Rink linker

The coupling and cycloaddition could also be achieved as a one-pot procedure on a polymer support, as shown in Eq. (11.34), in which a Rink linker on TentaGel was used. Negligible decomposition of the solid support was reported [50]. 

Fig. 1. Structural comparison of the Rink-linker compared to the linker used for the scale-up...

The introduction of alkoxy groups onto the benzhydryl system leading to a system cleavable by HE was first reported by Walter in 1976 [25] while one additional alkoxy group leads to the Rink linker (12), introduced in 1987 [26]. As quite mild conditions are sufficient for the release of the library components, the Rink resin has effectively been applied to the synthesis of several small molecule libraries [27]. 

For resin-bound carbamates (18-21), indole linker was the most acid-labile linker for this class of compounds. Rink linker ranked second. Resin (20) was cleaved with 0.5% TFA in 20 min. Resin (21) was cleaved with 1% TFA in 2 min. Resins (18) and (19) required higher concentration of TFA. Resin (18) was cleaved with 1% TFA in 5 h. Alternatively, resin (19) was cleaved with 1% TFA in 12 h and with 5% TFA in only 16 min (not shown). 

For resin-bound ureas (22-25), Indole and Rink linkers, generally ranked 1 and 2 in cleavage kinetics, were still the most acid-labile linker for this class of compounds. Resins (24) and (25) were cleaved with 0.5% TFA in 2 and 23 min, respectively. Resins (22) and (23) were cleaved with 1% TFA in more than 10 h. The order of cleavage rates is similar to carbamate compounds. 

The resin-bound secondary amides (19-22) are the most difficult to cleave among the compounds studied. Resin (29) was cleaved with 1% TFA in 2 h. Resin (28) was cleaved with 1% TFA in 8 h. Resins (26) and (27) required 5% TFA and 8-15 h. This was the only occasion that linker III was not the most labile bond. Rink linker, the second best in all other series, became the most labile bond. 

TFA). Among various linkers studied in this work, the indole linker [21] was found to be the most suitable linker in terms of cleavage kinetics and actual cost. Rink linker was the second best in term of kinetics. The rate of cleavage of various functional groups linked to the above-mentioned resins was as follows sul-fonamide>carbamate urea>amide. Results from this study demonstrated that optimization of cleavage conditions often led to more suitable conditions and safer release of precious compounds synthesized on a solid support. 

H-Cys(Trt)-Tyr(tBu)-Ile-Gln(Trt)-Asn(Trt)-Cys(Trt)-Pro-Leu-Gly-Rink-Linker-PEGA-resin (60mg, 0.09 mmol g 1,5.4 pmol) was suspended in 95% aq TFA (10 mL) for 1 h at rt, followed by the addition of DMSO (2mL) at 0°C. After 30 min at 0°C and 1 h at rt, the resin was rinsed with 95% aq AcOH. The solvent was removed under reduced pressure and the product precipitated with cold Et20 and purified by HPLC yield 3.0 mg (56%). The product was characterized by MALDI-MS, amino acid analysis, and HPLC. 

Larock.38 The method allows for variation in the aromatic ring component. An interesting feature of this work, probably influenced by the ease of cleavage of the Rink linker, is that all characterization and yield calculations were done off-bead. 

Lambert and co-workers49 (University of Melbourne) synthesized a library of cyclic thioether peptides with a pendant 9-aminoacridine moiety as a DNA-binding agent 81. Diversity in the library was achieved by assembling every permutation of four amino acid residues within the cyclic peptide (Scheme 24). The linear peptides 80 were synthesized in parallel with standard Fmoc chemistry on SynPhase Crowns functionalized with a Rink linker. The acridine moiety was incorporated onto the C-terminal lysine side chain using 9-phenoxyacridine. Cysteine deprotection and peptide cy-clization also took place under the acidic conditions used for the cleavage of 80 from the solid support. The library of cyclic thioether peptides 81 was obtained in high yields and purity (11 of 12 members had purities >95%). 

In a separate report, the regioselectivity and reactivity problems in the substitution of pyrimidines were avoided using 4,6-dichloro-5-nitropyrimi-dine as starting material,17 a very electron-poor heterocycle, which is highly reactive in nucleophilic aromatic substitutions. It reacts readily with the free amino group of the (trialkoxybenzhydrylamine) Rink linker on solid phase. This heterocycle could serve as a scaffold by itself and could also be used as a building block (precursor) to make other heterocycles such as purines. 

Release of peptides with ammonia might work only on homemade membranes. Commercially available membranes with amino functional groups often have other than ester bonds between the spacer and cellulose. For such membranes the use of additional linkers might be necessary (e.g., thioester (66), HMB linker (67), Rink linker (68)). 

Coupling of 4-(4-hydroxymethyl-3-methoxyphenoxy)-butyric acid (HMPB, for synthesis of peptide acids) or p-[(R S)-a-[l- (9H- fluorenyl- methoxyform-amido]- 2,4- dimethoxybenzyl] - phenoxyacetic acid (modified Rink linker, for synthesis of carboxamide peptides) linkers to MBHA resin For Fmoc chemistry several types of solid supports are available, which include hydroxymethyl-based, aminomethyl-based, and trityl chloride resins. We describe the use of the MBHA resin. In this case the respective linker (to achieve peptide acid or amide) is coupled to the resin and first amino acid is then coupled to the linker. Attachment of the linker to the resin is a reaction between the carboxyl-group of the linker and amino-group of the MBHA resin. Commercially available resins with linkers already attached could also be used. 

To produce a carboxyamide peptide The peptide will be linked to the modified Rink linker via an amide bond. The attachment of the first residue can be carried out under conditions for peptide bond formation (e.g., with TBTU) by using the activation procedures described in Subheading 3.3.2,2, (Methods A-E) of this chapter. Do not forget to deprotect the linker before coupling of the amino acid. 

R,5 )-a-[l-(9//)-fluo-ren-9-yl)methoxy-formamido]-2,4-dimeth-oxybenzyl]phenoxyacetic acid (Fmoc-Rink linker, linker AM)... 

In some cases, when Schwesinger base is used in reaction sequences, removal of polymer-associated base may be difficult In such cases, a fivefold wash with CH2CI2/ACOH (4 1, v/v) may be employed. The loss of polymer-bound substrate attached to a Rink linker via amide or amine functions is very minimal during this treatment. 

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