Synthetic Studies of Chiral Organometallics

当今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，生产具有对映体纯度的手性药物也变得很重要。几十年来，有机化学家已知的唯一立体选择性反应是在三角原子的异位面上加成第四个配体。这一类包括有机合成中几乎所有的立体选择性反应，我们对影响这些过程的电子、空间和动力学因素积累了大量的见解。在过去的10年里，手性有机金属化合物(特别是有机硫化合物)的亲电取代作为不对称合成的新方法取得了重大进展。这种反应模式不同于大多数其他不对称合成，因为它涉及到连接到立体生成碳原子上的金属的取代。用金属取代亲电试剂完成了对映体选择性合成。对发展方法论的机械性理解对于推动该领域的发展是必要的。当考虑立体碳负离子的亲电取代时，必须考虑构型稳定性、空间过程和聚集态。如果亲和性体是前手性的，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一种推测。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S型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。探索方法论的进一步扩展，如闭环化合。2.改进手性有机金属化合物的制备方法。3.进一步探索手性有机金属化合物的溶液和固态结构。评估配位原子和金属效应对手性碳负离子构型和结构动力学的影响。4.利用快速注入核磁共振，继续我们最近的发现，即可能的立体电子效应，以及锡-锂交换中杂原子参与的性质。

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.