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 N-acyloxyiminium ions derived from endo-oriented 1-methoxy- or 1-hydroxybicyclo[2.2.2]oct-5-enylamines 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, were prepared from 3-methylanisole in 12 steps and 16% overall yield.

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Alkaloids U 0600Aza-Cope Rearrangement-Mannich Cyclizations for the Formation of Complex Tricyclic Amines: Stereocontrolled Total Synthesis of (±)-Gelsemine. -(EARLEY, W. G.; JACOBSEN, J. E.; MADIN, A.; MEIER, G. P.; O'DONNELL, C.; OH, T.; OLD, D. W.; OVERMAN*, L. E.; SHARP, M. J.; J.

Significance: In consecutive papers, a detailed account is given of the synthesis of (±)-gelsemine in 1.1% overall yield. The highly functionalized hexacyclic ring system is constructed using a base-promoted aza-Cope rearrangement-Mannich cyclization sequence and an intramolecular Heck cyclization. For the second paper in the sequence, see: L. E. Overman et al. J. Am. Chem. Soc. 2005, 127, 18054-18065. Comment: An aza-Cope rearrangement occurred on treatment of A with KH and 18-crown-6 to generate B in 81% yield. b-Bromo enecarbamate C was heated in the presence of TFA to effect a Mannich cyclization to ketone E. The spirooxindole was installed using an intramolecular Heck reaction to afford G as an 11:1 mixture rich in the unnatural epimer. Heating nitrile H in the presence of DBU resulted in epimerization of the C7 and C3 stereocenters and subsequent intramolecular condensation of the alcohol and nitrile groups.