Endo-protected Maleimide Synthesis and Polymerization

“Click chemistry” has significantly enhanced the development of organic synthesis and has also been implemented in the areas of imaging technology, biomaterials and drug delivery systems. “Click” reactions offer a versatile platform that can be used in polymer synthesis, antibodies, fluorescent dyes, and cell studies. One such reaction involves the addition of thiols into electron-deficient alkenes such as maleimides. However, maleimides are too reactive for direct use in cell studies or polymerizations. Recent advances have enabled their applications by using furan to mask maleimide’s reactivity. Currently, the exo adduct of this Diels-Alder reaction is used as a protection technique to incorporate maleimide into polymers. While a significant advance in the field, certain limitations including the high temperature (90-110˚C) required for deprotection may preclude its widespread use with certain biological applications and temperature-sensitive compounds. Recent studies have shown that the two isomeric products of the Diels–Alder reaction (exo and endo) can be deprotected at different temperatures. The endo product is reversible at around 55˚C, which is a much lower temperature than its counterpart. This project is focused on the synthesis, purification and scalability of the endo isomer for the protection of maleimide. We can also take advantage of the different deprotection temperatures of the isomers by incorporating both endo and exo functionalities into a single system. This enables orthogonal control over maleimide reactivity using temperature (55 or 110 ˚C) and could find great utility in a materials or biological setting.