Azides as Synthons for Isonitriles: Facilitating Challenging Coupling Reactions

叠氮化物作为异腈的合成子：促进具有挑战性的偶联反应

• 批准号: 7808305
• 负责人: Jennifer Lynn Stockdill
• 金额: $ 3.04万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-21 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7808305
• 关键词: Address; Adverse effects; Amides; Amidines; Anhydrides; Azides; Biological Process; Biology; Carboxylic Acids; Chemicals; Coupling; Cyclosporine; Cyclosporins; Development; Drug Kinetics; Goals; Graft Rejection; Immunosuppressive Agents; Improve Access; Investigation; Methods; Modification; Pathway interactions; Patients; Pharmaceutical Preparations; Prevention; Property; Reaction; Research; Temperature; Testing; Toxic effect; analog; carboxylate; design; experience; formamidine; functional group; improved; insight; novel; public health relevance; research study

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.

描述（由申请人提供）：拟定的研究旨在实现对先前描述的异腈与羧酸的双组分偶联以获得伯酰胺衍生物和仲酰胺衍生物的功效的实质性改进。总的来说，提出的进展已经设计在合成计划的过程中对免疫抑制剂环孢菌素。初步调查将集中在一种新的Staudinger型方法的发展，直接将叠氮化物转化为异腈。此外，我们将研究甲脒可用于与羧酸和硫代酸的双组分偶联的程度。我们预计，这些实验将提供有价值的见解挥之不去的机械问题，关于分解的甲酰胺羧酸混合酸酐（FCMA）中间体在异腈/羧酸和异腈/硫代酸偶联反应的途径。甲脒偶联反应将用作拟定环孢菌素A合成中酰胺键形成的主要方法。采用脒的方法的修改将能够快速和模块化合成新的环孢菌素类似物。 公共卫生相关性：拟议的研究涉及开发一种新方法，以更容易获得具有一系列重要生物功能的化合物。具体而言，将完成预防和治疗移植排斥反应的重要药物免疫抑制剂环孢素A的合成。该项目的最终方向是设计和合成环孢菌素类似物，以减少患者对药物的副作用。

项目成果

A fascinating journey into history: exploration of the world of isonitriles en route to complex amides.

• DOI: 10.1002/anie.201106628
• 发表时间: 2012-03-19
• 期刊: ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
• 影响因子: 16.6
• 作者: Wilson, Rebecca M.;Stockdill, Jennifer L.;Wu, Xiangyang;Li, Xuechen;Vadola, Paul A.;Park, Peter K.;Wang, Ping;Danishefsky, Samuel J.
• 通讯作者: Danishefsky, Samuel J.

Expanding the limits of isonitrile-mediated amidations: on the remarkable stereosubtleties of macrolactam formation from synthetic seco-cyclosporins.

• DOI: 10.1021/ja2103372
• 发表时间: 2012-02-01
• 期刊: JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
• 影响因子: 15
• 作者: Wu, Xiangyang;Stockdill, Jennifer L.;Park, Peter K.;Danishefsky, Samuel J.
• 通讯作者: Danishefsky, Samuel J.