The Staudinger Ligation

Abstract

While the Staudinger reaction has first been described a hundred years ago in 1919, the ligation reaction became one of the most important and efficient bioconjugation techniques in the 1990s and this century. It holds the crucial characteristics for bioorthogonal chemistry: biocompatibility, selectivity, and a rapid and high-yielding turnover for a wide variety of applications. In the past years, it has been used especially in chemical biology for peptide/protein synthesis, posttranslational modifications, and DNA labeling. Furthermore, it can be used for cell-surface engineering, development of microarrays, and drug delivery systems. However, it is also possible to use the reaction in synthetic chemistry for general formation of amide bonds. In this review, the three major types, traceless and nontraceless Staudinger Ligation as well as the Staudinger phosphite reaction, are described in detail. We will further illustrate each reaction mechanism and describe characteristic substrates, intermediates, and products. In addition, not only its advantages but also stereochemical aspects, scope, and limitations, in particular side reactions, are discussed. Finally, the method is compared to other bioorthogonal labeling methods.

Divergent Solid‐Phase Synthesis and Biological Evaluation of Yaku'amide B and Its Seven E/Z Isomers

“…In this synthesis, a modified traceless Staudinger ligation was developed and applied to the stereoselective construction of the sterically cumbersome ( E )/( Z )‐ΔIle residues in solution (Figure 1 b). [21–25] We found that introducing two CF 3 groups and one methoxy group of 9 to the original phosphinophenol structure drastically improved the efficiency of the enamide formation from alkenyl azide 10 . When 9 and 10 were coupled in an aqueous solvent at room temperature, N 2 expulsion, intramolecular amidation from 11 , and release of phosphine oxide 12 proceeded to generate 13 with retention of the original E / Z stereochemistry of 10 .…”

“…In this synthesis, am odifiedt raceless Staudinger ligationw as developed and applied to the stereoselectivec onstruction of the sterically cumbersome( E)/(Z)-DIle residues in solution (Figure1b). [21][22][23][24][25] We found that intro-ducing two CF 3 groups ando ne methoxy group of 9 to the originalphosphinophenol structure drastically improved the efficiency of the enamide formation from alkenyla zide 10.W hen 9 and 10 werecoupled in an aqueous solvent at room temperature, N 2 expulsion, intramolecular amidation from 11,a nd release of phosphine oxide 12 proceeded to generate 13 with retention of the original E/Z stereochemistryo f10.A dduct 13 was in turn converted to the requisite Fmoc-protected dipeptide 15 by at wo-stepp rotective group manipulation. The three dipeptides with the (E)/(Z)-DIle residues were thus prepared and employed for peptide elongation on resin to attain the solid-phase total synthesis of 1.…”

Synthesis and formulation of self‐immolative PEG‐aryl azide block copolymers and click‐to‐release reactivity with trans‐cyclooctene

“…While the structure of the aryl azide dictates its reactivity, [33][34][35] functionalised aryl azides have relatively high biological stability, with selective reactivity for strained alkenes and alkynes ([3+2]-cycloadditions), [35][36][37] triphenylphosphines (Staudinger reaction), 38 or H 2 S. [39][40][41] We have developed the alkene-azide [3+2]-cycloaddition as a bioorthogonal click-to-release reaction for prodrugs 28,29,32 and hydrogels, 30,31 while others have investigated H 2 S; a gaseous transmitter in the body, as an activation mechanism for aryl azide-containing probes, prodrugs, and materials. [39][40][41] Alkyl azides can also be reduced by H 2 S 42 or glutathione, 43 however, aryl azides are considered more responsive to, and selective toward, alkenes and H 2 S, 44 even in the presence of other endogenous thiol/thiolate species (e.g., glutathione).…”

Visible‐Light‐Mediated Oxidative Amidation of Aldehydes by Using Magnetic CdS Quantum Dots as a Photocatalyst

“…[16] The most well-established routes for the formation of amides involve the reactiono fa mines with activated carboxylic acids or their corresponding derivatives, [17] the Schmidt reaction, [18] the Beckmann rearrangement reaction, [19] and modified Staudinger reaction. [20] From the perspective of green chemistry,t hesep rocesses generate al arge amount of byproducts andc hemical waste, so they need to be improved or replaced. Thus, much effort is being devoted to making the formation of amide bonds more "green."…”