Aza-Cope Rearrangement—Mannich Cyclizations for the Formation of Complex Tricyclic Amines: Stereocontrolled Total Synthesis of (.+-.)-Gelsemine.

A detailed examination of the use of aza-Cope rearrangement–Mannich cyclization sequences for assembling the azatricyclo[4.4.0.0 2,8 ]decane core of gelsemine is described. Iminium ions and Nacyloxyiminium ions derived from endo-oriented 1-methoxy- or 1-hydroxybicyclo[2.2.2]oct-5enylamines do not undergo the first step of this sequence, cationic aza-Cope rearrangement to form cis-hydroisoquinolinium ions. However, the analogous base-promoted oxy-aza-Cope rearrangement does take place to form cis-hydroisoquinolones containing functionality that allows iminium ions or N-acyloxyiminium ions to be generated regioselectively in a subsequent step. Mannich cyclization of cis-hydroisoquinolones prepared in this way efficiently assembles the azatricyclo[4.4.0.0 2,8 ] decane unit of gelsemine. Using a sequential base-promoted oxy-aza-Cope rearrangement/Mannich cyclization sequence, gram quantities of azatricyclo[4.4.0.0 2,8 ]decanone 18, a central intermediate in our total of (±)-gelsemine, was prepared from 3-methylanisole in 12 steps and 16% overall yield.