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...
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Veröffentlicht in: | Chemistry : a European journal 2013-08, Vol.19 (32), p.10741-10750 |
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Sprache: | eng |
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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). |
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ISSN: | 0947-6539 1521-3765 |
DOI: | 10.1002/chem.201300292 |