Lewis Base Ligands Designed to Control Carbon-Carbon Bond Formation

项目摘要/摘要： 合成化学对社会的影响怎么强调都不为过。有机化学改变了我们的世界 在重大方面，从通过发明避孕药具赋予妇女生育权，到创造 让我们养活地球的杀虫剂。不言而喻，医学上的创新总是与 有机化学的进展，因为大多数药物都是由有机化学家合成的。一直以来都是 认识到小分子的整体形状是控制其生物学特性的最基本因素 效果。幸运的是，不对称合成的快速发展为治疗学铺平了道路 去诊所。这些成就可以归功于对映体选择性键领域的许多创新。 形成过程，如不对称离子配对，有机催化，C-H活化，Lewis酸/碱，Br？nsted 酸/碱、还原/氧化、交叉偶联反应等。尽管取得了这些成就，但 最先进的技术仍然在许多方面与理想相距甚远。尽管概述的每一种独特的激活模式 以上允许实现高的化学选择性、非对映选择性和对映体选择性，在许多情况下用于所需的 要发生键形成事件，底物必须经常带有能够结合或 被手性催化剂激活的。特别是，对映体选择性地将惰性C-H键转化为碳-氢键的能力。 在没有导向基团的帮助下在特定位置形成碳键是非常可取的，因为这将进一步 药物发现过程。 为了应对这一挑战，我们的工作集中在开发新的去质子化替代 允许杂环中典型的非靶向位置被直接官能化的序列。 具体地说，我们发现Lewis碱可以从强有机锂试剂中提取锂离子，从而 产生高碱性离子对，进而形成杂环中典型的远程和惰性C-H键 去质子化。其次，我们开发了一类新的手性膦配体，使 对映体与外消旋供体试剂的交叉偶联。这项提议寻求将这些概念融合在一起 通过开发不对称去质子化交叉耦合序列 碳中心有待功能化。这一建议的具体目标包括：(1)发展两者 有机锂试剂和Lewis碱结合时，允许生物碱中典型的惰性C-H键 去质子化；(2)新的手性膦配体的发展使对映体收敛Negishi 与外消旋给体试剂的交叉偶联反应；以及(3)不对称去质子化的进展 交叉偶联序列，允许生物相关的生物碱在单个 综合作业。

PROJECT SUMMARY/ABSTRACT: The impact of synthetic chemistry on society cannot be overstated. Organic chemistry has changed our world in momentous ways, from giving women reproductive rights through the invention of contraceptives, to creating pesticides that allow us to feed the globe. It is axiomatic that innovations in medicine are invariably linked to advancements in organic chemistry as most medicines are synthesized by organic chemists. It has long been recognized that the overall shape of a small molecule is the most fundamental factor that controls its biological effects. It is fortunate that rapid developments in asymmetric synthesis have paved the way for therapeutics to reach the clinic. These triumphs can be attributed to the many innovations in the realms of enantioselective bond forming processes such as asymmetric ion pairing, organocatalysis, C–H activation, Lewis acid/base, BrØnsted acid/base, reductions/oxidations, cross-coupling reactions and many more. Despite these achievements, the state of the art still falls short in many ways from the ideal. Although each of the unique activation modes outlined above allow for high chemo-, diastero- and enantio-selectivities to be achieved, in many cases for the desired bond forming event to occur the substrate must often bear a functional group that is capable of binding or being activated by a chiral catalyst. In particular, the ability to enantioselectively convert inert C–H bonds into carbon- carbon bonds at specific locations without the aid of directing groups is highly desirable because it would further the drug discovery process. To address this challenge, our work has focused on the development of new deprotonation substitution sequences which allow for typically untargetable positions within heterocycles to be directly functionalized. Specifically, we have found that Lewis bases can extract Li cations from strong organolithium reagents allowing highly basic ion pairs to be produced and in turn for typically remote and inert C–H bonds in heterocycles to be deprotonated. Secondly, we have developed a new class of chiral phosphine ligands that enable enantioconvergent cross-couplings with racemic donor reagents. This proposal seeks to merge these concepts by developing asymmetric deprotonation cross-coupling sequences that can allow for typically inaccessible carbon centers to be functionalized. Specific goals of this proposal include: (1) the development of both organolithium reagents and Lewis bases that when combined allow for typically inert C–H bonds in alkaloids to be deprotonated; (2) the development of new chiral phosphine ligands that enable enantioconvergent Negishi cross-coupling reactions with racemic donor reagents; and (3) the development of asymmetric deprotonation cross-coupling sequences that allow for biologically relevant alkaloids to be directly functionalized in a single synthetic operation.