Total Synthesis of the Tetracyclic Antimalarial Alkaloid (±)-myrioneurinol

Open Access
Nocket, Anthony Joseph
Graduate Program:
Doctor of Philosophy
Document Type:
Date of Defense:
April 22, 2015
Committee Members:
  • Steven M Weinreb, Dissertation Advisor
  • Alexander Thomas Radosevich, Committee Member
  • Ken S Feldman, Committee Member
  • Edward G Dudley, Committee Member
  • Total Synthesis
  • Alkaloid
  • Myrioneuron
  • falciparum
  • anti-Malarial
The first total synthesis of the tetracyclic antimalarial alkaloid myrioneurinol (19) in racemic form has been completed in twenty-seven steps and in 1.8% overall yield from commercially available materials. The spiranic A/D-ring subunit of the metabolite with the attendant C5,6-stereocenters was constructed via a highly diastereoselective intramolecular Michael addition (IMA) of N-Cbz lactam/(E)-α,β-unsaturated ester cyclization precursor 61 to afford spirocycle 62. After a series of failed attempts to alkylate various ester enolate and pyrrolidinoenamine derivatives of 62 at C7, an umpolung strategy involving the conjugate addition of a malonate enolate to the nitrosoalkene intermediate 124, derived from α-chloro-O-silylaldoxime 122, provided oxime geometric isomers 123a/b. Both of these isomers possessed the correct C7-stereochemistry for the natural product. Several methods were then explored to accomplish the pivotal C9,10 carbon-carbon bond formation to construct the B-ring within the cis-decahydroquinoline (DHQ) scaffold of the alkaloid. These approaches included the unsuccessful nitrile α-anion/imidate cyclization of precursor 133 and the olefin/lactam Rainier metathesis of N-sulfonyllactam precursors 156 and 160 to provide tricyclic enesulfonamides 157 and 161, respectively. Although the latter ring-closing metathesis method was successful, we were unable to functionalize tricycles 157 and 161 at C9 in order to complete the total synthesis. We were pleased to discover that an intramolecular allyl silane/N-sulfonyliminium ion variant of the Sakurai reaction could be utilized to construct the B-ring of the cis-DHQ system, resulting in a single diastereomer of tricycle 191 with the desired C9,10 relative configuration, which we were able to elaborate to (±)-myrioneurinol.