Bélanger Guillaume, Larouche-Gauthier Robin, Ménard Frédéric, Nantel Miguel, Barabé Francis
Laboratoire de synthèse organique et de développement de stratégies de synthèse Département de Chimie, Université de Sherbrooke 2500 boulevard Université, Sherbrooke, Québec, J1K 2R1, Canada.
J Org Chem. 2006 Jan 20;71(2):704-12. doi: 10.1021/jo052141v.
[reaction: see text] Vilsmeier-Haack type cyclizations proved to be particularly efficient for generating parts of the polycyclic cores of many alkaloids, although only monocyclizations have so far been reported. With the goal of rapidly and efficiently constructing polycyclic alkaloids, we decided to exploit the Vilsmeier-Haack reaction by utilizing iminium ions successively generated and trapped with tethered nucleophiles. To develop such a strategy, we had to set the first cyclization. This constitutes a great challenge in itself because amide activation conditions are usually not compatible with tethered nucleophiles, except for indoles and aromatic rings which have already been reported. This paper describes the comprehensive study of intramolecular addition of silyl enol ethers, allylsilanes, and enamines to chemoselectively activated formamides, aliphatic amides, and lactams. Good to excellent yields were obtained for the 5-exo, 6-exo, and 6-endo modes of cyclization. Moreover, we demonstrated that the species in solution after the cyclization are iminium ions. This is highly encouraging for the development of bis-cyclization strategies. An expeditious total synthesis of (+/-)-tashiromine is also reported.
[反应：见正文] 事实证明，Vilsmeier-Haack型环化反应对于构建许多生物碱的多环核心部分特别有效，尽管迄今为止仅报道了单环化反应。为了快速高效地构建多环生物碱，我们决定利用Vilsmeier-Haack反应，通过相继生成亚胺离子并使其与连接的亲核试剂捕获。为了开发这样一种策略，我们必须设定第一次环化反应。这本身就是一个巨大的挑战，因为酰胺活化条件通常与连接的亲核试剂不相容，除了已经报道的吲哚和芳香环。本文描述了硅烯醇醚、烯丙基硅烷和烯胺对化学选择性活化的甲酰胺、脂肪族酰胺和内酰胺进行分子内加成的全面研究。对于5-外向、6-外向和6-内向环化模式，获得了良好到优异的产率。此外，我们证明了环化后溶液中的物种是亚胺离子。这对于双环化策略的开发极具鼓舞作用。还报道了(±)-塔希罗明的快速全合成。
