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Solid-phase organik syntheses - Burdges K.

Burdges K. Solid-phase organik syntheses - John Wiley & Sons, 2000. - 283 p.
ISBN 0-471-22824-9
Download (direct link): phaseorganicsynthesis2000.pdf
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Figure 6.2. Schematic of crown surface.
• It is not necessary to weigh the solid support when setting up reactions because the scale of the reaction is determined by the crown loading.
• Unlike resins, polymer solvation is limited to the graft polymer, so there is little increase in overall crown dimensions.
• The graft polymers are well solvated in a variety of solvents.
• Crowns can be locked into an array format for multiple parallel
handling and ready identification (i.e., the Multipin method, as shown in Figure 6.1). ‘
• Alternatively, individual crowns can be uniquely tagged for multiple parallel handling (TranStem/TranSort method).
• Removal of excess reagents and solvent can be achieved without any risk of blockage; either by rapid filtration through a coarse mesh or simply lifting a “block” of crowns (Figure 6.1) out of a solvent bath, and shaking off excess reagent/solvent.
• No loss of solid support occurs, which could lower compound yield, during washing or transfer steps in a multistep synthesis.
The handling advantages of this type of solid support for carrying out multiple parallel syntheses mean that libraries involving tens to hundreds of compounds are conveniently prepared. The use of tagging techniques expands the potential library size into the thousands (see Section 6.4).
6.1.3. Optimization of Solid-Phase Chemistry
A large proportion of the time spent in library production involves optimizing the chemistry. This optimization process usually entails translating chemistry from the solution phase to the solid phase and achieving satisfactory yield and purity. Another form of optimization may involve the translation of chemistry developed on one solid phase (e.g., TentaGel) to another type of solid phase (e.g., 2% cross-linked polystyrene beads). Either way, the process typically involves investigation of general conditions to see if the chemistry will proceed on the chosen solid phase and then the fine tuning to obtain satisfactory purities and yields. Conditions that may be varied to improve yield include time, temperature, concentration of reagent(s), ratio of reagents, selection of reagents and/or catalysts, choice of solvent and/or co-solvents, and the selection of the graft polymer type. Hundreds of experiments may be required to achieve an optimal set of conditions.
SynPhase crowns may be used to perform large numbers of optimization reactions in parallel. This “library of reaction conditions” may be analyzed by assaying product purities after cleavage from the solid phase using high-throughput techniques such as HPLC and ESMS. Overall, this approach can greatly reduce the time required for this critical step of compound library development.
The reaction screening approach described above is used routinely in our laboratories and has been illustrated using reductive amination of 4-oxoproline on methacrylic acid/dimethyl acrylamide (MD) grafted SynPhase crowns.9 In this example, the concentrations of the amine and sodium cyanoborohy-dride as well as the solvent and the pH of the reaction solution were varied. Product analysis revealed that high amine concentration and moderately low reductant concentration were beneficial to the reaction and that methanol gave slightly improved results over ethanol. More importantly, it was observed that pH had a major influence on the reaction, with pH 5-6 giving superior results to pH 7 for primary amines. When the optimization studies were expanded to include anilines, high amine concentration was again found to be beneficial, as was very low reductant concentration, although pH 7 was preferable to pH 5-6 (Scheme 1).
Consideration of reaction mechanisms helps reduce the number of reaction variables, but trial and error still plays a large part in optimization processes. Large numbers of reactions therefore are required to fully optimize chemistries. In our experience, one variable for which the optimal
Scheme 1.
condition is not readily predictable is solvent. The solvent in a solid-phase reaction has many roles to play, not only as a solvating agent for the reactants, intermediates, and transition states, but also to solvate the polymer well, and must aid in the transport of the solution-phase reactants into the polymer network. We have frequently found that the optimal solvent for a solid-phase reaction is not the same as that routinely used for the same solution-phase reaction. For example, whereas tetrahydrofuran would be used for a solution-phase Mitsunobu ether formation or a Suzuki aryl alkylation, we have found dimethylacetamide to be beneficial for ether formation10 and ethoxy ethanol to be the solvent of choice for the Suzuki reaction."
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