Novel polymer coupling chemistry based upon latent cysteine-like residues and thiazolidine chemistry

The development of simple and efficient crosslinking techniques is sought after for a variety of applications including bioconjugation, material synthesis and design, and surface functionalization. The use of ‘‘Click’’ reactions is becoming increasingly popular because it offers excellent coupling efficiency and is applicable to many synthetic situations. One of the most popular methods is the copper cata­ lyzed, 1,3-dipolar cycloaddition between an azide and an alkyne. A significant limitation of this methodology is that a metal catalyst, typically a Cu catalyst, is required. This catalyst can be difficult to remove which is detrimental to biological applications because the metal catalyst is not biocompatible. The Bertozzi group has devel­ oped specialty alkynes that undergo the ‘‘Click’’ reaction without the presence of a metal catalyst; however, these compounds are not commercially available and require multiple steps. Thiol–ene chemistry, which is a reaction between an alkene and a thiol, has become increasingly popular. Here, the thiol is added across the alkene via a radical mechanism that is initiated by either light or heat. Thiol–ene chemistry has been extensively utilized to prepare materials in the fabrication of microfluidic devices. Similar to ‘‘Click’’ chemistry, there are a few synthetic hurdles encountered when incorporating these functional groups into systems. This method can occur in the presence of oxygen and the absence of solvent. No metal catalyst is required, but an external stimulus such as light in the presence a photoinitiator or heat is necessary to generate a radical species. The Grinstaff group developed a methodology focused upon the thiazolidine linkage, which occurs in the presence of a cysteine residue and an aldehyde (Fig. 1). Such a reaction occurs without a cata­ lyst, is biocompatible, and proceeds without an external stimulus. The Grinstaff group was able to fabricate materials for replacement of sutures in cataract surgery. The significant limitation of the current methodology is the synthetic schemes utilized, which require the extensive use of peptide chemistry and protecting groups. This approach limits the incorporation of this technique to a smaller