Rink-amide resins

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 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]. 

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. 

A common goal of library synthesis is to maximize diversity around a core, so the synthetic route described above was extended to accommodate a variety of substituted aryl groups. The modified route is shown in Scheme 11. The solid-phase starting material was Rink amide resin,36 which had been loaded with y-bromocrotonic acid (attempts to load with other suitable fragments, such as fumaraldehydic acid, or the pentafluorophenol-activated ester, failed). Substituted ort o-iodoanilines could then be used to alkylate... 

Spear et al. chose the Heck reaction to elaborate 4-iodophenylsulfonyl chloride attached to Rink amide resin, that is, sulfonamide 18.43 The reaction (Scheme 16) was reported to be quantitative, as was a simple Stille coupling on the same molecule. Raju and Kogan used a Suzuki coupling on solid support (see below)44 to illustrate use of a new carbamate linker for the generation of more diverse sulfonamides than those above. 

In a subsequent paper on the use of the Stille reaction to form biaryls,58 the reaction was carried out under ambient conditions to allow robotic automation of the process. Attachment of the tin species to resin was very straightforward, in that 4-tri-n-butylstannylphenyl acetic acid was linked to Rink amide resin simply using a DIC coupling. Loading of this species was determined by tin elemental analysis and correlated with a quantitative ninhydrin test of free amines remaining on the support (Scheme 24). 

To Rink amide resin iieylated with. 1-iodobenzyloxy acetic acid (0.2 g, 0.094 mmol) were added DMA (4.7 mL), sodium acetate (23 mg, 0.28 mmol, 3 equiv.), B114NCI (56 mg, 0.20 mmol, 2 equiv.), and dimethyl itaconate (119 mg, 0.75 mmol,... 

Figure 10.9. Boc group removal from Rink amide resin [247],...

SnCl2 H20, NaOAc, DMF, then PhMe, 110 °C, 12 h (PS) Rink amide resin... 

Microwave-promoted palladium-catalysed processes have found wide general application (see Chapter 2). A Larock-type heteroannulation of an iodoaniline and an internal alkyne has been employed in the synthesis of substituted indoles9 (Scheme 3.7). The microwave conditions were carefully optimised using a focused microwave reactor. Application of microwave heating provided clear advantages in reaction rate and yield over conventional thermal conditions. It is interesting to note that fixed microwave power input provided improved yields over constant temperature conditions (variable microwave power input). This chemistry was successfully extended to a solid-phase format (Rink amide resin)10. 

Solid-phase synthesis of the peptide was carried out manually on a Rink amide resin (435 mg, substitution level 0.46 mmol -g 1) applying the Fmoc strategy. After removal of the Fmoc group attached to the resin with 20% piperidine in DMF (20 min), Fmoc-Tyr(tBu)-OH (230 mg, 0.5 mmol) was introduced with DIC (78 pL, 0.5 mmol) in the presence of HOBt (68 mg, 0.5 mmol) (reaction time 2h). After... 

The helical peptide sequence [I] 59 was prepared on Rink amide resin by Fmoc SPPS with cysteine residues at the N- and C-terminus as described in Section 13.1.2.5.2. Briefly, starting from resin (606 mg, substitution level 0.33 mmol-g 1), the fully protected peptide-resin (1.03 g) was obtained. The fully protected peptide-resin (200 mg) was treated with 1M TMSBr/PhSMe in TFA (10 mL) containing 2% m-cresol and 2% EDT under ice-cooling for 1.5 h, then at 20 °C for 30 min. After precipitation with Et20 (40 mL), lyophilization, purification by Sephadex G-10, and subsequently HPLC, a white fluffy powder was obtained yield 25.5 mg (25% overall) LSI-MS mlz [M + H]+ calcd, 2571.1 found, 2570.7. For the... 

HBTU/HOBt in NMP (1.4 equiv) was used to couple the protected N-terminal fragment (1.2 equiv) to Glull of the resin-bound C-terminal fragment over 24 h. To then cleave the fully assembled protected peptide from the Rink amide resin, reagent K (TFA/PhOH/H20/PhSH/ethylene glycol 82.5 5.5 5 2.5) was used. 

Peptide 35 was synthesized using Fmoc chemistry with Rink amide resin. Deprotection and cleavage were performed by treatment with TFA/EDT/anisole (95 1.25 3.75) for 1.5 h, and the peptide was precipitated with the addition of ice-cold EtjO. The precipitate was dissolved in aq AcOH and purified by preparative RP-HPLC using 0.1% TFA in a H20/MeCN gradient. The purified peptide sequence was confirmed by Edman degradation sequence analysis. FAB-MS analysis gave [M + H]+ 2331.2 Da (calcd 2331.1 Da). 

The synthesis of 1,4-thiazepines from chalcones 184 is also possible on solid support. This has been shown by Lee etal. In an one-step bis-nucleophilic attack of 75, loaded on Wang or Rink amide resin, to the a,[)-unsaturated ketone 184, the seven-membered ring 192 is formed. TFA cleavage afforded more than 29% overall yield (Equation 14) <2001TL109>. 

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