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

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• 作者：William G. Earley ; Jon E. Jacobsen ; Andrew Madin ; G. Patrick Meier ; Christopher J. O'Donnell ; Taeboem Oh ; David W. Old ; Larry E. Overman ; and Matthew J. Sharp
• 刊名：Journal of the American Chemical Society
• 出版年：2005
• 出版时间：December 28, 2005
• 年：2005
• 卷：127
• 期：51
• 页码：18046 - 18053
• 全文大小：208K
• 年卷期：v.127,no.51(December 28, 2005)
• ISSN：1520-5126

文摘

A detailed examination of the use of aza-Cope rearrangement-Mannich cyclization sequencesfor assembling the azatricyclo[4.4.0.0^2,8]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[4.4.0.0^2,8]decane unit of gelsemine. Using asequential base-promoted oxy-aza-Cope rearrangement/Mannich cyclization sequence, gram quantitiesof azatricyclo[4.4.0.0^2,8]decanone 18, a central intermediate in our total of (±)-gelsemine, were preparedfrom 3-methylanisole in 12 steps and 16% overall yield.