Polymer-bound hydrazides

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. 

A parallel synthesis of 1,2,3-thiadiazoles employing a catch-and-release strategy has been reported using the Hurd-Mori reaction. A polymer-bound tosyl hydrazide resin reacted with a-methylene ketones to afford a range of sulfonyl hydrazones. Treatment of these sulfonyl hydrazones with thionyl chloride causes 1,2,3-thiadiazole formation and cleavage of the resin in one step <1999JOC1049>. 

A robust catch, cyclize, and release preparation of 3-thioalkyl-1,2,4-triazoles mediated by the polymer-bound base P-BEMP has been described <02TL5305>. Reaction of solid-supported hydrazides 103 with isocyanates or isothiocyanates followed by base-induced cyclization/cleavage afforded 1,2,4-trisubstituted urazoles and thiourazoles 104 <02JCO491, 02TL3899>. Polymer-supported V-acyl-1 //-benzotriazole- 1-carboximidamides 105 reacted with hydrazines followed by acidic cyclizative release to give 3-alkylamino-l,2,4-triazoles 106 <02OL1751>. 

Lam and Raghavendra have also highlighted the synthesis of 1,2,3-triazoles through an intramolecular cyclization of a diazo intermediate that was generated from the Bamford-Stevens reaction between a tosyl hydrazone and abase. Polystyrene sulfonyl hydrazide 74 was treated with 1,1-dichloroacetone in THF to yield polymer-bound a-dichloro carbonyl sulfonylhydrazone 75 (Scheme 12.19). Alternative reaction of 74 with 1,1,1-trichloroace-taldehyde and pyridine derivatives yielded resin 76 and 77. When treated with excess amine,... 

The activation of acids by oxidation or dehydration of their derivatives has been studied by a German school. Oxidation of an acid diphenylhydrazide by JV-bromosuccinimide yields the azonium ion (96), which functions as a highly activated acid derivative, azobenzene being eliminated on nucleophilic attack. A related activation by oxidation has been performed in the solid phase by production of the polymer-bound azo-compound (97), nitrogen being expelled on amide-bond formation. Dehydrative activation is exemplified by conversion of the ester (98), prepared from the acid and 1,1-diphenylethylene glycol, into the enol ester (99). The generation of azo-compounds by anodic oxidation of hydrazides has been reported. All of these procedures have been utilized successfully in peptide synthesis. 

The technique is also used to introduce diene moieties, which enable the polymer for a highly efficient modification with dienophile components via Diels-Alder reaction [354], Therefore, methyl octa-4,6-dienoate is converted to octa-4,6-dienoic acid hydrazide, which is bound to dextran via reaction with BrCN. The maleimide-modified protein (albumin) is easily attached to the polymer backbone by Diels-Alder reaction (Fig. 50). 

Higgins et al. synthesized a biotin-functionalized terthiophene 2.210 by reaction of biotin hydrazide and a terthiophene which was functionalized by a succinimidyl active ester (Chart 1.43) [299]. The copolymerization of 2.210 with terthiophene on a Pt electrode formed poly(terthiophene) films containing intact biotin moieties. The binding of 5 x 10 " mol of the glycoprotein avidin to the pendant biotin units of the polymer film resulted in a positive shift of the oxidation potential due to specific inferactions and blocking of the ion transport to and from the polymer by the bound protein. 

Ferruti et al. prepared polymeric derivatives of daunomycin by reacting its carbonyl group at C-13 or its 3 -amino group with a polymer. In the former reaction daunomycin is bound to a polymeric hydrazide, poly[NLmethacryloyl-e-amino-caproylhydrazine], and in the latter process daunomycin is reacted with the bis-... 

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