Azide: A Unique Dipole for Metal‐Free Bioorthogonal Ligations

Abstract

Covalently bound azide on a (small) organic molecule or a (large) biomolecular structure has proven an important handle for bioconjugation. Azides are readily introduced, small, and stable, yet undergo smooth ligation with a range of reactive probes under mild conditions. In particular, the potential of azides to undergo metal‐free reactions with strained unsaturated systems has inspired the development of an increasing number of reactive probes, which are comprehensively summarized here. For each individual probe, the synthetic preparation is described, together with reaction kinetics and the full range of applications, from materials science to glycoprofiling. Finally, a qualitative and quantitative comparison of azido‐reactive probes is provided.

Strain-Promoted 1,3-Dipolar Cycloaddition of Cycloalkynes and Organic Azides

“…5). Efforts from our own laboratory led to the development of DIBAC [16], a cyclooctyne that combined excellent stability with a reaction rate constant that is top among the family members. Interestingly, Kuzmin et al [33] and CampbellVerduijn et al [13] rapidly followed with publications of the same molecule, albeit obtained by different synthetic paths and with different given names (ADIBO and aza-DBCO, respectively).…”

Efficient Synthesis of DNA Conjugates by Strain‐Promoted Azide–Cyclooctyne Cycloaddition in the Solid Phase

“…dibenzocyclooctyne. [32,33] It is known that lipid conjugation facilitates both cellular uptake and intracellular delivery of oligonucleotides and so provides hope for a nontoxic alternative to the cationic lipophilic or polymeric siRNA delivery systems, [41,42] and we wished to extend the scope of the SPAAC reaction to include steroidal examples. However, despite the advances in methodologies for the postsynthetic modification of oligonucleotides, the synthesis of steroidal conjugates remains nontrivial.…”

Structural and Kinetic Considerations for the Application of the Traceless Staudinger Ligation to Future 18F Radiolabeling Using XRD and 19F NMR

“…Both the chemical modification of the biological active molecule and the preparation of the labeling building block are also quite facile. In general, one of the reactants is modified with an azide function [27,28] and the other is functionalized with a phosphane moiety [29,30].…”