Rink’s amide

Brown EG, Nuss JM. Alkylation of Rink s amide linker on polystyrene resin a reductive amination approach to modified amine-linkers for the solid phase synthesis of /Y-substiuited amide derivatives. Tetrahedron Lett 1997 38 8457-8460. 

Scheme 14 shows a typical example in a series of reactions in which a supported amino acid reacted with fluorenylmethoxycarbonyl isothiocyanate to give a supported (on Rink s amide)35 thiourea.36 Removal of the protection followed by 5-alkylation gave supported isothioureas. Reaction of these with amines, then cleavage from the resin, afforded substituted guanidines. For 10 examples the purities were between 40 and 92%. An aryl group separates the resin from the guanidine, just as in the sequences shown in Schemes 11 and 12. 

The same combination of reagents (TMSOTf/2,6-lutidine) has been employed to deprotect (V-ferf-butoxycarbonyl groups from substrates in the solid phase synthesis of several peptides, without cleaving the substrates from the support as would occur in the case of using TFA with TFA-sensitive resins (such as Rink s amide resin) (eq 100). This method has great potential for the solid-phase synthesis of small molecule libraries. Such a reagent combination had been previously developed for solution phase reactions of nonpeptidic substrates. ... 

Brol997a Brown, E.G. and Nuss, J.M., Alkylation of Rink s Amide Linker on Polystyrene Resin A Reductive Amination Approach to Modified Amine-Linkers for the Solid Phase Synthesis of N-Substituted Amide Derivatives, Tetrahedron Lett., 38 (1997) 8457-8460. 

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

Experimenter s notes The same procedure can be used to attach the sugar to Rink amide resin for Fmoc-based synthesis. The Rink amide resin must be deprotected as usual before coupling of the sugar. 

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. 

Via Heck reactions Resins/ linkers used Rink amide, Wang and Tentagel S-OH Several Pd catalysts investigated. 

Chloromethyl resin Wang resin 2-Chlorotrityl resin Rink amide resin Kaiser oxime resin TentaGel S RAM... 

Chlorotrityl resin Rink amide resin Hydroxymethl resin Sasrin resin TentaGel S PHB... 

Cleavage, nonstandard Aminomethyl resin Chloromethyl resin Benzoic acid resin Hydroxymethyl resin Rink amide resin Wang resin PAL amide resin MBHA resin Kaiser oxime resin REM resin TentaGel S OH TentaGel S PHB Spheron Ara 1000 ... 

Microwave heating has been used as a tool for the generation of a library of 625 peptoids (Scheme 4.18). The method, involving the synthesis of Af-alkylglycine oligomers, used a set of 10 commercially available primary amines as a source of chemical diversity. The synthetic steps wae carried out in teabags. The overall synthetic strategy involved an initial room temperature deprotection of Fmoc-protected Rink amide resin. This was followed by five repetitive acylation (35 °C for 30 s) and amination (90 °C for 90 s) steps in the microwave unit. Two sublibraries were... 

Trautwein and co-workers described an efficient method for the solid-phase s thesis of TV-substituted pyrroles, including tetrasubstituted pyrroles. Highly substituted pyrroles are functional components of compounds such as atorvastatin (Lipitor), an HMG-CoA reductase inhibitor used for lowering cholesterol. Reaction of p-ketoamides 29, prepared from polymer bound acetoacetamide using a series of primary amines in trimethylorthoformate (not shown), with a-bromoketone derivatives 30 in the presence of 2,6-di-tertbutylpyridine (DTBP) and DMF yielded pyrroles 31 with diverse functionality in high purity. The authors found that polystyrene Rink amide resin was the best solid support because it was able to withstand the acetoacetylation conditions required to produce the polymer bound acetoacetamide. 

Starting from scaffold 178 linked to Rink amide resin, two libraries of psolaren analogs (181 and 182) were prepared from a common o-dianilino intermediate 180. The benzoimidazole ring of psolaren analogs 181 was formed upon treatment of 180 with aryl isothiocyanates in the presence of Die, whereas for analogs 182 cyclization was carried out with l,T-thiocarbonyldiimidazole (TCD) followed by S-alkylation with alkyl hahdes in the presence of Af,Af-diisopropylethylamine. The unique spectral properties of these coumarin derivatives indicated that they may be useful in photochemotherapy. 

Scheme 12.7 Formation of amide 11 using 0,S-protected, 3-dithio-2-hydroxypropionic acid and Rink resin...

TentaGel S with Fmoc-Rink amide linker, loading 0.23 mmol/g (Rapp Polymere GmbH, Tubingen, Germany). 

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