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

螺环在19世纪90年代末首次被合成，可以描述为由两个垂直的环组成的化学结构，这些环由一个共同的原子连接在一起。特别是，由于药物化合物的刚性结构，将张力四元环结合到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，这可能会改善靶标受体的结合。因此，不足为奇的是，在过去的15年里，至少含有一个四元环的螺环的期刊和专利文献显著增加。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，并且与相应的传统饱和杂环类似物相比具有许多结构优势；脱羧基不对称烯丙基烷基化反应(DAAA)是一种催化反应，可用于构建对映体、季碳原子，并已在广泛的底物上非常成功地生成不对称C-C、C-N和C-O键。3本项目的目的包括开发Pd催化的应变型四元磺酸的DAAA反应以生成对映体中心，并在进一步官能化和螺环作用后，开发一系列用于药物化学应用的新型对映体螺环。这一方法随后将扩展到其他四元底物，以提供基于舒坦、恶烷和氮杂环的螺环。1 E.M.Carreira和T.C.Fessard，Chem.首页--期刊主要分类--期刊细介绍--期刊题录与文摘--期刊详细文摘内容1947.3 D.C.Behenna和B.M.Stoltz化学。社会科学院，2004年，第126页，15044-15045页。

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.