Diels–Alder and Inverse Diels–Alder Reactions

Abstract

Among the expanding repertoire of methodologies for the derivatization of biomolecules, the Diels-Alder (DA) and inverse Diels-Alder (DAinv) reactions are especially attractive chemical ligation strategies for the conjugation of biomolecules, generating significant interest since they can be rapid, high yielding, and efficient in aqueous media, all while maintaining chemoselectivity. This chapter covers the fundamentals, the chemical aspects, and the practical applications of Diels-Alder and inverse Diels-Alder cycloadditions from the perspective of bioconjugation. The introduction of bioorthogonal labeling techniques has also shed light on surface immobilization of proteins to develop biochips for in vitro characterization of biochemical activities or interactions between proteins. The study of the inverse Diels-Alder between tetrazines and olefins is highlighted with some recent applications. Diels-Alder and inverse Diels-Alder reactions are fast enough to achieve the bioconjugation of radiolabeled markers while the chemoselectivity of the reaction allows them to be performed in vivo.