16-Hydroxy-16,22-dihydroapparicine

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]decan...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Chemistry : a European journal 2013-08, Vol.19 (32), p.10741-10750
Hauptverfasser: Hirose, Tomoyasu, Noguchi, Yoshihiko, Furuya, Yujiro, Ishiyama, Aki, Iwatsuki, Masato, Otoguro, Kazuhiko, Ōmura, Satoshi, Sunazuka, Toshiaki
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
Beschreibung
Zusammenfassung: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. Composed by cascade: A concise method for the construction of an azabicyclo[4.2.2]decone with an indole ring by using a phosphinimine‐mediated cascade reaction enabled the structure determination and efficient synthesis of (+)‐16‐hydroxy‐16,22‐dihydroapparicine. This synthesis also features a stereospecific 1,2‐addition construction of the tetrasubstituted carbon center and an intramolecular chirality‐transferring Michael reaction as key steps (see picture).
ISSN:0947-6539
1521-3765
DOI:10.1002/chem.201300292