Rink acid linker

Variants Rink acid linker Peptide acids o ... 

The trialkoxy benzhydrol linker, developed by Rink in 1987 [46] ( Rink acid resin , Figure 3.4) is a further acid-labile linker for carboxylic acids. Esters of this linker can, like trityl esters, be cleaved with acids as weak as acetic acid or HOBt [47], and care must be taken to avoid loss of the product during synthetic operations. 

Benzhydrylamines are better suited than benzylamines as acid-labile linkers for amines. The MBHA linker ( methylbenzhydrylamine ), which is usually used to prepare peptide amides (see Section 3.3), can also be used as a linker for amines (Entry 1, Table 3.21). Hydrogen fluoride is, however, required as the cleavage reagent. Easier to cleave are alkoxy-substituted benzhydrylamines (Entries 2-5, Table 3.21), which can be prepared from the corresponding benzhydryl chlorides [263] or by reductive alkylation [410] or solvolysis [411] of the Rink amide linker. In the case of benzhydrylamines linked to polystyrene as benzyl ethers, treatment with TFA can lead to the release of the linker into solution (acidolysis of the benzylic C-O bond, see Figure 3.18). 

SynPhase Crowns with a Rink amide linker were used by Linn et al.38 at Glaxo-Wellcome to synthesize a library of 1,3,5-trisubstituted pyridin-2-ones (Scheme 12). The solid bound amide 38 was treated with 3-amino-5-methoxycarbonyl-l/f-pyridin-2-one with CS2CO3 in DMF to afford pyridine-2-one 39. Coupling of diphenylacetic acid FIATU and DIEA in... 

The synthesis was carried out using 125 Chiron Mimotopes Crowns (capacity 5.3 pmol each) derivatized with an Fmoc -Rink amide linker. The procedure was started with the formation of five strings by threading 25 crown units on Berkley Fire Line fishing line. Five Fmoc-protected amino acids were used in each coupling position as demonstrated in the flow diagram of the synthesis (Fig. 11). 

The hydroxyl version of the Rink amide linker, known as the Rink acid resin (25), was developed as a tool for the preparation of protected peptide fragments [13]. The peptide-linker ester bond is labile to extremely weak acids, such as HOBt or acetic acid, allowing peptides bearing t-butyl-based side-chain protection to be cleaved intact. Conversion of the hydroxyl group into chloride [66] or trifluoroacetyl [67] provides linkers that have been used for immobilization of various nucleophiles, including alcohols, N-protected hydroxylamines, phenols, purines, amines, anilines and thiols [66-68], The stability of the cation derived from this tinker is such that even thiols and amines can be cleaved from this tinker with TFA (Figure 14.12). 

Another example of a conformationally restricted carbohydrate-derived library was reported by Overkleeft and coworkers. They prepared carboxyhc acid 30 in eight steps from D-mannitol (29) derived from o-matmose (Scheme 7.7). After coupling 30 onto the Rink amide linker, the hydroxyl and azide, upon conversion into carbamates and amides, respectively, furnished hw-olefln 32. The oxacycle core-contairung compounds 33 were generated upon RCM cleavage off solid-support. 

Glycopeptide 31 was synthesized in a custom-made, fully automatic continuous-flow peptide synthesizer constructed essentially as described elsewhere (19). A resin consisting of a cross-linked polystyrene backbone grafted with poly(ethylene glycol) chains (TentaGel , Rapp Polymer, Germany) and functionalized with the Rink amide linker (p-[a-(fluoren-9-ylmethoxyformamido)-2,4-dimethoxybenzyl]phenoxyacetic acid, Nova-biochem, Switzerland) was used for the syntheses. DMF was distilled before use. 

The protocol for treatment with dilute TFA is for peptide sequences attached to acid-sensitive linkers such as Rink acid, 2-chlorotrityl, 2-methoxy-4-alkoxybenzyl alcohol (SASRIN), and Sieber resins. This protocol provides fully side-chain protected peptide sequences. 

In the submonomer approach, peptoids are synthesized from the C to N terminus on a Rink amide linker resin using a two-step coupling cycle (Fig. 2). First step involves a DIC-mediated coupling of bromoacetic acid to the resin followed by a SN2-nucleophilic displacement by a primary amine. This cycle is repeated until the desired compound is obtained. The peptoid is then cleaved from the resin with 95 % aqueous TFA. Following removal of TFA by evaporation, the peptoid is precipitated and lyophilized. Finally, the identity of the product is verified by chromatography combined... 

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