Rink Amide Resin Research Articles

Palladium-Catalyzed α-Arylation of Ketones on Solid Support

The authors have reported the palladium-catalyzed α-arylation of ketones on solid phase using modified Buchwald-Hartwig reaction conditions. Immobilized 4-bromobenzamide 1, which was prepared from polystyrene Rink amide resin, reacted with various aromatic, heteroaromatic, and aliphatic ketones in the presence of 20 mol% Pd2(dba)3 and 80 mol% BINAP as catalyst and an excess of NaOt-Bu as base to form the corresponding coupling compounds 2. Subsequent cleavage from the Rink amide resin was carried out with trifluoroacetic acid in dichloro­methane to give the desired α-aryl ketones 3 in moderate to high yield and good to excellent purity.

Proteomics analysis of a novel compound: Cyclic RGD in breast carcinoma cell line MCF-7

In studies of cell adhesion, migration, growth, differentiation, and apoptosis, synthetic peptides containing the RGD (Arg-Gly-Asp) motif have been extensively used as the inhibitors of integrin-ligand interactions. The RGD motif is an integrin-recognition motif found in many ligands, so that the RGD-containing peptides can be used to probe integrin functions in various biological systems. A linear RGD is a tripeptide consisting of a flexible structure that makes the motif bind to its receptor with inefficient chelating affinity. Therefore, we designed a cyclic-RGD peptide (Tpa-RGDWPC, cRGD) with rigid skeleton to closely bind with its receptor. The cRGD was obtained by solid-phase peptide synthesis method using Rink amide resin. We showed that the cRGD exerts more potency than linear RGD on inhibiting cell growth of MCF-7 breast carcinoma cells. This stimulated us to question how cRGD inhibits cell growth of MCF-7 cells. Moreover, understanding what molecular mechanism underlies the effect that RGD motif exerts on MCF-7 cells is also of considerable importance. We used proteomics and bioinformatics to survey the global changes in proteins after cRGD treatment in MCF-7 cells. The classification of these proteins is shown according to the different biological processes in which they are involved. Most of the proteins that appear to be strongly influenced by cRGD treatment are involved in metabolism, cell growth, responsive to external stimulus, cell communication, reproduction and cell death. This is the first report which monitors the protein expression profile of MCF-7 cells in response to treatment with RGD-containing peptides in a time-course analysis. The clustering data indicated temporal patterns of altered protein expression that can be categorized into early, intermediate and late response proteins. These patterns of protein expression may be important for predicting its response to cRGD. In summary, these results provide a molecular explanation for the properties of cRGD in breast cancer cells and present a valuable in-depth description of their possible impact on breast cancer therapy.

Efficient Remote Axial-to-Central Chirality Transfer in Enantioselective SmI2-Mediated Reductive Coupling of Aldehydes with Crotonates of Atropisomeric 1-Naphthamides

Control of enantioselectivity by remote amide conformation has been studied in SmI2-mediated reductive coupling of aldehydes with the crotonates possessing different 2-substituted 8-methoxy-1-naphthamides. The enantiomers of atropisomeric 8-methoxy-1-naphthamides were prepared through a chemical resolution process, and their absolute stereochemistry was determined by X-ray crystal structural analysis. It was found that the linkage between crotonate and the C2 position of 8-methoxy-1-naphthamides remarkably influenced the efficiency of remote chirality transfer originated from the amide conformation. Among the four crotonates examined, the one derived from 2-hydroxy-8-methoxy-1-naphthamide reacted with pentanal to afford the highest ee of > 99% for the cis-gamma-butyrolactone and in 90% combined yield with a cis/trans ratio of 90:10. We developed a new procedure for attaching the chiral crotonate via the C8 oxygen to a Rink amide resin under mild conditions and obtained the same level of highly remote axial-to-central chirality transfer in the solid-phase reaction.

C-terminalN-alkylated peptide amides resulting from the linker decomposition of the Rink amide resin. A new cleavage mixture prevents their formation

Decomposition of the resin linkers during TFA cleavage of the peptides in the Fmoc strategy leads to alkylation of sensitive amino acids. The C-terminal amide alkylation, reported for the first time, is shown to be a major problem in peptide amides synthesized on the Rink amide resin. This side reaction occurs as a result of the Rink amide linker decomposition under TFA treatment of the peptide resin. The use of 1,3-dimethoxybenzene in a cleavage cocktail prevents almost quantitatively formation of C-terminal N-alkylated peptide amides. Oxidized by-product in the tested Cys- and Met-containing peptides were not observed, even if thiols were not used in the cleavage mixture.

Subtilisin‐Catalyzed Glycopeptide Condensation

AbstractFor Abstract see ChemInform Abstract in Full Text.

Trifluoroacetic Anhydride-Mediated Solid-Phase Version of the Robinson−Gabriel Synthesis of Oxazoles

A traceless solid-phase synthesis of oxazoles 4 via Robinson-Gabriel reaction of solid-supported alpha-acylamino ketones 2 has been achieved. The reaction requires that the cyclization precursor be linked to a benzhydrylic-type linker (compounds 2) and that trifluoroacetic anhydride be used as the cyclodehydrating agent. The solvent has a dramatic effect on the latter reaction, which goes to completion and follows a cyclative-type mechanism only when an ethereal solvent is used. Different synthetic routes have been investigated toward assembling compounds 2. The most straightforward one, which we have validated more extensively, comprises the reaction of Merrifield alpha-methoxyphenyl (MAMP) resin with an alpha-amino ketone to form compounds 1, which are, in turn, acylated. Other methodologies and strategies allowing for the synthesis of compounds 1 that have been investigated include direct alkylation of Rink amide resin; reductive amination of the latter with alpha-keto aldehydes; reaction of MAMP resin with alpha-amino alcohols, followed by oxidation; and protection of Rink amide resin with either 2,4-dinitrosulfonyl or allyl group, followed by alkylation and removal of protecting group. In addition, we disclose a novel variant of the Ugi four-component reaction that allows for the preparation of compounds 2 in a single synthetic step.

Preparation of a novel polystyrene-based urea resin

A urea-functionalized polystyrene-resin with a Rink linker was prepared by adaptation of a solution-phase synthesis to solid-phase chemistry. Thereby, a resin-bound acylurea was formed by reacting a Rink-amide resin with trichloroacetyl isocyanate, followed by the thermal removal of the trichloroacetyl group and thus generating the unsubstituted solid-supported urea.

Solid-Phase Synthesis of Arginine-Containing Peptides and Fluorogenic Substrates Using a Side-Chain Anchoring Approach

Attachment of an amino acid to a solid support by its side chain is sometimes necessary to take advantage of an alpha-carboxylic group available for diverse modifications, including the incorporation of a fluorophore for the preparation of fluorogenic substrates. In contrast to most other amino acids, anchoring the guanidinium group of an arginine to a resin requires the use of a supplementary linker. To avoid the usually multistep synthesis of such a linker as well as its difficult attachment to the guanidine group, we developed a simple method where the guanidine group is built on a Rink amide resin. Our strategy followed the steps of guanidine formation: (i) addition of an isothiocyanate derivative of ornithine to the amino group of a solid support, yielding Nomega-linked thiocitrulline; (ii) S-methylation of thiourea; (iii) guanidinylation using ammonium acetate. Cleavage of the resin generated the arginine-containing compound, the amine group of the resin becoming part of the guanidine. We have demonstrated the usefulness of this method by the synthesis of a series of fluorogenic substrates for trypsin-like serine proteases, which were obtained in high yield and purity. Then, our strategy also allowed generation from the same precursor differentially substituted arginine derivatives, including Nomega-methyl- and Nomega-ethylarginines. The ability to prepare such analogues together with the intermediates thiocitrulline and S-methylisothiocitrulline from a unique precursor while the alpha-amine and carboxylic groups remain available for modification also makes this method a powerful tool for combinatorial solid-phase synthesis of NO synthase inhibitors.

Synthesis of tripeptides containing a very crowded α,α-disubstituted glycine with pyridine rings by solid-phase Ugi reaction

Tripeptides containing a novel α,α-disubstituted glycine with two pyridine rings, α,α-di(2-pyridyl)glycine (2Dpy), were synthesized by the solid-phase Ugi reaction using di(2-pyridyl)methanimine attached directly to a Rink amide resin. Thereby, yields of the tripeptides, Z-AA 1-2Dpy-AA 3-OMe (AA 1 and AA 3 = Gly or Aib), were markedly improved, compared with yields by the solution method.

Solid-phase synthesis and spectral properties of 2-alkylthio-6H-pyrano[2,3-f]benzimidazole-6-ones: a combinatorial approach for 2-alkylthioimidazocoumarins.

The solid-phase synthesis of 2-alkylthio-6H-pyrano[2,3-f]benzimidazole-6-ones (2-alkylthioimidazocoumarins) is described. 7-Fluoro-4-methyl-6-nitro-2-oxo-2H-1-benzopyran-3-carboxylic acid was coupled to Rink amide resin via its carboxyl group. The resin-bound scaffold then underwent aromatic nucleophilic substitution with primary amines, followed by reduction of the nitro group with tin (II) chloride. Subsequent cyclization of the o-dianilino intermediates with thiocarbonyldiimidazole (TCD) afforded resin-bound 1,3-dihydro-2-thioxo-6H-pyrano[2,3-f]benzimidazole-6-ones, which were then S-alkylated with alkyl halides in the presence of N,N-diisopropylethylamine (DIEA). The desired products were obtained in good yield with high purity after trifluoroacetic acid cleavage. The unique spectral properties of 2-alkylthioimidazocoumarins indicate that they may be useful in photodynamic therapy.

Subtilisin-catalyzed glycopeptide condensation.

This method describes the use of subtilisin-catalyzed peptide condensation to form a 15-residue glycopeptide from two smaller synthetic peptides. A 12-residue peptide ester is synthesized by solid-phase peptide synthesis using a PAM-modified Rink amide resin that allows the formation of a peptide ester suitable for subtilisin ligation. The 12-residue acyl donor peptide ester is then ligated to a 3-residue acyl acceptor glycopeptide amide using subtilisin (EC 3.4.21.62) in a buffered mixture of water and DMF (1:9).

Solid‐Phase Synthesis of N‐Aryl‐N′‐Carboalkoxy Guanidines by the Mitsunobu Reaction of Fmoc‐Guanidines

A new method for the solid‐phase synthesis of N‐aryl‐N′‐carboalkoxy guanidines is described. Aromatic amines were reacted with Fmoc‐isothiocyanate to provide Fmoc‐thioureas, which were coupled with Rink amide resin to provide the corresponding resin‐bound Fmoc‐guanidines. Subsequent Mitsunobu alkylation with a variety of alcohols delivered N‐aryl‐N′ carboalkoxy guanidines in good to high purity after resin cleavage.

Combinatorial synthesis of a small-molecule library based on the vinyl sulfone scaffold.

[reaction: see text] A 30-member library of small molecules based on the vinyl sulfone scaffold was prepared on rink amide resin, using solid phase-based reactions such as oxidation and Horner-Wadsworth-Emmons reaction. The library was designed such that three points of diversity were readily introduced in the library to accommodate the S(1)', S(1), and S(2) binding pockets of different cysteine proteases, making the strategy suitable for high-throughput generation of potential cysteine protease inhibitors.

Solid Phase Synthesis of 3‐Toluenesulfonylglutarimides

AbstractA novel route for the synthesis of 3‐toluenesulfonylglutarimides on a solid support is described. The cyclization step involves stepwise [3+3] strategy of Rink Amide resin bound onto an α‐toluenesulfonyl group with various α,β‐unsaturated esters.

A new and efficient multicomponent solid-phase synthesis of 2-acylaminomethylthiazoles

A new multicomponent reaction (MCR) for the preparation of 2-substituted thiazole libraries using Rink amide resin is described. Thiazoles are assembled in a one-pot MCR of a thiocarboxylic acid, aldehyde, 3-( N, N-dimethylamino)-2-isocyanoacrylate with a resin-bound primary amine. Aliphatic and aromatic thiocarboxylic acids as well as aliphatic and (hetero-) aromatic aldehydes work in the reaction. Cleavage of the product yields the substituted thiazoles in reasonable to good purity.

Catalytic peptide dendrimers.

Enzyme catalysis is made possible by the folding of linear peptide chains into well-defined three-dimensional structures. The aim of de novo enzyme design is to create selective catalysts through the catalytically productive combination of amino acids.[1] A variety of a-helical peptides have been designed that are catalytically active.[2] Thus, the spatial proximity of amino acid side chains placed one turn apart in an a helix were shown to induce catalysis. Protected b-turn peptides have been found to be selective catalysts in organic solvents.[3] Such approaches have required the linear peptides to form a properly folded structure for catalysis to be observed. Alternatively one can design three-dimensional structures by chemical synthesis using a dendrimeric architecture, which enforces a globular shape by steric crowding and therefore obviates the folding requirement and greatly simplifies design.[4] Whereas catalytic dendrimers based on ether linkages and incorporating catalytically active subunits such as metal complexes and cofactors are known,[5] peptide dendrimers have to date only been reported as antigendisplay units (multiple antigenic peptides)[6] or in structural studies.[7] Herein we report the preparation of the first catalytic peptide dendrimers. The peptide dendrimers exhibit enzymelike kinetic properties, including selective substrate binding and rate acceleration in aqueous media. We prepared dendrimeric peptides with the sequence ((CapCONH-A)2BA)2B-Cys-A-NH2 (Scheme 1). The symmetrical, achiral diamino acid (1,3-diaminoisopropyloxy)acetic acid was chosen as the branching unit B, which provides the dendrimeric architecture. The sequences were terminated by acylation with the 3-dimethylaminoisophthaloyl group (= Cap, introduced as the mono-tert-butyl ester), which provided a spectroscopic signature and allowed the homogeneous solubility of the dendrimers under both the acidic conditions of HPLC purification and the neutral conditions of aqueous buffers. Permutations of the catalytic triad of the amino acids histidine (His), aspartate (Asp), and serine (Ser) were chosen as the variable positions A1, A2, and A3 to generate a family of esterolytic peptide dendrimers. The solid-phase peptide synthesis was carried out on a Rink amide resin with Fmoc-

Solid support synthesis of 2,4-disubstituted thiazoles and aminothiazoles

3-Iodobenzoic acid was loaded on Rink amide resin. Pd(0) coupling reaction with tributyl(1-ethoxyvinyl)tin followed by bromination using NBS gave an α-bromoketone bound to a solid support. Condensation of thioamide or thiourea, followed by TFA cleavage from the resin, gave 2,4-disubstituted thiazoles or 2-aminothiazoles, respectively. The primary amine of aminothiazole was treated with various acyl or sulfonyl chlorides to provide 2-substituted thiazole analogs.

Traceless solid-phase synthesis of 1,2,4-triazoles using a novel amine resin.

[reaction: see text]. A solid-phase route to 5-aryl-3-arylthiomethyl-1,2,4-triazoles has been developed that permits the incorporation of two elements of diversity. The heterocycle was constructed upon a novel 4-benzyloxy-2-methoxybenzylamine (BOMBA) resin, from which traceless cleavage could be effected with dilute TFA. A library of 96 triazoles was produced with an average yield of 26% (84% yield per step) and an average purity of 80%. In a direct comparison, the new BOMBA resin proved to be markedly superior to Rink Amide resin for this application.

A simple solid-phase synthesis of disubstituted guanidines using Rink amide resin as an amine component

A practical solid-phase synthesis that simply uses Rink amide resin as an amine component in reacting with aromatic isothiocyanates and aliphatic amines to generate disubstituted guanidines is described. No special linker or guanylation reagents are involved in this method. The product is obtained in a ‘traceless-linker’ fashion and in high yield and purity when an electron-deficient isothiocyanate is employed.

Mass spectrometry analysis for the determination of side reactions for cyclic peptides prepared from an Fmoc/t}Bu/Dmab protecting group strategy

The Association of Biomolecular Resource Facilities (ABRF) Peptide Synthesis Research Group (PSRG) proposed for their annual study that laboratory members prepare cyclo(Tyr-Glu-Ala-Ala-Arg-DPhe-Pro-Glu-Asp-Asn) according to the following synthetic pathway: (i) side-chain anchoring Fmoc-Asp(OH)-ODmab to a Rink amide resin; (ii) linear assembly; (iii) Dmab and Fmoc removal, respectively; (iv) on-resin cyclization with an uronium-based coupling reagent; (v) final cleavage/deprotection with TFA. Based upon this protocol, a variety of side-products were identified:(i) N-terminal guanidine formation; (ii) C-terminal piperidyl amide formation; and (iii) a novel C-terminal benzyl amide-guanidine derivative that formed due to a chemical reaction between the Dmab protecting group and the uronium-based coupling agent. The elemental composition and subsequent structure determination of this unexpected derivative was established by tandem mass spectrometry, i.e. low energy collision-induced dissociation experiments with fragment mass determination within 5 ppm.