Scavenger resins solution phase synthesis

Solution-phase synthesis [5] often needs purification or clean-up procedures after each reaction step to remove excess reagent. These methods include scavenging, extractions and associated plate transfers. All these procedures cause the loss of the desired compound. Although the purity can be improved after treatment, the chemical yield is seriously compromised. In contrast, SPOS has a unique advantage in purifying bound compound without losing compound mass. However, if the reaction is not complete at each step, the side products will form on resin and they cannot be removed while bound to the resin. The final yield and purity wiU both suffer as a result. A 90% yield for a four-step synthesis wiU produce the final product in a disappointing 65% yield. 

The use of scavenger resins in solution-phase synthesis illustrates a type of procedure that is actually a hybrid between solution-phase and solid-phase methods. The first step of this procedure is clearly a form of solution-phase synthesis since the reactions take place totally within a dissolved state with no solid support provided for any of the reactants. The separation stage of the process occurs only after products have become attached to solid supports—the scavenger resins—from which they may or may not then be removed. 

Because no separation is used, only crude information about the purity of the compounds can be obtained. For example, if unreacted, synthetic starting materials (Fig. 10b) are present in a sample of a combinatorial product (Fig. 10a), these can show up in the mass spectrum of the crude product (Fig. 10c). Because the starting materials are often structurally different from the finished product, a simple extraction can be used after the synthesis to remove much of the unused reactants and obtain a cleaner mass spectrum (Fig. lOd) for a solution-phase product. Conversely, washing the resin after solid-phase synthesis or using a scavenger resin in a solution-phase synthesis can also yield improved purity by removing these excess reactants. When direct flow injection is used to characterize combinatorial libraries, it is best to avoid dimethyl sulfoxide (DMSO) as a solvent, because it interferes with reliable ionization of the analytes. 

Under certain condition, however, reactions are still preferably conducted in solution. This is the case e.g., for heterogeneous reactions and for conversions, which deliver complex product mixtures. In the latter case, further conversion of this mixture on the solid support is not desirable. In these instances, the combination of solution chemistry with polymer-assisted conversions can be an advantageous solution. Polymer-assisted synthesis in solution employs the polymer matrix either as a scavenger or for polymeric reagents. In both cases the virtues of solution phase and solid supported chemistry are ideally combined allowing for the preparation of pure products by filtration of the reactive resin. If several reactive polymers are used sequentially, multi-step syntheses can be conducted in a polymer-supported manner in solution as well. As a further advantage, many reactive polymers can be recycled for multiple use. 

In 2001, Sarko and coworkers disclosed the synthesis of an 800-membered solution-phase library of substituted prolines based on multicomponent chemistry (Scheme 6.187) [349]. The process involved microwave irradiation of an a-amino ester with 1.1 equivalents of an aldehyde in 1,2-dichloroethane or N,N-dimethyl-formamide at 180 °C for 2 min. After cooling, 0.8 equivalents of a maleimide dipo-larophile was added to the solution of the imine, and the mixture was subjected to microwave irradiation at 180 °C for a further 5 min. This produced the desired products in good yields and purities, as determined by HPLC, after scavenging excess aldehyde with polymer-supported sulfonylhydrazide resin. Analysis of each compound by LC-MS verified its purity and identity, thus indicating that a high quality library had been produced. 

Fig. 1. Polymer-assisted solution phase (PASP) synthesis combines the merits of solution-phase chemistry with the advantages of facilitated phase separation by using polymer reagents (a) or scavenger resins (b).

This chapter will cover an overview of recent advances in solid-phase-assisted solution-phase combinatorial synthesis, specifically the use of scavenger resins in assisting in the isolation of pure product without the need for chromatography. In addition, an experimental section has been included. 

One of the most used resins in solid-phase combinatorial organic synthesis, which has found a myriad of applications, is the Merrifield resin (17).61 This resin is also the building block for a tremendous amount of novel resins being developed in combinatorial chemistry with applications in both solid-phase as well as solid-phase-assisted solution-phase combinatorial chemistry. A recent, useful, and novel example is the report of its being employed as a triphenylphosphine scavenging resin.76 During the conversion of azidomethylbenzene (51) into benzylamine, excess triphenyl-phosphine is allowed to react with Merrifield resin (17) in the presence of sodium iodide in acetone. A phosphonium-substituted resin (52) is thus formed. Upon simple filtration, pure benzylamine is isolated as shown in Fig. 22. 

The synthesis of fused alicyclic ft-lactams by the four-center three-component Ugi reaction (U-4C-3CR) on a solid support has been reported. Also, resins have been used as scavengers in the purification of fused /3-lactams prepared in the solution phase <2004MI215>. 

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