Functionalized cross-linked poly(vinyl alcohol) resins as reaction scavengers and as supports for solid-phase organic synthesis

New hydrophilic poly(vinyl alcohol) (PVA-OH) resins were prepared by an inverse suspension polymerization using epichlorohydrin as a cross-linker. These novel resins swell in a variety of solvents commonly used in solid-phase organic synthesis, such as dicholomethane, dioxane, methanol, tetrahydrofuran, and dimethylformamide. In addition, PVA-OH shows excellent swelling in water. The cross-linked PVA-OH beads were functionalized with an aldehyde group and were tested as scavengers for primary amines in three different reactions: amide bond formation, reductive amination reaction, and urea formation. With 1-2 equiv of the PVA aldehyde resin, all the excess primary amines were successfully scavenged. The utility of PVA-OH resins as solid supports in mono- and dipeptide synthesis was also investigated using symmetrical anhydride and MSNT/MeIm (2,4,6-mesitylenesulfonyl-3-nitro-1,2,4-triazolide in the presence of 1-methylimidazol) methods.     

Polystyrene resins cross-linked with di- or tri(ethylene glycol) dimethacrylates as supports for solid-phase peptide synthesis

Polystyrene resins cross-linked with di(ethylene glycol) dimethacrylate (DEGDMA) and tri(ethylene glycol) dimethacrylate (TEGDMA), DEGDMA-PS and TEGDMA-PS, were synthesized by suspension copolymerization. Four functionalized resins, chloromethyl resin, 4-hydroxymethylphenoxymethyl resin (Wang resin), 4-methylbenzhydrylamine resin (MBHA resin) and 2-chlorotrityl chloride resin, were prepared from DEGDMA-PS and TEGDMA-PS. DEGDMA-PS and TEGDMA-PS showed high reactivity in the functionalization reactions in comparison with Merrifield resin (polystyrene cross-linked with divinylbenzene, DVB-PS). DEGDMA-PS-Wang resin and TEGDMA-PS-Wang resin were used as the solid-phase support for the synthesis of a difficult sequence, the fragment of acyl carrier protein 65-74. The yields of the crude peptide synthesized using DEGDMA-PS-Wang resin, TEGDMA-PS-Wang resin and DVB-PS-Wang resin were 92.3%, 91.6% and 78.8%, respectively. The purities of the crude peptides were 85.7%, 88.1% and 73.3%, respectively.     

Core-shell-type resins for solid-phase peptide synthesis: comparison with gel-type resins in solid-phase photolytic cleavage reaction

[reaction: see text] Novel core-shell-type resins with a rigid core and amino-functionalized flexible shell were prepared with 2,4,6-trichloro-1,3,5-triazine (CNC) and Jeffamine ED-600 starting from 1% cross-linked aminomethyl (AM) polystyrene resins. All of the amino groups were located outside the resin beads, and the loading capacity was 0.2-0.4 mmol/g. The amount of CNC treated was a determining factor in the properties of the final resins. The core-shell-type resins showed superior performances in terms of the initial loading of amino acid and the photocleavage reaction compared to the gel-type resins.     

Colorimetric tools for solid-phase organic synthesis

One of the unresolved problems of solid-phase organic synthesis (SPOS) is the availability of general and rapid methods to monitor the transformation of functional groups present in molecules supported on insoluble supports. Color tests, far from providing the ultimate solution, may help in detection (and sometimes in quantification) of different functional groups. In this short review, we have collected most of the methods available and applied in SPOS with an Experimental Section that describes the procedure we have successfully applied to bead analyses in our laboratories.     

Ionic liquid incorporated polystyrene resin for solid-phase peptide synthesis

Ionic liquid (IL) resins with an ionic liquid environment on solid support were prepared by immobilizing ionic liquid spacers on polystyrene (PS) resin. The properties of IL resins were dramatically changed as the anions of IL were exchanged. The performance of IL resins for solid-phase peptide synthesis (SPPS) was evaluated by measuring coupling kinetics of the first amino acid and synthesizing several peptides on IL resins.     

New stable backbone linker resins for solid-phase peptide synthesis

[reaction: see text] Two new 4-methoxybenzaldehyde backbone linker resins were developed for the solid-phase synthesis of peptides. The linkers are very stable during the cleavage of common protecting groups for amines (Fmoc, Boc) and carboxylic acids (Me, All, tBu) in peptide synthesis. Cleavage from the resin with refluxing TFA is sufficiently mild for peptides containing polar and nonpolar amino acids.     

Gel-phase 19F NMR spectral quality for resins commonly used in solid-phase organic synthesis; a study of peptide solid-phase glycosylations

The spectroscopic properties for seven different commercial resins used in solid-phase synthesis were investigated with (19)F NMR spectroscopy. A fluorine-labeled dipeptide was synthesized on each resin, and the resolution of the (19)F resonances in CDCl(3), DMSO-d(6), benzene-d(6) and CD(3)OD were measured with a conventional NMR spectrometer, i.e. without using magic angle spinning. In general, resins containing poly(ethylene glycol) chains (ArgoGel, TentaGel and PEGA) were found to be favorable for the (19)F NMR spectral quality. Three serine containing tri-, penta-, and heptapeptides were then prepared on an ArgoGel resin functionalized with a fluorine-labeled linker. The resin bound peptides were glycosylated utilizing a thiogalactoside glycosyl donor carrying fluorine-labeled protective groups. Monitoring of the glycosylations with gel-phase (19)F NMR spectroscopy allowed each glycopeptide to be formed in similar 80% yield, using a minimal amount of glycosyl donor (3 x 2 equivalents). In addition, it was found that the glycosylation yields were independent of peptide length.     

Reporter resins for solid-phase chemistry

[reaction: see text] An analytical construct resin, designed to aid the analysis of solid-phase chemistry, has been mixed in a small proportion with a conventional resin. The analytical construct ("reporter resin") contains two orthogonal linkers that allow cleavage of either the synthetic intermediates (at linker 2) or their analytically enhanced derivatives (at linker 1). The convenient and rapid monitoring of each step in the syntheses of representative library compounds was possible using small resin aliquots.     

A 'triflate-like' tetrafluoroarylsulfonate linker for multifunctional solid-phase organic synthesis

An arylsulfonate solid-phase linker is suitable for 'traceless' synthesis and Pd(0) catalyzed cross-coupling reactions.     

Cation-exchange resins and non-ionic cross-linked polymers in analysis of aqueous solutions for organic contaminants

Cyclohexane derivatives with a hydroxyl or carboxylic acid group separated by one or two methylene groups from the ring are, in acidified aqueous solution, adsorbed more strongly than the corresponding aromatic compounds both on sulfonated styrene—divinylbenzene resins and on non-ionic styrene—divinylbenzene resins. These observations and the lower temperature dependence observed for the cyclohexane derivatives indicate that hydrophobic interactions have a marked influence on the adsorption. Possible losses of non-ionic compounds by adsorption on cation-exchange resins and by leakage through columns packed with non-ionic resins used for concentration of organic compounds are discussed.     

A chiral cyclohexanone linked to polystyrene for solid-phase synthesis of chiral alpha-carbonyls

Two chiral cyclohexanones were linked to polystyrene resin. The polymer-bound auxiliaries were subjected to a sequence of four reactions, the last of which cleaves the desired alpha-chiral carbonyl compound off the resin, concurrently regenerating the resin-bound auxiliary in its original form. The resin can then be reused.     

Phenolic resins for solid-phase peptide synthesis: Copolymerization of styrene and p-acetoxystyrene

Details are given of the synthesis and purification of p-acetoxystyrene and its solution and suspension copolymerization with styrene. Reactivity ratios, evaluated by the Tidwell-Mortimer method, were r₁ (p-acetoxystyrene) = 1.18, and r₂ (styrene) = 0.88 for (bulk) solution copolymerization. Corresponding values of the reactivity ratios for suspension copolymerization were, within experimental error, indistinguishable from unity. Thus the copolymer composition is governed simply by the monomer feed composition. Use of a specially designed reactor vessel permits convenient suspension copolymerization of styrene, p-acetoxystyrene, and divinylbenzene to give crosslinked resins having comparatively narrow particle size distributions. Acetoxy groups in the crosslinked resin are cleaved by hydrazine hydrate under very mild conditions to give crosslinked polystyrenes having phenolic groups which, in turn, provide a useful alternative to the more usual chloromethylated polystyrene resins for solid-phase peptide synthesis.     

Research on gamma-ray irradiation-assisted synthesis of cross-linked polystyrene via bulk polymerization

Journal of Radioanalytical and Nuclear Chemistry - Controlling heat accumulation is one of the major challenges for block materials synthesizing via bulk polymerization. In the paper, cross-linked...     

Chemically modified resins for solid-phase extraction

The packings most widely used for solid-phase extraction are hydrophobic and make poor surface contact with aqueous samples unless the resins are first treated with an activating organic solvent such as methanol. Insertion of an acetyl- or hydroxymethyl group into a porous polystyrene-divinylbenzene resin provides a more hydrophilic surface that is easily wetted by water alone. Small columns of the chemically modified resins were found to be very efficient for the solid-phase extraction of many types of organic solutes from aqueous samples. Comparative recovery studies showed that the modified resins are superior to both silica packings and unmodified organic resins for the solid-phase extraction of organic compounds, and especially for polar organics such as phenols.     

A convenient procedure for the solid-phase synthesis of hydroxamic acids on PEGA resins

An efficient method for the solid-phase synthesis of hydroxamic acids is described. The method comprises the nucleophilic displacement of esters immobilized on PEGA resins with hydroxylamine/sodium hydroxide in isopropanol. The hydroxyaminolysis protocol is compatible with a broad range of PEGA-supported peptide and peptidomimetic esters. The methodology was found to be compatible with two new strategies for the synthesis of solid-supported lactams and diketopiperazines, respectively, both relying on the high inter- and intramolecular reactivity of cyclic N-acyliminium ions with electron-rich aromatics and heteroaromatics, ultimately affording hydroxamic acid derivatives in high purities.     

Diversity-oriented synthesis and solid-phase organic synthesis under controlled microwave heating

Diversity-oriented organic synthesis (DOS) and solid-phase organic synthesis (SPOS) are proven technologies for generating small molecule libraries for chemical genetics studies. Integration of controlled microwave heating with DOS and SPOS not only speeds up the library preparation process but also offers unique opportunities in tackling issues which are hardly addressed by thermal heating. Microwave-assisted synthesis is illustrated for (a) highly regioselective Wittig olefination of cycloalkanones by accurate regulation of temperature; (b) tandem Wittig-IMDA sequence toward stereochemical diversity of gamma-butyrolactones; (c) one-pot alkylation-amidation approach toward appendage diversity through use of building blocks; and (d) one-pot U-4CR-annulation strategy toward skeletal diversity via careful reaction design. Microwave-assisted solid-phase organic synthesis (MASPOS) is highlighted by incorporating with split-pool combinatorial synthesis (SPCS) of indole sulfonamides via a key on-resin Cu(II)- or Pd(II)-catalyzed heteroannulation under microwave heating. Design and fabrication of a novel diglycine-derived catlinker are described and its role in facilitating on-resin reaction is evaluated. A traceless synthesis of indole sulfonamides via microwave-assisted Cu(II)-catalyzed heteroannulation of the catlinker-tethered substrates is also given.     

Deazapurine solid-phase synthesis: construction of 3-substituted pyrrolo[3,2-d]pyrimidine-6-carboxylates on cross-linked polystyrene bearing a cysteamine linker

The first solid-phase methodology for the preparation of pyrrolo[3,2-d]pyrimidines is presented. Merrifield resin bearing a cysteamine "traceless" linker was treated with 4-oxo-N-(PhF)proline benzyl ester (10; PhF = 9-(9-phenylfluorenyl)) to provide resin-bound aminopyrrole 20, which was treated with ethyl, phenyl, 4-phenoxyphenyl, and 2,4-dimethoxyphenyl isocyanates to furnish resin-bound ureidopyrroles 21a-d. Resin-bound pyrrolo[3,2-d]pyrimidines 22a-d were then obtained by acylation of 21 using trichloroacetyl chloride in dioxane followed by treatment with Cs2CO3 in DMF. Cleavage of pyrrolo[3,2-d]pyrimidines 22a-d from the resin was achieved in two steps, by oxidation of the sulfur to the sulfone followed by beta-elimination in the presence of t-BuONa. Four pyrrolo[3,2-d]pyrimidines, 24a-d, with different alkyl and aryl substituents at the N3 pyrimidine nitrogen, were thus obtained in overall yields of 42-50% and purities of 90-100%.     

An acid-stable tert-butyldiarylsilyl (TBDAS) linker for solid-phase organic synthesis

[reaction: see text] A new, robust tert-butyldiarylsilyl (TBDAS) linker has been developed for solid-phase organic synthesis. This linker is stable to both protic and Lewis acidic reaction conditions, overcoming a significant limitation of previously reported silyl linkers. Solid-phase acetal deprotection, olefination, asymmetric allylation, and silyl protecting group deblocking reactions have been demonstrated with TBDAS-linked substrates.     

The sulfamate functional group as a new anchor for solid-phase organic synthesis

[reaction: see text] Sulfamate derivatives were loaded on trityl chloride resin, and two variants of cleavage were developed for this sulfamate anchor: an acid treatment to easily restore the free sulfamate and a nucleophilic treatment to generate the corresponding phenol. In addition to loading/cleavage assays and stability experiments, a model sequence of reactions was performed with the new sulfamate anchor to show its applicability in further combinatorial solid-phase synthesis of libraries of biologically relevant sulfamate derivatives.     

Resin capsules: permeable containers for parallel/combinatorial solid-phase organic synthesis

A resin capsule is a permeable container for resin beads designed for multiple/combinatorial solid-phase organic synthesis. Resin capsules consist of a high density polyethylene ring sealed with peek mesh on both sides. The cylindrical shape of resin capsules enabled space-saving packing into plastic columnlike reaction vessels commonly used for solid-phase organic synthesis. Resin capsules have been evaluated for their use in combinatorial synthesis, and a set of model compounds with excellent purity was prepared.