Resin-capture approach

In contrast to this method, another PASP strategy, known as the resin-capture approach, makes use of resins that transiently sequester solution-phase products, allowing solution-phase reactants, reagents, and by-products to be filtered from the resin-bound products. The products are subsequently released from the sequestering resin to afford the desired purified solution-phase products (Scheme 18). 

Another resin-capture approach has been pubhshed in relation to the synthesis of tetrasubstituted ethylenes via Suzuki coupling reactions (Scheme 20) [42, 53]. A 25-member hbrary was synthesized using five alkynes, five aryl halides, and a polymer-bound aryl iodide. The alkynes 55 were converted into bis(boryl)alkenes 56 in solution, and the crude intermediates were used in Suzuki reactions with an excess of aryl halide. When all of the bis(boryl)alkene 56 had been consumed, the aryl iodide resin 59 was added to the reaction mixture and the reaction continued on the solid support. Side products such as 58, arising from a double Suzuki reaction, remained in solution and could be washed away. Compounds 60 were cleaved from the polymer using trifluoroacetic acid and products 61 were obtained in > 90% purity. 

The resin-capture approach combines the ease of solution synthesis with the ease of solid-supported isolation and purification (Section 6.3), but the unreacted starting materials and possible side products have to be inert to the capture. 

The resin capture approach, which was recently introduced by Keating et al. [39], uses the solid support to trap the final reaction products of a solution-phase... 

Figure 15 Purification of compounds using the resin capture approach.

The use of supported reagents offers an attractive option for improving the quality of products prepared using solution-phase chemistry. Additionally, liquid-phase synthesis, for example using PEG, provides opportunities to combine some of the benefits of solid-phase approaches with the versatility of solution-phase synthesis. Smart methods such as resin capture for isolating specific compounds from mixtures of products will also help to increase the utility of solution-based approaches. This chapter encompasses developments in each of these areas. 

The same group reported an approach to trisubstituted pyrazolones beginning with a solution-phase acylation of Meldrum s acid 21 and resin-capturing of the intermediates 22 with the add-stable resin 27. The products 23 were a-alky-lated using tetrabutylammonium fluoride (TBAF) and primary alkyl halides under strict exclusion of moisture, as otherwise the yields dropped dramatically. Treatment of the products 24 with phenyUiydrazines produced the corresponding hydrazones 25, which were cleaved from the solid phase by cyclization using 2% TFA in acetonitrile at room temperature to form pyrazolones 26 [15[ (Scheme 7). 

Procter and coworkers" have described a Sm(II)-mediated (106), asymmetric capture and release approach (Scheme 7.22) to y-butyrolactones (107) that involves intermolecular radical additions to a,[3-unsaturated esters (105) attached to resin through an ephedrine chiral linker (108). Resin capture-release is a hybrid technique that combines elements of traditional solid-phase synthesis and the use of supported reagents. Fukuzawa s Sm(II)-mediated, asymmetric method to y-butyrolactones was chosen to demonstrate the feasibility of such a process. y-Butyrolactones (107) were obtained by capture of a reactive intermediate from solution through an asymmetric transformation starting from a,p-unsaturated esters (105) immobilized on an ephedrine chiral resin. Lactone products were obtained in moderate yields with selectivities up to 96% ee. Nevertheless, the ephedrine resin can be efficiently reused for many cycles although in some cases lower yields were obtained on reuse of the chiral resin. 

Chemistry on solid support has gained tremendous importance during the last few years, mainly driven by the needs of the pharmaceutical sciences. Due to the robust and tolerable nature of the available catalysts, metathesis was soon recognized as a useful technique in this context. Three conceptually different, RCM-based strategies are outlined in Fig. 11. In the approach delineated in Fig. 1 la, a polymer-bound diene 353 is subjected to RCM. The desired product 354 is formed with concomitant traceless release from the resin. This strategy is very favorable, since only compounds with the correct functionality will be liberated, while unwanted by-products remain attached to the polymer. However, as the catalyst is captured in this process by the matrix (355), a higher catalyst loading will be required, or ancillary alkenes have to be added to liberate the catalyst. 

In subsequent work, it was shown that a renewable separation-column approach could be used to capture and purify "Tc on a TEVA-Resin column set up between a pair of 2-position valves, as shown in Figure 9.6.83 After loading the sample and washing away interferences, the separation material was released from the column and delivered downstream to a collection vial. Scintillation cocktail was added to the vial off-line and the "Tc was determined radiometrically. In this approach, there is no need to elute the "Tc with strong acid, and a fresh suspension of separation material is delivered to the column body for each sample. 

New applications of this technique, especially as a hybrid approach to perform each combinatorial step in the more convenient medium for its success, should become frequent in the near future. The use of capture resins bearing traceless linkers [153-155] could be particularly interesting, because the library components would then be released in solution without chemical modifications. 

An essential feature of this approach is that well-to-well cross-contamination with reagent solution or resin is avoided by the fact that the plates are tilted, while the direction of centrifugation is horizontal. Consequently, any liquid or resin expelled from the wells is either captured in the inter-well space of the plate or collected on the wall of the centrifugal drum. HPLC/MS analysis of all products prepared on the microtiter plate proved the fact that cross-contamination is not an issue. 

Typically, it is desirable for a polymer to have a certain level of melt strength so that it processes well in these types of fabrication operations. Ideally, one would like to characterize the melt strength of a resin using a test method that best captures the type of deformation experienced by a polymer in a commercial fabrication operation. Owing to the complex flows associated with such operations, the approach that is most commonly used is to characterize the melt strength of a polymer in a uniform flow field and then infer from this information its performance in a real fabrication operation. 

Ideal reactions for solution-phase parallel synthesis are those that are kinetically and thermodynamically favored, are tolerant of diverse functionality, and have a broad range of reactant tolerance. In this approach, capture resins and extraction procedures are often used for preliminary purification. The solution-phase reaction conditions must be validated in terms of scope and optimal reaction conditions over the range of reactants. Two common strategies for solution libraries involve derivatization of preformed functionalized scaffolds and multicomponent condensation reactions, for example, the Ugi reaction, the Passerini reaction, and the formation of hydroxyamininimides from an ester, a hydrazine, and an epoxide. 

Magic bullet resins for Mab-capture have also been developed using small molecular ligands, for example, by Prometic or Xeptagen but so far they are not widely used. Therefore, these approaches are discussed in Section 3.1.2.3 Customized Adsorbents. ... 

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