Palladium-Catalysed Decarboxylative Asymmetric Allylic Alkylation for the Synthesis of Chiral Four-Membered Ring-Containing Spirocycles

钯催化脱羧不对称烯丙基烷基化合成手性四元环螺环

• 批准号: 2165671
• 金额: --
• 依托单位: Lancaster University
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2165671
• 关键词: Palladium; Catalysed; Decarboxylative; Asymmetric; Allylic

Spirocycles were first synthesised in the late 1890s and can be described as chemical structures which consist of two perpendicular rings linked together by one common atom. In particular, incorporation of strained four-membered rings into spirocyclic fragments of drug compounds is of great interest due to their rigid structure. This reduces conformational flexibility which could improve binding at the target receptor. It is, therefore, not surprising that there has been a significant increase in journal and patent references over the past 15 years of spirocycles containing at least one four-membered ring.1 Spirocycles, are present in many biologically active natural products and drug molecules and possess many structural advantages over the corresponding conventional saturated heterocyclic analogues; such as lower lipophilicity, increased aqueous solubility as well as improved metabolic stability.2 Decarboxylative asymmetric allylic alkylation (DAAA) is a catalytic reaction which can be used for the construction of enantiopure, quaternary carbon atoms and has been very successful for a broad range of substrates to generate asymmetric C-C, C-N and C-O bonds.3The aim of this project involves the development of the Pd-catalysed DAAA reaction of strained four-membered sulfones to generate enantiopure centres, and, upon further functionalisation and spirocyclisation, a series of novel enantiopure spirocycles for medicinal chemistry applications. This methodology will subsequently be extended to other four-membered substrates to provide spirocycles based on sultam, oxetane and azetidine rings. 1 E. M. Carreira and T. C. Fessard, Chem. Rev., 2014, 114, 8257-8322.2 J. A. Burkhard, C. Gue'rot, H. Knust, M. Rogers-Evans and E. M. Carreira, Org. Lett., 2010, 12, 1944-1947.3 D. C. Behenna and B. M. Stoltz, J. Am. Chem. Soc., 2004, 126, 15044-15045.

首先在1890年代后期合成了螺旋环，可以描述为化学结构，由两个垂直环组成，由一个共同的原子连接在一起。特别是，由于其刚性结构，将紧张的四元环掺入药物化合物的螺旋细胞片段引起了人们的极大关注。这降低了构象柔韧性，可以改善目标受体的结合。因此，毫不奇怪的是，在过去的15年中，日志和专利参考的烟气流已经显着增加，至少包含一个四元环。1螺旋出在许多生物活性的天然产物和药物分子中都存在，并且在相应的常规饱和饱和杂种杂种类似物中具有许多结构优势；诸如较低的亲脂性，水溶性增加以及改善的代谢稳定性。2羧基不对称的烯丙基烷基化（DAAA）是一种催化反应，可用于构造对映体，Quaternary碳原子，并非常成功地构建了构成的构图，并涉及coptimate 3的构造和coptrate contractrate和contrate的cons.c-c-N紧张的四元千磺酮的PD催化性DAAA反应的开发，以产生对映体中心，并在进一步的功能化和螺旋分化后，为药物化学应用提供了一系列新型的对映体螺旋细胞。此方法随后将扩展到其他四元的底物，以提供基于苏丹，甲氧烷和氮杂丁环的螺旋弹性。 1 E. M. Carreira和T. C. Fessard，化学。 Rev.，2014，114，8257-8322.2 J. A. Burkhard，C。Gue'rot，H。Knust，M。Rogers-Evans和E. M. Carreira，Org。 Lett。，2010，12，1944-1947.3 D. C. Behenna和B. M. Stoltz，J。Am。化学Soc。，2004，126，15044-15045。