Rink amide

Rink amide resin Deshpande. M.S. Tetrahedron Lett., 1994, 35, 5613... 

In another application, the group of Berteina-Raboin demonstrated the solid-supported synthesis of the indole core of melatonin analogues under microwave irradiation (Scheme 7.6) [26]. A benzoic acid derivative was coupled to Rink amide resin by... 

A more recent publication by Weigand and Pelka has disclosed a polymer-bound Buchwald-Hartwig amination [40], Activated, electron-deficient aryl halides were coupled with conventional PS Rink resin under microwave irradiation. Subsequent acidic cleavage afforded the desired aryl amines in moderate to good yields (Scheme 7.22). Commercially available Fmoc-protected Rink amide resin was suspended in 20% piperidine/N,N-dimethylformamide at room temperature for 30 min to achieve deprotection. After washing and drying, the resin was placed in a silylated microwave vessel and suspended in dimethoxyethane (DME)/tert-butanol... 

The same authors performed a microwave assisted Stille reaction on the Rink amide (RAM) Tentagel polymer-tethered 4-iodobenzoic acid [5 b]. Successful palladium-catalyzed coupling of heteroaryl boronic acid with anchored 4-iodobenzoic acid enabled both >99% conversion of the starting material within 3.8 min (45 W) and a minimal decomposition of the solid support. The coupling reactions were realized in a mixture of polar solvents (H20-EtOH-DME, 2.5 1.5 6). 

Interestingly, the Suzuki reaction worked smoothly on solid supports and high yields of a variety of products were reported under these reaction conditions (Eq. 11.22) [36]. 4-Bromo- and 4-iodobenzoic acid linked to Rink-amide TentaGel re-... 

The first example describes the synthesis of a pyrimidine derivative. Starting from a, 3-unsaturated ketones (see Schemes 1, 8), a library of different heterocycles was prepared in research (Felder and Marzinzik 1998). In preparation for any large-scale synthesis, the availability of starting materials is always considered (Lee and Robinson 1995). For this work, we had to replace Rink amide resin B (Rink 1987), which was used by our colleagues in research for the synthesis of pyrimidine 1 due to its unavailability in large quantities (see Fig. 1). It was replaced with the Rink amide acetamido resin 4, which is well established in peptide amide synthesis (Bernatowicz et al. 1989) and easily accessible. 

The cyclization of IV-allyl-o-haloanilines was adapted to the solid phase for both indoles [332, 333] and oxindoles [334]. For example, as illustrated below, a library of l-acyl-3-aIkyl-6-hydroxyindoles is readily assembled from acid chlorides, allylic bromides, and 4-bromo-3-nitroanisole [332], Zhang and Maryanoff used the Rink amide resin to prepare Af-benzylindole-3-acetamides and related indoles via Heck cyclization [333], and Balasubramanian employed this technology to the synthesis of oxindoles via the palladium cyclization of o-iodo-N-acryloylanilines [334], This latter cyclization route to oxindoles is presented later in this section. 

Due to the importance of this heterocycle in medicinal chemistry, solid-phase synthesis of derivatives based on this condensation reaction have been investigated. The first report in this area uses a sodium benzenesulfinate resin 247 and gives access in five steps and good overall yields to a library of imidazo[l,2- ]pyridines 248 functionalized at C-2 with an enone moiety <2002OL3935>. Later on, the preparation of libraries of compounds related to 250 or 251 from Rink amide resin 249 have been published (Scheme 68) <2003TL6265>. 

In a later study, an insoluble Rink amide resin was employed with the linkage of the glucuronic-acid-based acceptor through an amide bond (Scheme 4.68) [347,378]. 

Rink amide MBHA resin was purchased from Novabiochem, substitution = 0.54 mmol/g, lot A20678. 

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. 

Benzhydryl- (phenylbenzyl) and 4-methylbenzhydrylamine resins (see Section 5.18) are available for preparing primary amides, using Boc/Bzl chemistry. 4-Methylben-zhydrylamine, Rink amide, Sieber amide and dhnethoxytritylamine resins and the linkers PAL and XAL (see Section 5.20) are available for preparing primary amides, using Fmoc/tBu chemistry. Secondary amides can be synthesized by making use of AJ-alkyl-Sieber or ALalkyl-PAL linkers. 

The monomeric peptides [Cys-I], [Cys,Cys(Acm-II], [Cys(Acm),Cys-III], and [Cys-IV] were synthesized by Fmoc chemistry on Rink-amide resin as 5-Mob derivatives and cleaved/deprotected with 1M TMSBr/thioanisole in TFA in the presence of m-cresol and 1,2-ethanedithiol as scavengers. Following gel filtration on Sephadex G-10 with 1M AcOH as solvent and HPLC purification the peptides were obtained in 30—40% yield. Each product was characterized by LSIMS, HPLC, and amino acid analysis. 

Table 1 Optimized Protocol of the Synthesis of Selenocysteine Peptides on Rink-Amide-MBHA Resin According to the Fmoc Strategy 10 ...

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