Rink amide linker

To 100 MicroTubes in 100 mL of DCM, the following were added sequentially 4.96 g (9.2 mmol) Rink amide linker (note 6), 3.20mL (18.4mmol) DIEA, and6.9g (18.4mmol) HATU (note 7). The reaction mixture was shaken at room temperature for 48 h. After the supernatant was removed by aspiration, the MicroTubes were washed sequentially with DMF, MeOH, and DCM for three cycles. The MicroTubes were dried under vacuum for 5 h after a final washing with ethyl ether. 

Our library synthesis was carried out with a set of 27 tube-shaped solid phase synthesis support, called MicroTubes. These supports are prepared by radiation grafting of polystyrene ( — 350 pmol) onto polypropylene tubes, chemically functionalizing the polystyrene with aminomethyl groups to afford about 55 imol of amine per tube, inserting a reusable Rf ID tag into each tube, and heat-sealing the tube ends to prevent loss of the tag. The chemical conversion of all 36 aminomethyl tubes was carried out simultaneously using standard procedures with rink amide linker, each with —46 pmol of available amine per tube.1 2... 

Rink amide linker was purchased from Midwest Biotech. 

Tentagel with Rink amide linker. determined by the author. 

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). 

Rink amide linker, (2,4-dimethoxyphenyl)(4-alkoxyphenyl)-methylamine... 

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). 

Fmoc-Rink amide linker (NovaBiochem, Laufelfingen, Switzerland)... 

Peptoid dendrimers were synthesised using an Fmoc solid-phase strategy using a Rink amide linker and an aminomethyl-polystyrene resin and microwave-mediated DIC/HOBt chemistry (Fig. 25). The use of microwave heating allowed each... 

Some linkers, such as Rink amide linker, are sold A-Fmoc protected. The first removal of the Fmoc group may require a longer deprotection time particular with highly loaded resin (>0.9 mmol/g). In these cases it should be useful to repeat steps 2 and 3 of Protocol 7. 

For this, the polystyrene resin bearing 3-bromobenzamide attached to the solid phase via a Rink amide linker was used. The 3-bromophenyl resin (75) (500 mg, 0.39 mmol), Pd(PPh3)2Cl2 (13.7 mg, 0.020 mmol), Cul (7.4 mg, 0.039 mmol), triphenylphosphine (20.5 mg, 0.078 mmol), the alkyne (28) (0.43 mmol), diethylamine (1.5 mL, 13.60 mmol), and DMF (0.5 mL) were stirred in a modified heavy-walled Smith Process Vial [200] at 120 °C for 25 min in the microwave cavity. The resin was then washed as follows ... 

Figure 14.3 Rink amide linker 7 acting as an ammonia equivalent.

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. 

Phenol is thou t to offer some protection to Tyr and Trp residues (58). Trialkylsilanes, such as triisopropylsilane (TIS) and triethylsilane (TES), ve been shown to be effective, non-odorous substitutes for EDT (59), particularly for peptides containing Arg(Pmc)/Arg(Pbf) and Trp(Boc) (60, 61). These reagents are also very efficient at quenching highly stabilized cations liberated on cleavage of Trt (59), Tmob (61,62), and the Rink amide linker, and hence their use is strongly recommended when these moieties are present. 

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. 

Because of the origins of solid phase chemistry in peptide synthesis, amide formation is historically one of the most important reactions on solid supports. The most pubUc resins are the Rink amide linker 123 [146,147] and its derivatives that are formed by addition of the Knorr hnker [148] to polystyrene-derived resins. 

For syntheses of peptides as their C-terminal amides in Fmoc-SPPS, the most common linker is a benzhydryl-type handle, the Rink amide linker. Most commonly used resins are available with a Rink amide linker preinstalled. The PAL [46, 47] ( peptide amide linker ) handle, which has a trisalkoxybenzyl structure, is also very suitable for Fmoc-SPPS of peptide amides. 

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