New Metal-mediated Cyclisation Methods for the Generation of Heteroatom Functionalised Polycyclic Systems

该合作项目将探索钴介导的Pauson-Khand方法和手性镁酰胺介导的前手性酮不对称去质子化的新应用的组合。获得具有烯醇磷酸酯基序的对映体富集的新型双环底物将允许通过迭代的交叉偶联-氧化-杂环形成序列转化为手性的、富含sp3的杂双环框架，从而能够快速构建广泛的新型杂双环支架。这种极性的三维结构近年来吸引了相当大的制药兴趣，由于其有利的物理性质和占领化学空间的未充分探索区域。联合提案包含了GSK和斯特拉斯克莱德大学关于不对称去质子化和靶向合成领域的联合目标和可交付成果。拟议的工作结合了双方合作伙伴的专业知识，充分探索有机环化技术，不对称方法，以及适用于这些新工艺的双环底物类，以提供广泛的功能化化学支架，这些支架将对制药行业特别感兴趣，以及更广泛的制备化学界。作为整体工作计划的一部分，计算驱动的方法将为试剂设计提供信息，指导反应范围，并研究反应机制。EPSRC的主要研究领域是催化，化学反应动力学和机理，以及合成有机化学。

This collaborative project will explore a combination of cobalt-mediated Pauson-Khand methodology and new applications for chiral magnesium amide-mediated asymmetric deprotonation of prochiral ketones. Access to enantiomerically-enriched novel bicyclic substrates possessing enol phosphate motifs will allow transformation into chiral, sp3-rich heterobicyclic frameworks through an iterative cross-coupling-oxidation-heterocycle formation sequence, enabling the rapid construction of a broad range of novel heterobicyclic scaffolds. Such polar, three-dimensional structures have attracted considerable pharmaceutical interest in recent years, due to their favourable physical properties and occupation of underexplored regions of chemical space.The joint proposal contains the combined aims and deliverables from both GSK and the University of Strathclyde regarding the areas of asymmetric deprotonation and target synthesis. The proposed work combines the expertise of both partners to fully explore the organic cyclisation techniques, the asymmetric methodology, and the bicyclic substrate classes amenable to these new processes, to deliver a wide range of functionalised chemical scaffolds that will be of particular interest to the pharmaceutical industry, as well as to the wider preparative chemistry community. As part of the overall programme of work, computationally-driven methods will inform reagent design, direct reaction scope, and investigate reaction mechanism. The main EPSRC research areas addressed are Catalysis, Chemical Reaction Dynamics and Mechanism, and Synthetic Organic Chemistry.