Synthetic Studies of Chiral Organometallics

目前许多药物都含有饱和氮杂环，因此，开发合成和修饰氮杂环的新方法具有重要意义。同样，以对映异构的纯形式生产手性药物也变得很重要。几十年来，有机化学家所知道的唯一立体选择性反应是在三角形原子的异位面上添加第四配体。这一类别包括有机合成中几乎所有的立体选择反应，并且我们已经积累了对影响这些过程的电子、空间和动力学因素的重要见解。近十年来，手性有机金属化合物（特别是有机锂）的亲电取代作为不对称合成的新方法取得了重大进展。这种反应模式与大多数其他不对称合成不同，因为它涉及到金属与立体碳原子的取代。金属取代亲电试剂完成对映选择性合成。对开发方法论的机械理解是推动该领域发展所必需的。当考虑立体碳离子的亲电取代时，必须考虑构型稳定性、空间过程和聚集状态。如果亲电试剂是前手性的，就会形成两个新的立体中心，从而产生非对映选择性的问题。回答这些问题并不总是可能的；但如果没有答案，机械的解释充其量只是推测。本项目的具体目标是：1。继续研究α -氨基有机锂亲电取代和异位重排的范围和局限性，重点研究具有多个立体中心的化合物的立体选择性。探索该方法的进一步扩展，如闭合环元分解。2. 开发手性有机金属化合物的改进制备方法。3. 进一步探索手性有机金属的溶液和固态结构。评价连接原子和金属效应对手性碳的构型和结构动力学的影响。4. 利用快速注入核磁共振技术研究锡锂交换中可能的立体电子效应和杂原子参与的性质。

Many of today's drugs contain saturated nitrogen heterocyclic rings, thus, it is important to develop new ways to synthesize and modify nitrogen heterocycles. Likewise, it has become important to produce chiral drugs in enantiomerically pure form. For decades, the only stereoselective reactions known to organic chemists were additions of a fourth ligand to heterotopic faces of a trigonal atom. This category includes almost all stereoselective reactions in organic synthesis, and we have accumulated significant insight into the electonic, steric, and dynamic factors that influence these processes. In the past 10 years, significant advances in applying electrophilic substitutions of chiral organometallics (especially organolithiums) as new methods for asymmetric synthesis have been made. This reactivity mode is different from most other asymmetric syntheses in that it involves substitution of a metal attached to a stereogenic carbon atom. Substitution of the metal for an electrophile completes the enantioselective synthesis. Mechanistic understanding of developing methodology is necessary to advancing the field. When contemplating electrophilic substitutions of stereogenic carbanions, one must consider configurational stability, steric course, and aggregation state. If the electrophile is prochiral, two new stereocenters are formed and the question of diastereoselectivity arises. Answering these questions is not always possible; but without answers, mechanistic interpretation is speculative, at best. The specific aims of this project are: 1. To continue our investigation into the scope and limitations of alpha-aminoorganolithium electrophilic substitutions and sigmatropic rearrangements, with emphasis on stereoselectivity in compounds with multiple stereocenters. Explore further extensions of the methodology such as ring-closing metathesis. 2. To develop improved methods of preparation of chiral organometallics. 3. To further explore the solution and solid state structure of chiral organometallics. Evaluate the effects of ligating atoms and metal effects on configurational and structural dynamics of chiral carbanions. 4. To pursue our recent findings relating to possible stereoelectronic effects on transmetalation and the nature of heteroatom participation in tin-lithium exchanges using rapid injection NMR.