Bioorthogonal Phosphines: Then and Now

Abstract Bioorthogonal chemistry traces its roots to a seminal report by Saxon and Bertozzi, who described a modified Staudinger reaction between organic azides and triaryl phosphines. This finding not only inspired several biological pursuits, but also launched an entire field of reaction discovery. Over the years, much effort has been directed at identifying alternative bioorthogonal transformations with organic azides; less work has focused on leveraging triaryl phosphines for new reaction development. The landscape has changed in recent years, with the generation of faster‐reacting Staudinger probes and novel classes of bioorthogonal reagents. This perspective covers newly developed phosphine‐based chemistries and their application in biological settings. We focus, in particular, on reactions with cyclopropenones and related analogs. These transformations feature unique mechanisms that are broadening the scope of bioorthogonal reactivity.