文摘
A detailed examination of the use of aza-Cope rearrangement-Mannich cyclization sequencesfor assembling the azatricyclo[4.4.0.02,8]decane core of gelsemine is described. Iminium ions andN-acyloxyiminium ions derived from endo-oriented 1-methoxy- or 1-hydroxybicyclo[2.2.2]oct-5-enylaminesdo 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 placeto form cis-hydroisoquinolones containing functionality that allows iminium ions or N-acyloxyiminium ionsto be generated regioselectively in a subsequent step. Mannich cyclization of cis-hydroisoquinolonesprepared in this way efficiently assembles the azatricyclo[4.4.0.02,8]decane unit of gelsemine. Using asequential base-promoted oxy-aza-Cope rearrangement/Mannich cyclization sequence, gram quantitiesof azatricyclo[4.4.0.02,8]decanone 18, a central intermediate in our total of (±)-gelsemine, were preparedfrom 3-methylanisole in 12 steps and 16% overall yield.