The tetrazine ligation between trans-cyclooctene (TCO) and s-tetrazine, among the various click chemistries that have been developed over the past decade, has the fastest reactivity. Described in this talk will be how flow chemistry enabled the first practical and scalable synthesis of TCO and its derivatives as well as computational design towards the synthesis of new generation of TCO which created coupling partners with rate constants in excess of k2 = 106 M-1s-1.Among various applications of tetrazine ligation in different areas, introduced here will be the applications in the field of biomaterials. The rapid reactivity was used to generate hyaluronic acid-based hydrogel microspheres with spatial patterns and water-filled channels thru a diffusion controlled interfacial crosslinking process. Prostate cancer LNCaP cells could be 3D encapsulated in the hydrogel microspheres with up to 99% viability, proliferated in the HA matrix to formed cell aggregates. In another research, tetrazine ligation was used to construct polyethylene glycol (PEG)-based multiblock copolymer fibers from an interfacial polymerization within the two-phase interface of two immiscible solutions. It also enabled the synthesis of cell-adhesive as well as other functionalized fibers by including functionalized polymer blocks in the reaction process.Figure 1: (A) tetrazine ligation between trans-cyclooctene and s-tetrazine (B) hydrogel microspheres formed from interfacial crosslinking (C) multiblock copolymer fiber being pulled out of aqueous�organic interface

Tetrazine ligation: Developing fast bioorthogonal chemistry and applications in biomaterial-related research

248th National Meeting (2014)

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