Linker hydrazide resins

Thus, gel-type polystyrene-sulfonyl-hydrazide resin 20, which originally was developed for carbonyl scavenging applications [30] can also serve as a linker for carbonyl compounds in solid phase synthesis and gives access to support-bound sulfonyl hydrazones 21 (Scheme 8)... 

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). 

Thiadiazoles. Sulfonyl hydrazide resin 74 could also serve as a sulfone linker in SPS. Porco and coworkers have demonstrated the use of resin 74 for the preparation of sulfonylhydrazone resin 112, which was subsequently applied to the synthesis of 1,2,3-thiadiazoles 113 (Scheme 12.27a).Resin 74 has also been efficiently employed in the resin capture of ketones in a hybrid solution/solid-phase synthesis of 1,2,3-thiadiazoles (Scheme 12.27b). The resin-bound sulfonylhydrazones with aryl halide substituents 112a could be subjected to Stille reaction for the generation of more diverse thiadiazole structures 113a. 

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). 

The Kenner sulfonamide-based SC linker 1.27 was supported on PS resin (84) allowing the attachment of carboxylic acids or amino acids to the sulfonamide function. After synthetic elaboration, treatment with diazomethane produces the A-methylacylsulfonamide, which can be cleaved with nucleophiles such as 0.5 N NHs-dioxane or hydrazine-MeOH, 0.5 N NaOH, releasing amides, hydrazides, or carboxylic acids, respectively. A modification using iodoacetonitrile produces the more labile A-cyanomethyl derivative, which can be cleaved completely with stoichiometric amounts of amines to release the corresponding amides into solution. 

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. 

For the reversible immobilization of amines to such linkers, the most frequently used strategy is conversion of the hydroxymethyl linkers into activated carbonic esters (Figure 14.7) [8, 39, 40]. These react with primary and secondary amines or hydrazines to form immobilized carbamates or carbazates analogous to the classical benzyloxycarbonyl protecting group. Amines and hydrazides attached by this strategy to Wang resin can be cleaved with TFA [8, 40]. 

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). 

Photolabile a-halophenacyl resins (lo-lq) have been used to form an acid-stable anchor to the carboxyl group of amino acids prior to peptide elongation [97]. Cleavage of the final products was achieved by irradiation with light of wavelength 350 nm. Related linkers that differ in the mode of attachment to the resin have been reported [98-100]. Carboxylic acids can also be released by treatment of these supports with base [101] or cyanide ion [102] and peptide hydrazides have been released by treatment with hydrazine [97,103]. 

HMBA resin, an aminomethyl polystyrene resin acylated with 4-(hydro-xymethyl)benzoic acid. It is completely resistant towards treatment with acids (even liquid HE), and enables on-resin side-chain deprotection. The highly versatile linker is cleaved by a variety of nucleophiles such as hydroxide ions (to give peptide acids), alcohols (to give esters), ammonia or amines (to give amides), hydrazine (to give peptide hydrazides), or UBH4 (to give peptide alcohols) [R. C. Sheppard, B. J. Williams, Int.J. Pept. Protein Res. 1982, 20, 451]. 

Millington CB., Quarrell R, Lowe G (1998) Aryl hydrazides as linkers for solid phase synthesis which are cleavable under mild oxidative conditions. Tetrahedron Lett 39 7201-7204 Atherton E, Gait MJ, Sheppard RC, Williams BJ (1979) The polyamide method of solid phase peptide and oligonucleotide synthesis. Bioorg Chem 8 351-370 Story SC, Aldrich JV (1992) Preparation of protected peptide amides using the Fmoc protocol—comparison of resins for solid-phase synthesis. Int J Pept Protein Res 39 87—92... 

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