Azides as Synthons for Isonitriles: Facilitating Challenging Coupling Reactions

Stockdill, Jennifer

Abstract

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.