Methylation Approach Aids Cyclosporine A Synthesis

A method for forming tertiary amides in large biomolecules, a particularly challenging synthetic transformation, has been developed by Samuel J. Danishefsky and coworkers of Sloan-Kettering Institute for Cancer Research (J. Am. Chem. Soc., DOI: 10.1021/ja100517v). Danishefsky’s group previously devised a way to create amides by treating isonitriles with carboxylic acids (J. Am. Chem. Soc. 2008, 130, 5446). Xiangyang Wu, Jennifer L. Stockdill, Ping Wang, and Danishefsky have now applied the isonitrile coupling reaction to make tertiary amides for the first time. They demonstrated the approach in the synthesis of the macrocyclic peptide cyclosporine A, an immunosuppressant used to prevent transplant rejection. Cyclosporine A’s bioavailability and resistance to proteolysis in the body are highly dependent on methylation of seven of its 11 amino acids. The researchers used isonitrile methylation not only to access N-methylation in five of the amino acids (shown in red), but also to carry out the final macrocyclization step. Isonitrile amidation may prove useful in other peptide, cyclic peptide, and glycopeptide syntheses, they note.