Azides as Synthons for Isonitriles: Facilitating Challenging Coupling Reactions

描述(由申请人提供)：拟议的研究旨在实现对先前描述的异腈与羧酸的两组分偶联以获得伯胺和仲胺衍生物的功效的实质性改进。总体而言，建议的进展是在针对免疫抑制剂环孢素的综合规划过程中设计的。最初的研究将集中在开发一种新的Staudinger类型的方法，将叠氮化合物直接转化为异腈。此外，我们还将研究甲胺类化合物在与羧酸和硫代酸的双组分偶联中的应用范围。我们预计，这些实验将为甲酰胺羧酸盐混合酸酐(FCMA)中间体在异腈/羧酸和异腈/硫酸偶联反应中的分解途径提供有价值的见解。在环孢菌素A的合成过程中，甲双胺偶联反应将作为形成酰胺键的主要方法。将该方法改进为使用酰胺类化合物，将能够快速和模块化地合成新的环孢素类似物。 公共卫生相关性：拟议的研究涉及开发一种新方法，以便更容易地获取一系列重要生物功能的化合物。具体地说，免疫抑制剂环孢素A的合成将完成，环孢素A是预防和治疗移植排斥反应的重要药物。该项目的最终方向是设计和合成环孢素类似物，以减少患者在药物上经历的副作用数量。

DESCRIPTION (provided by applicant): The proposed research is designed to achieve substantial improvements to the efficacy of the previously described two-component coupling of isonitriles with carboxylic acids to access primary and secondary amide derivatives. Overall, the proposed advancements have been designed during the course of synthetic planning toward the immunosuppressant cyclosporine. Initial investigations will focus on the development of a novel Staudinger-type method to convert azides directly to isonitriles. Additionally, we will examine the extent to which formamidines may be utilized in two-component couplings with carboxylic acids and thioacids. We anticipate that these experiments will offer valuable insights into lingering mechanistic questions regarding the pathways for decomposition of the formamidate carboxylate mixed anhydride (FCMA) intermediates in isonitrile/carboxylic acid and isonitrile/thioacid coupling reactions. The formamidine coupling reaction will be utilized as the primary method for amide bond formation in the proposed synthesis of cyclosporine A. Modification of the method to employ amidines will enable the rapid and modular synthesis of novel cyclosporine analogs. PUBLIC HEALTH RELEVANCE: The proposed research involves the development of a new method to more readily access compounds of a range of important biological functions. Specifically, the synthesis of the immunosuppressant cyclosporine A, an important drug for prevention and treatment of transplant rejections, will be completed. The ultimate direction of the project is the design and synthesis of cyclosporine analogs that will reduce the number of side effects experienced by patients on the drug.