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.

螺环首次在 1890 年代末合成，可以描述为由两个通过一个共同原子连接在一起的垂直环组成的化学结构。特别是，由于其刚性结构，将应变四元环掺入药物化合物的螺环片段中引起了极大的兴趣。这降低了构象灵活性，从而可以改善与目标受体的结合。因此，过去 15 年中含有至少一个四元环的螺环的期刊和专利参考文献显着增加也就不足为奇了。1 螺环存在于许多具有生物活性的天然产物和药物分子中，并且与相应的常规饱和杂环类似物相比，具有许多结构优势；例如较低的亲脂性、增加的水溶性以及改善的代谢稳定性。2 脱羧不对称烯丙基烷基化 (DAAA) 是一种催化反应，可用于构建对映体纯的季碳原子，并且在广泛的底物产生不对称 C-C、C-N 和 C-O 键。3该项目的目的是开发 Pd 催化的 DAAA 反应。四元砜产生对映体纯中心，并在进一步官能化和螺环化后，产生一系列用于药物化学应用的新型对映体纯螺环。该方法随后将扩展到其他四元底物，以提供基于磺内酰胺、氧杂环丁烷和氮杂环丁烷环的螺环。 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。社会学会，2004 年，126，15044-15045。