Hydrazide linker

Aryl hydrazide linker 38 stable to both acid and base was utilized in SPPS [46], Treatment of the resin with a copper(II) catalyst in the presence of a base and nucleophile gave the corresponding acid, amide, or ester (Scheme 13). 

More recently, Somfai and coworkers have reported on the efficient coupling of a set of carboxylic acids suitable as potential scaffolds for peptide synthesis to a polymer-bound hydrazide linker [24]. Indole-like scaffolds were selected for this small library synthesis as these structures are found in numerous natural products showing interesting activities. The best results were obtained using 2-(7-aza-l H-benzo-triazol-l-yl)-l,l,3,3-tetramethyluronium hexafluoride (HATU) and N,N-diisopropyl-ethylamine (DIEA) in N,N-dimethylformamide as a solvent. Heating the reaction mixtures at 180 °C for 10 min furnished the desired products in high yields (Scheme 7.4). In this application, no Fmoc protection of the indole nitrogen is required. 

Scheme 7.4 Coupling of an indolyl acid to polystyrene-bound hydrazide linker.

Scheme 3. The hydrazide linker 10 can be activated by mild oxidation (NBS, N-bromosuccinimide).

For the complete solid-phase synthesis of H- and A-Ras peptides, the hydrazide linker turned out to be the linker of choice (14). This linker is cleaved by oxidation to an acyldiazene that is then attacked by a suitable nucleophile. The linker is orthogonal to classic urethane protecting groups such as Boc, Fmoc, and... 

The solid-phase synthesis of lipidated Rab peptides has relied on the hydrazide linker, similar to the lipidated Ras peptides (15). By employing geranylgeranylated or fluorescent labeled lipidated cysteines as building blocks, a highly flexible... 

Peters C, Waldmann H. Solid-phase synthesis of peptide esters employing the hydrazide linker. J. Org. Chem. 2003 68 6053-6055. 

To utilize the N -protected hydrazide approach for solid-phase synthesis, different hydrazide linkers for polystyrene resins were developed by Wang and MerrifieldP l (Table 2). Generally, the first N -protected amino acid is attached to the linker by treatment with DCC in presence of additives (HOBt, HOSu). The Bpoc groupf which is readily cleaved with 0.5% TFA in dichloromethane in 15 minutes at room temperature, was used as temporary N -protection. After completion of the peptide synthesis on the solid support, the hydrazides are cleaved from the resin with 50% TFA in 30 minutes. The dibenzocycloheptadienyl-hydrazide linker allows the synthesis of protected hydrazides by the Fmoc/tBu strategy, as the hydrazides are cleaved from the resin with 1% TFA in dichloromethane in less than 3 hours. 

Besides the benzyl hydrazide linker 44, Wieland et al. introduced a 2,2-diphenyl-2-hydroxyethyl-ester derived resin [58], This linker type can be activated by acid-catalyzed dehydration (aq. TFA) to give the reactive enol ester 51, which affords amides 53 upon treatment with amines (Scheme 16.12). 

Waldmann s safety-catch hydrazide linker is also part of the class of traceless linkers [55]. Starting from hydrazide resin 126, which is converted into an activated species by oxidation with Cu(OAc)2, the molecules are cleaved by the addition of nucleophiles like amines to give arenes 127 (Scheme 16.30). 

Scheme 5 Synthesis of N-Ras protein C-terminus for MIC ligation using hydiazide linker and Elhnan sulphonamide linker, (a) Cleavage of the hydrazide linker by oxidation and nucleophilic attack and Elhnan sulphonamide linker by activation and nucleophilic attack of a nucleophile, (b) Synthesis of famesylated and pahnitoylated N-Ras C-terminus with maleimido group using hydrazide linker and Ellman sulphonamide linker...

Fig. 4 Chemoselective ligation methods a maleimide linker, b silyl linker, c Diels-Alder ligation, d glyoxylyl linker, e diazobenzylidene linker, f Staudinger ligation, g Huisgen [3 + 2] cycloaddition, h hydrazide linker, i glycal immobilization...

Woo Y-H, Mitchell AR Camarero JA (2007) The use of aryl hydrazide linkers for the solid phase synthesis of chemically modified peptides. Int J Pept Res Ther 13 181-190... 

Fig. 6 Synthesis of Rab7 C-terminus using the hydrazide linker...

Rosenbaum, C. and Waldmann, H. (2001) Solid phase synthesis of cyclic peptides by oxidative cydative deavage of an aryl hydrazide linker-synthesis of stylostatin 1. Tetrahedron Lett., 42, 5677-5680. 

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