Structure Determination and Total Synthesis of (+)‐16‐Hydroxy‐16, 22‐dihydroapparicine. Issue 32 (20th June 2013) - Hirose, Tomoyasu
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.