Earley William G, Jacobsen Jon E, Madin Andrew, Meier G Patrick, O'Donnell Christopher J, Oh Taeboem, Old David W, Overman Larry E, Sharp Matthew J
Department of Chemistry, University of California, Irvine, 516 Rowland Hall, Irvine, California 92697-2025, USA.
J Am Chem Soc. 2005 Dec 28;127(51):18046-53. doi: 10.1021/ja055710p.
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.
本文描述了对使用氮杂-Cope重排-曼尼希环化序列来构建钩吻素子的氮杂三环[4.4.0.0(2,8)]癸烷核心的详细研究。由内向型1-甲氧基或1-羟基双环[2.2.2]辛-5-烯基胺衍生的亚胺离子和N-酰氧基亚胺离子不会经历该序列的第一步，即阳离子氮杂-Cope重排，以形成顺式氢化异喹啉鎓离子。然而，类似的碱促进的氧杂氮杂-Cope重排确实会发生，以形成含有官能团的顺式氢化异喹啉酮，该官能团允许在后续步骤中区域选择性地生成亚胺离子或N-酰氧基亚胺离子。以这种方式制备的顺式氢化异喹啉酮的曼尼希环化有效地组装了钩吻素子的氮杂三环[4.4.0.0(2,8)]癸烷单元。使用连续的碱促进的氧杂氮杂-Cope重排/曼尼希环化序列，从3-甲基苯甲醚经12步反应以16%的总收率制备了克级量的氮杂三环[4.4.0.0(2,8)]癸烷酮18，它是我们全合成(±)-钩吻素子中的一个关键中间体。
