Expanding the bioorthogonal chemistry toolbox: innovative synthetic strategies for cyclooctynes

Abstract

Cyclooctyne derivatives represent an important class of compounds that play a key role in bioorthogonal chemistry. The presence of an endocyclic triple bond endows these molecules with the necessary reactivity for strain-promoted azide–alkyne cycloaddition (SPAAC); however, stability issues may hamper their use in biological systems. Many research groups, with the aid of computational studies, are devoting their efforts to finding ideal cyclooctyne candidates that strike a delicate balance between reactivity and stability. In this context, providing reliable and general synthetic procedures for accessing such chemical scaffolds is of critical importance. This review covers the recent synthetic strategies found in the literature to achieve this goal. Specifically, six main methodologies are discussed, highlighting the synthetic pathways, the key precursors for each, the applicability to a wide range of cyclooctyne derivatives and the challenges encountered in fulfilling this target.