Staudinger ligation, traceless

Figure 17.22 Certain unique phosphine derivatives can be used in the design of modification or conjugation reagents to create a traceless Staudinger ligation process, wherein the phosphine group is lost and an amide bond between an azide-containing molecule and the phosphine-containing molecule results.

Figure 17.23 A traceless Staudinger ligation process involves the formation of an intermediate aza-ylide with subsequent attack of the nucleophilic nitrogen atom on the neighboring electrophilic group. The formation of an amide bond then occurs concomitant with the loss of the phosphine component, thus forming a zero-length crosslink between the two molecules.

Staudinger ligation and its traceless version have been explored in the preparation of glycoconjugates [70, 71]. It was used to label cell-surface carbohydrates [72, 73] and, more recently, to prepare glycoproteins by modification of L-azidohomoalanine-containing proteins [74, 75],... 

Saxon E, Armstrong JI, Bertozzi CR. A traceless Staudinger ligation for the chemoselective synthesis of amide bonds. Org.Lett. 2000 2 2141-2143. 

A second approach relies on the traceless Staudinger ligation between an appropriately functionalized phosphine and an azide to produce a new amide bond [54]. This method has found extensive utility in the labeling of peptides and proteins [215]. Importantly, this method has also been used for the construction of native iV-linked glycans through the reaction between a glycosyl azide and a phosphine containing amino acid [216,217]. 

Tam A, Soellner MB, Raines RT (2007) Water-soluble phosphinothiols for traceless staudinger ligation and integration with expressed protein ligation. J Am Chem Soc 129 11421-11430... 

Fig. 29 Comparison between the Staudinger reaction, the Staudinger ligation and the so-called traceless Staudinger ligation...

It is important to cite several other recently developed methods for peptide ligation, which include the traceless Staudinger ligations of Bertozzi [62], Raines [63], and their co-workers, the decarboxylative amide ligation (KAHA ligation) developed by Bode et al. [64], and the Ser/Thr ligation of Li et al. [65, 66]. While these methods can be considered complementary to NCL, they have various constraints which limit their general utility. 

Fig. 8 The head-to-tail macrocyclization of peptides through a traceless Staudinger ligation...

Hackenberger and Kleineweischede reported a traceless Staudinger ligation for the head-to-tail macrocyclization of peptides without a deprotection step (Fig. 8) [63]. In this strategy, a phosphine tethered to a thioester at the C-terminus of a peptide reacts intramolecularly with an azide at the N-terminus to form the cyclic peptide. 

Kleineweischede R, Hackenberger CPR (2008) Chemoselective peptide cyclization by traceless Staudinger ligation. Angew Chem Int Ed 47 5984-5988... 

Scheme 16.13 Two-component traceless Staudinger ligations using phosphine-derivatized ester 51 (Af or thioester 56 (B) ...

Scheme 1.17 Staudinger and traceless Staudinger ligation click reactions.

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