A “Traceless” Staudinger Ligation for the Chemoselective Synthesis of Amide Bonds

Abstract

[reaction: see text] Here we report a novel modification of our previously reported "Staudinger ligation" that generates an amide bond from an azide and a specifically functionalized phosphine. This method for the selective formation of an amide bond, which does not require the orthogonal protection of distal functional groups, should find general utility in synthetic and biological chemistry.

Selective chemical protein modification

“…Applications of Staudinger ligation in bioconjugation have been reviewed 58 , with uses as diverse as fluorogenic labelling 59 , epitope tagging of G-protein-coupled receptors 60 and the installation of photoswitches 61 . Soon after the initial report, a 'traceless' variant was reported by the groups of Raines 62 and Bertozzi 63 . Thus, an amide bond can be generated without residual phosphine oxide (Fig.…”

Diels–Alder Ligation of Peptides and Proteins

“…[43] Furthermore, approaches to find a traceless Staudinger ligation method, where a phosphane ligand is cleaved by hydrolysis thus leaving a native bond at the ligation site, are currently under development. [44][45] Although the Staudinger ligation can potentially be applied for noninvasive imaging and therapeutic targeting, [46] the reaction has some drawbacks. The required phosphines are susceptible to air oxidation and the optimization of their water solubility and increased reaction rate has proven to be synthetically challenging.…”

Discovery of competing anaerobic and aerobic pathways in umpolung amide synthesis allows for site-selective amide 18 O-labeling

“…The same homolytic nitro-carbon fragmentation can be diverted by capture of the carbon radical intermediate with oxygen gas (O 2 ) to deliver the amide oxygen from O 2 . This understanding was used to develop a straightforward protocol for the preparation of 18 O-labeled amides in peptides by simply performing the umpolung amide synthesis reaction under an atmosphere of 18 O 2 . P reparative needs in amide synthesis, particularly those in the peptide regime, continue to drive new methods for their construction (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15). The increasing success of peptide therapeutics, as well as continuing biophysical studies of peptides, have generally outpaced the scope of purely chemical methods for their preparation on scale (16,17).…”