Modern separation techniques for the efficient workup in organic synthesis

The shift of paradigm in combinatorial chemistry, from large compound libraries (of mixtures) on a small scale towards defined compound libraries where each compound is prepared in an individual well, has stimulated the search for alternative separation approaches. The key to a rapid and efficient synthesis is not only the parallel arrangement of reactions, but simple work-up procedures so as to circumvent time-consuming and laborious purification steps. During the initial development stages of combinatorial synthesis it was believed that rational synthesis of individual compounds could only be achieved by solid-phase strategies. However, there are a number of problems in solid-phase chemistry: most notably there is the need for a suitable linker unit, the limitation of the reaction conditions to certain solvents and reagents, and the heterogeneous reaction conditions. Further disadvantages are: the moderate loading capacities of the polymeric support and the limited stability of the solid support. In the last few years several new separation techniques have been developed. Depending on the chemical problem or the class of compounds to be prepared, one can choose from a whole array of different approaches. Most of these modern separation approaches rely on solution-phase chemistry, even though some of them use solid-phase resins as tools (for example, as scavengers). Several of these separation techniques are based on liquid-liquid phase separation, including ionic liquids, fluorous phases, and supercritical solvents. Besides being benign with respect to their environmental aspects, they also show a number of advantages with respect to the work-up procedures of organic reactions as well as simplicity in the isolation of products. Another set of separation strategies involves polymeric supports (for example, as scavengers or for cyclative cleavage), either as solid phases or as soluble polymeric supports. In contrast to solid-phase resins, soluble polymeric supports allow reactions to be performed under homogeneous conditions, which can be an important factor in catalysis. At the same time, a whole set of techniques has been developed for the separation of these soluble polymeric supports from small target molecules. Finally, miscellaneous separation techniques, such as phase-switchable tags for precipitation by chemical modification or magnetic beads, can accelerate the separation of compounds in a parallel format.     

Novel non-PEG derived polyethers as solid supports. 2. Solid-phase synthesis studies

Novel non-PEG derived polyether resins, coined SLURPS (Superior Liquid Uptake Resins for Polymer-supported Synthesis), were studied for their performance in solid-phase synthesis. Novel amino functional resins, SLURPS-NH2, were prepared with a loading of up to 8.5 mmol/g and employed successfully in the solid-phase synthesis of Leu-Enkephalin. The peptide was obtained with the same purity when compared to its synthesis with commercial standard poly(dimethyl acrylamide) resins. Furthermore we show loading and cleavage of aromatic carboxylic acids in excellent yield. The advantageous solvent compatibility of our support was demonstrated through the biphasic dihydroxylation of alkenes with OsO4 in t-BuOH/water mixtures producing bound 1,2-diols and synthesis and removal of a bound oxime using ethanol/water mixtures both in excellent yields. Reactions were easily monitored by gel-phase NMR and FTIR. These results show that SLURPS are very well suited for organic transformations using highly polar solvent mixtures and reagents and at much higher loading levels than standard amphiphilic resins of similar solvent compatibility.     

Dendritic polyglycerol as a high-loading support for parallel multistep synthesis of GABA lactam analogues

A general route to 4-substituted azolidin-2-ones (GABA lactam analogues) on a soluble high-loading polyglycerol support has been developed and optimized. These biologically interesting compounds (anticonvulsive drugs) can be synthesized in three steps commencing from a polyglycerol supported (diethylphosphono)acetic acid and a carbonyl compound. The key features of this parallel approach are the cyclative cleavage and simple separation techniques (i.e., dialysis).     

Polystyrene-graft-polyglycerol resins: a new type of high-loading hybrid support for organic synthesis

The preparation of a dendritic graft polymer by a very efficient synthesis of polyglycerol directly on a polystyrene resin is presented. This one-step process can be performed on a multigram scale to provide a chemically stable polymeric support. The resulting hybrid polymers were fully characterized by diverse analytical methods (NMR, IR, ESEM, UV detection of cleaved protecting groups, and mass-spectrometric methods). They combine a high loading capacity (up to 4.3 mmol g(-1)) with good swelling properties in a wide range of solvents (including water), which is the major drawback for many existing solid phase supports. In comparison to the widely employed PEGylated resins, these hybrid materials offer a 10-fold higher loading capacity. Their suitability as supports for organic synthesis and for the immobilization of reagents has been demonstrated. These materials also swell in water, and consequently, it should be possible to use these new hybrid materials for synthesis in protic solvents.     

Facile preparation and reactivity of polystyrene-supported (dichloroiodo)benzene: a convenient recyclable reagent for chlorination and oxidation

A facile one-pot preparation of polystyrene-supported (dichloroiodo)benzene (loading of -ICl₂ up to 1.35 mmol/g) from polystyrene, iodine, and bleach has been developed. This recyclable reagent is useful for efficient chlorination of organic substrates and selective oxidation of various alcohols to the corresponding carbonyl compounds in high yields under mild conditions. The final products are conveniently separated from the polymeric byproduct by simple filtration and isolated in good purity after evaporation of solvent.     

Tailoring ultraresins based on the cross-linking of polyethylene imines. Comparative investigation of the chemical composition, the swelling, the mobility, the chemical accessibility, and the performance in solid-phase synthesis of very high loaded resins

Ultraresins have been prepared from polyethyleneimines and cross-linking molecules and have been provided with various degrees of cross-linking. The total nitrogen loading and the loading with secondary and with tertiary amines have been determined in all products. Nitrogen loadings of the novel resins were up to 15 mmol/g, reactive secondary amines up to 13.8 mmol/g. In addition to the exceptionally high loading, the novel resins displayed efficient swelling volumes in polar and nonpolar solvents. The mobility of resin-bound species as determined by EPR-spectroscopy, depending on the amount of cross-linker, indicated good flexibility and reactivity of this resin type. The novel, high-loaded resins have been investigated subsequently in solid-phase synthesis. The Rink amide linker and two different hydroxy linkers (hydroxyacetamide, HMPB) have been attached to the resin. Despite the high loadings, the secondary amines were easily accessible and could be functionalized exhaustively. Reactivity of the linker-coupled resins was found to be closely related to the resin composition. Increased resin cross-linking led to reduced swelling, reduced mobility, and reduced reactivity in the synthesis of a medium-sized model peptide. As the result of the systematic investigation of structure-property relations in Ultraresins, a support material was identified that combined high reactivity and a mobility in the range of the extremely flexible Tentagel supports. In the optimized Ultraresin, >95% of all available secondary nitrogens could be coupled with Rink linker or with the small 2-hydroxyacetamide anchor, resulting in loadings from 2.7 to 6.8 mmol/g, respectively. A resin with an attached HMPB linker and spacer delivered analytically pure peptides in solid-phase synthesis, fully exploiting the exceptionally high loadings.     

Traceless liquid-phase synthesis of biphenyls and terphenyls using pentaerythritol as a tetrapodal soluble support

Application of a novel sulfonate-based traceless multifunctional linker system using pentaerythritol as a tetrapodal soluble support was demonstrated using liquid-phase parallel and combinatorial preparation of biphenyl and terphenyl compounds. Nickel-catalyzed reactions of pentaerythritol tetrakis(arenesulfonate)s with arylmagnesium bromides generated the desired products in sufficient yields through reductive cleavage/cross-coupling of the C-S bond. Homogeneous pentaerythritol-supported reactions could be accomplished using less nucleophile with shorter reaction periods than could the corresponding heterogeneous polymer-supported reactions. This liquid-phase approach using a small polyfunctionalized support combines advantages of solution-phase and solid-phase syntheses by allowing high reactivity, high atom economy, simple isolation, and real-time monitoring of the reaction progress.     

Versatile soluble oligomeric styrene supports for peptide synthesis

Soluble oligomeric styrene supports are reported here with high loading capacities of 1.5–1.6 mmol/g similar to resins used in solid phase peptide synthesis. Oligoether and alkyl chains are incorporated into the scaffold to improve the support solubility and act as spacers between the attachment sites. Amino acids have been attached to the support in 59–85% yields and 0.87–1.3 mmol/g loading. The supports have been used to synthesize tri‐ to hexapeptides in 38–64% yields using only 2 equivalents of coupling reagents, which is much lower than the amount of reagents typically used in solid phase synthesis. A modular synthetic approach is used to obtain the supports so that any efficient styrene‐based attachment site can be readily incorporated into our soluble support scaffold. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2015 , 53, 2501–2509     

Mixed 1,1-bisphosphorus compounds: synthesis, alkylation, and Horner-Wadsworth-Emmons olefination reactions

Mixed 1,1-bisphosphorus compounds were prepared by the reaction between a phosphonate diester anion and a P(III) chlorophosphine, or its P(V) borane complex. After deprotonation either in situ or in a separate step, the resulting products can be alkylated or reacted with carbonyl compounds. A variety of olefination products were obtained, generally with high E-stereoselectivity. The reaction is competitive with other methods for the synthesis of alkenyl phosphorus compounds, and in the case of trisubstituted alkenes, regio- and stereocontrolled olefination provides products not easily accessible via any other process. The deprotection of phosphine-borane adducts was also demonstrated. Overall, a variety of novel organophosphorus reagents and products were synthesized easily and in good yields.     

Traceless sulfone linker cleavage triggered by ozonolysis: solid-phase synthesis of diverse α-β-unsaturated carbonyl compounds

The highly efficient and convenient protocol to prepare diverse α,β-unsaturated aldehydes, ketones, and acids via the parallel solid-phase synthesis is developed. The key sulfone linker cleavage strategy is performed by ozonolysis to generate a carbonyl moiety followed by base-mediated polymer-bound sulfinate elimination to release our desired molecules from the resin. All α,β-unsaturated carbonyl compounds are prepared in good purities and yields without further purification.     

Ionic liquid supported synthesis of β-lactam library in ionic liquid batch

An efficient and general ionic liquid supported synthesis of cis-β-lactam library via multistep reactions have been successfully carried out in a single ionic liquid batch. The method exhibited the advantages over soluble and insoluble polymeric support strategies, such as high loading capacity, avoiding of large excesses of reagents and easy purification. Also, the products were obtained in good yields and purities.     

Exploring the solid-phase synthesis of 3,4-disubstituted beta-lactams: scope and limitations

This work describes a comprehensive study on the solid-phase synthesis of 3,4-disubstituted beta-lactams. In situ generated ketenes react with immobilized aldimines under mild conditions to generate libraries of beta-lactams in good to very good overall isolated yields. Different commercially available solid supports were studied, with the cost-effective Wang resin proving to be the most effective. The utility of the protocol was also demonstrated by the highly efficient asymmetric versions when homochiral ketenes or homochiral aldimines were used. A practical technique for the preparation of manual solid-phase parallel libraries of biologically interesting beta-lactam compounds, using Mukaiyama's salt as dehydrating agent, is also presented. Reactions were easily monitored by FT-IR and gel-phase 13C NMR using conventional equipment.     

Development of a new traceless aniline linker for combinatorial solid-phase parallel synthesis of rod-shaped liquid crystals with an azomethine linkage

A new traceless linker was developed to synthesize a library of 28 compounds possessing an azomethine linkage using combinatorial solid-phase parallel synthesis. The loading of the substrates on a solid support and cleavage from the solid support were performed by an imine synthesis and by imine-exchanged process in the mild conditions, respectively. Products with a thioester group exhibited liquid crystalline properties with the higher transition temperatures than the others.     

Development of a new traceless aniline linker for solid-phase synthesis of azomethines. Application to parallel synthesis of a rod-shaped liquid crystalline library

A new traceless linker was developed to synthesize a library of 42 compounds possessing an azomethine linkage using combinatorial solid-phase parallel synthesis. The loading of the substrates on a solid support and cleavage from the solid support were performed by an imine synthesis and by imine-exchanged process under mild conditions, respectively. Thioesters with a hydroxy group on the central core exhibited liquid crystalline properties with the widest transition temperatures in the library.     

Stereoselective aza Diels-Alder reaction on solid phase: a facile synthesis of hexahydrocinnoline derivatives

As part of our continuing studies of polymer-supported pericyclic reactions for preparing biologically interesting heterocyclic compounds, we have introduced a traceless solid-phase synthesis of hexahydrocinnolines. We developed a method in which mild reaction conditions can be used for the hetero-Diels-Alder reactions on a polymeric support. The dienoic 3-vinyl-2-cyclohexenol attached to a Wang resin through an ether linkage undergoes [4 + 2] cycloaddition reaction with several azadienophiles. The highly stereoselective Diels-Alder reaction showed preferential formation of a single cycloadduct resulting from an anti attack of the dienophile on the polymer-bound diene. Trifluoroacetic acid-mediated cleavage of the polymer-bound cycloadducts yields fused nonaromatic hexahydrocinnolines in moderate yields in three steps.     

A short synthesis of α-allenic alcohols from α,β-unsaturated carbonyl compounds with dichloromethyl p-tolyl sulfoxide

The reaction of the α-sulfinyl carbanion of dichloromethyl p-tolyl sulfoxide with α,β-unsaturated carbonyl compounds gave 1-chlorocyclopropyl p-tolyl sulfoxides having a carbonyl group in good to high yields. The carbonyl groups in the products were reduced or treated with alkylmetals to give alcohols. Finally, the alcohols were treated with Grignard reagent to give α-allenic alcohols via the rearrangement of the cyclopropylmagnesium carbenoid intermediates, which were generated by the sulfoxide-magnesium exchange reaction, in good to high yields. This procedure provides a new method for a short synthesis of various α-allenic alcohols in two or three steps from relatively easily available α,β-unsaturated carbonyl compounds.     

Electrolysis as an efficient key step in the homogeneous polymer-supported synthesis of N-substituted pyrroles

[reaction: see text]. An efficient and general route to the soluble polymer-assisted synthesis of a set of 14 different N-substituted pyrroles using dendritic polyglycerol as a high-loading support is presented. The transformation of furan to the key intermediate 2,5-dialkoxytetrahydrofuran was performed by electrochemical oxidation followed by catalytic hydrogenation with Pt/C in high yield. Both reactions required heterogeneous reagents which can be conveniently used with polyglycerol as a soluble support.     

A convergent approach to biocompatible polyglycerol "click" dendrons for the synthesis of modular core-shell architectures and their transport behavior

Dendrimers are an important class of polymeric materials for a broad range of applications in which monodispersity and multivalency are of interest. Here we report on a highly efficient synthetic route towards bifunctional polyglycerol dendrons on a multigram scale. Commercially available triglycerol (1), which is highly biocompatible, was used as starting material. By applying Williamson ether synthesis followed by an ozonolysis/reduction procedure, glycerol-based dendrons up to the fourth generation were prepared. The obtained products have a reactive core, which was further functionalized to the corresponding monoazido derivatives. By applying copper(I)-catalyzed 1,3-dipolar cycloaddition, so-called "click" coupling, a library of core-shell architectures was prepared. After removal of the 1,2-diol protecting groups, water-soluble core-shell architectures 24-27 of different generations were obtained in high yields. In the structure-transport relationship with Nile red we observe a clear dependence on core size and generation of the polyglycerol dendrons.     

Macroporous polystyrene-supported IBX amide: the improved oxidative properties in various solvents

In this study, macroporous polystyrene-supported IBX (MPS-IBX) amides were prepared in two simple steps, and the polymeric reagent was then evaluated for its efficiency in converting a range of alcohols to the corresponding carbonyl compounds in various solvents. The results indicated that the MPS-IBX amides were compatible with a variety of solvents, and had a more efficient oxidation activity toward alkyl alcohols than the gel type polystyrene-supported IBX amides. Finally, the resin that was consumed in the oxidation reaction was regenerated to give a restored loading level of 0.44-0.54 mmol/g.     

Parallel synthesis of 3-amino-4H-quinolizin-4-ones, fused 3-amino-4H-pyrimidin-4-ones, and fused 3-amino-2H-pyran-2-ones

On the basis of the enaminone methodology, libraries of 3-amino-4H-quinolizin-4-ones, fused 3-amino-4H-pyrimidin-4-ones, and fused 3-amino-2H-pyran-2-ones were synthesized by the solid-phase and by the solution-phase parallel synthesis. The solution-phase approach turned out to be advantageous over the solid-phase approach. The solution-phase synthesis afforded, in most cases, analytically pure products in high yields, whereas the solid-phase approach gave products in poor yields and in low purity.