Mizoguchi Haruki, Micalizio Glenn C
Department of Chemistry, Burke Laboratory, Dartmouth College, Hanover, New Hampshire 03755, United States.
J Am Chem Soc. 2015 May 27;137(20):6624-8. doi: 10.1021/jacs.5b02107. Epub 2015 May 12.
Bridged bicyclic metallacyclopentenes generated from the [4 + 2] cycloaddition of metallacyclopentadienes with alkenes have been proposed as reactive intermediates in the course of [2 + 2 + 2] annulation reactions. Recently a collection of alkoxide-directed Ti-mediated [2 + 2 + 2] annulation reactions have been discovered for the synthesis of densely functionalized hydrindanes, where the bridged bicyclic metallacyclopentenes from intramolecular [4 + 2] were treated as fleeting intermediates en route to cyclohexadiene products formed by formal cheletropic extrusion of Ti(Oi-Pr)2. In studies aimed at understanding the course of these organometallic cascade reactions it was later discovered that these bridged bicyclic intermediates can be trapped by various elimination processes. Here, we have realized metallacycle-mediated annulation reactions for the assembly of angularly substituted decalins--structural motifs that are ubiquitous in natural products and molecules of pharmaceutical relevance. In addition to defining the basic annulation reaction we have discovered a surprising stability associated with the complex organometallic intermediates generated in the course of this coupling process and document here the ability to control the fate of such species. Ligand-induced cheletropic extrusion of the titanium center delivers cyclohexadiene-containing products, while several distinct protonation events have been identified to realize polycyclic products that contain three new stereocenters (one of which is the angular quaternary center that is a hallmark of alkoxide-directed titanium-mediated [2 + 2 + 2] annulation reactions). Examples of this metallacycle-mediated annulation reaction are provided to demonstrate that a range of stereodefined fused bicyclo[4.4.0]decanes are accessible, including those that contain aromatic and aliphatic substituents, and an empirical model is presented to accompany the observations made.
由金属环戊二烯与烯烃的[4 + 2]环加成反应生成的桥连双环金属环戊烯，被认为是[2 + 2 + 2]环化反应过程中的活性中间体。最近，人们发现了一系列由醇盐导向的钛介导的[2 + 2 + 2]环化反应，用于合成功能密集的氢化茚，其中分子内[4 + 2]反应生成的桥连双环金属环戊烯被视为在通过Ti(Oi-Pr)2的形式螯合挤出形成环己二烯产物的过程中的瞬态中间体。在旨在理解这些有机金属级联反应过程的研究中，后来发现这些桥连双环中间体可以通过各种消除过程被捕获。在此，我们实现了金属环介导的环化反应，用于构建角取代的十氢化萘——这种结构基序在天然产物和具有药物相关性的分子中普遍存在。除了确定基本的环化反应外，我们还发现了在该偶联过程中生成的复杂有机金属中间体具有惊人的稳定性，并在此记录了控制此类物种命运的能力。配体诱导的钛中心螯合挤出产生含环己二烯的产物，同时已确定了几种不同的质子化事件，以实现含有三个新立体中心的多环产物（其中一个是角季碳中心，这是醇盐导向的钛介导的[2 + 2 + 2]环化反应的标志）。提供了这种金属环介导的环化反应的实例，以证明一系列立体定义的稠合双环[4.4.0]癸烷是可获得的，包括那些含有芳族和脂族取代基的化合物，并给出了一个经验模型以配合所做的观察。
